Tissue mimicking materials for the detection of prostate cancer using shear wave elastography: A validation study

PubMed Central

Cao, Rui; Huang, Zhihong; Varghese, Tomy; Nabi, Ghulam

2013-01-01

Purpose: Quantification of stiffness changes may provide important diagnostic information and aid in the early detection of cancers. Shear wave elastography is an imaging technique that assesses tissue stiffness using acoustic radiation force as an alternate to manual palpation reported previously with quasistatic elastography. In this study, the elastic properties of tissue mimicking materials, including agar, polyacrylamide (PAA), and silicone, are evaluated with an objective to determine material characteristics which resemble normal and cancerous prostate tissue. Methods: Acoustic properties and stiffness of tissue mimicking phantoms were measured using compressional mechanical testing and shear wave elastography using supersonic shear imaging. The latter is based on the principles of shear waves generated using acoustic radiation force. The evaluation included tissue mimicking materials (TMMs) within the prostate at different positions and sizes that could mimic cancerous and normal prostate tissue. Patient data on normal and prostate cancer tissues quantified using biopsy histopathology were used to validate the findings. Pathologist reports on histopathology were blinded to mechanical testing and elastographic findings. Results: Young's modulus values of 86.2 ± 4.5 and 271.5 ± 25.7 kPa were obtained for PAA mixed with 2% Al2O3 particles and silicone, respectively. Young's modulus of TMMs from mechanical compression testing showed a clear trend of increasing stiffness with an increasing percentage of agar. The silicone material had higher stiffness values when compared with PAA with Al2O3. The mean Young's modulus value in cancerous tissue was 90.5 ± 4.5 kPa as compared to 93.8 ± 4.4 and 86.2 ± 4.5 kPa obtained with PAA with 2% Al2O3 phantom at a depth of 52.4 and 36.6 mm, respectively. Conclusions: PAA mixed with Al2O3 provides the most suitable tissue mimicking material for prostate cancer tumor material, while agar could form the surrounding background to simulate normal prostate tissue. PMID:23387774

FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer

PubMed Central

Andren, Ove; Ohlson, Anna‐Lena; Carlsson, Jessica; Andersson, Swen‐Olof; Giunchi, Francesca; Rider, Jennifer R.; Fiorentino, Michelangelo

2017-01-01

Background The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. Methods Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. Results In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT‐stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart. Conclusions Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti‐tumor immune response may be initiated even before the primary tumor is established. PMID:29105795

Prostate Cancer Detection Using Near Infrared Spectral Polarization Imaging

DTIC Science & Technology

2005-07-01

position. This indicates the polarization preservation nature of Cybesin. Time Resolved Fluorescence Intensity of Cybesin 60000 Perpendicular 3000 0...absorption than that of normal tissue at water absorption peaks indicating cancer tissue has less water content than that of normal tissue; (5) preliminary...rectum-and-membrane tissues.’ This indicates that our proposed approach of imaging a prostate gland through rectum using spectral polarization imaging

Investigation of c-KIT and Ki67 expression in normal, preneoplastic and neoplastic canine prostate.

PubMed

Fonseca-Alves, Carlos Eduardo; Kobayashi, Priscilla Emiko; Palmieri, Chiara; Laufer-Amorim, Renée

2017-12-06

c-KIT expression has been related to bone metastasis in human prostate cancer, but whether c-KIT expression can be similarly classified in canine prostatic tissue is unknown. This study assessed c-KIT and Ki67 expression in canine prostate cancer (PC). c-KIT gene and protein expression and Ki67 expression were evaluated in forty-four canine prostatic tissues by immunohistochemistry, RT-qPCR and western blot. Additionally, we have investigated c-KIT protein expression by immunoblotting in two primary canine prostate cancer cell lines. Eleven normal prostates, 12 proliferative inflammatory atrophy (PIA) prostates, 18 PC, 3 metastatic lesions and two prostate cancer cell cultures (PC1 and PC2) were analysed. The prostatic tissue exhibited varying degrees of membranous, cytoplasmic or membranous/cytoplasmic c-KIT staining. Four normal prostates, 4 PIA and 5 prostatic carcinomas showed positive c-KIT expression. No c-KIT immunoexpression was observed in metastases. Canine prostate cancer and PIA samples contained a higher number of Ki67-positive cells compared to normal samples. The median relative quantification (RQ) for c-KIT expression in normal, PIA and prostate cancer and metastatic samples were 0.6 (0.1-2.5), 0.7 (0.09-2.1), 0.7 (0.09-5.1) and 0.1 (0.07-0.6), respectively. A positive correlation between the number of Ki67-positive cells and c-KIT transcript levels was observed in prostate cancer samples. In the cell line, PC1 was negative for c-KIT protein expression, while PC2 was weakly positive. The present study identified a strong correlation between c-KIT expression and proliferative index, suggesting that c-KIT may influence cell proliferation. Therefore, c-KIT heterogeneous protein expression among the samples (five positive and thirteen negative prostate cancer samples) indicates a personalized approach for canine prostate cancer.

Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men.

PubMed

Koochekpour, Shahriar; Marlowe, Timothy; Singh, Keshav K; Attwood, Kristopher; Chandra, Dhyan

2013-01-01

Reduction or depletion of mitochondrial DNA (mtDNA) has been associated with cancer progression. Although imbalanced mtDNA content is known to occur in prostate cancer, differences in mtDNA content between African American (AA) and Caucasian American (CA) men are not defined. We provide the first evidence that tumors in AA men possess reduced level of mtDNA compared to CA men. The median tumor mtDNA content was reduced in AA men. mtDNA content was also reduced in normal prostate tissues of AA men compared to CA men, suggesting a possible predisposition to cancer in AA men. mtDNA content was also reduced in benign prostatic hyperplasia (BPH) tissue from AA men. Tumor and BPH tissues from patients ≥ 60 years of age possess reduced mtDNA content compared to patients <60 years of age. In addition, mtDNA content was higher in normal tissues from patients with malignant T3 stage disease compared to patients with T2 stage disease. mtDNA levels in matched normal prostate tissues were nearly doubled in Gleason grade of >7 compared to ≤ 7, whereas reduced mtDNA content was observed in tumors of Gleason grade >7 compared to ≤ 7. Together, our data suggest that AA men possess lower mtDNA levels in normal and tumor tissues compared to CA men, which could contribute to higher risk and more aggressive prostate cancer in AA men.

A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

PubMed

Sharpe, Benjamin; Alghezi, Dhafer A; Cattermole, Claire; Beresford, Mark; Bowen, Rebecca; Mitchard, John; Chalmers, Andrew D

2017-05-01

There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness. © 2017 Wiley Periodicals, Inc.

Differential expression of androgen, estrogen, and progesterone receptors in benign prostatic hyperplasia

PubMed Central

Song, Lingmin; Shen, Wenhao; Zhang, Heng; Wang, Qiwu; Wang, Yongquan; Zhou, Zhansong

2016-01-01

This study aimed to identify the differential expression levels of androgen receptor (AR), estrogen receptors (ERα, ERβ), and progesterone receptor (PGR) between normal prostate and benign prostatic hyperplasia (BPH). The combination of immunohistochemistry, quantitative real-time reverse transcription polymerase chain reaction, and Western blotting assay was used to identify the distribution and differential expression of these receptors at the immunoactive biomarker, transcriptional, and protein levels between 5 normal human prostate tissues and 40 BPH tissues. The results were then validated in a rat model of BPH induced by testosterone propionate and estradiol benzoate. In both human and rat prostate tissues, AR was localized mainly to epithelial and stromal cell nuclei; ERα was distributed mainly to stromal cells, but not exclusively; ERβ was interspersed in the basal layer of epithelium, but sporadically in epithelial and stromal cells; PGR was expressed abundantly in cytoplasm of epithelial and stromal cells. There were decreased expression of ERα and increased expression of PGR, but no difference in the expression of ERβ in the BPH compared to the normal prostate of both human and rat. Increased expression of AR in the BPH compared to the normal prostate of human was observed, however, the expression of AR in the rat prostate tissue was decreased. This study identified the activation of AR and PGR and repression of ERα in BPH, which indicate a promoting role of AR and PGR and an inhibitory role of ERα in the pathogenesis of BPH. PMID:27294569

Elastic light single-scattering spectroscopy for detection of dysplastic tissues

NASA Astrophysics Data System (ADS)

Canpolat, Murat; Denkçeken, Tuba; Akman, Ayşe.; Alpsoy, Erkan; Tuncer, Recai; Akyüz, Mahmut; Baykara, Mehmet; Yücel, Selçuk; Başsorgun, Ibrahim; ćiftçioǧlu, M. Akif; Gökhan, Güzide Ayşe.; Gürer, ElifInanç; Peştereli, Elif; Karaveli, Šeyda

2013-11-01

Elastic light single-scattering spectroscopy (ELSSS) system has been developed and tested in diagnosis of cancerous tissues of different organs. ELSSS system consists of a miniature visible light spectrometer, a single fiber optical probe, a halogen tungsten light source and a laptop. Measurements were performed on excised brain, skin, cervix and prostate tumor specimens and surrounding normal tissues. Single fiber optical probe with a core diameter of 100 μm was used to deliver white light to and from tissue. Single optical fiber probe mostly detects singly scattered light from tissue rather than diffused light. Therefore, measured spectra are sensitive to size of scatters in tissue such as cells, nuclei, mitochondria and other organelles of cells. Usually, nuclei of tumor cells are larger than nuclei of normal cells. Therefore, spectrum of singly scattered light of tumor tissue is different than normal tissue. The spectral slopes were shown to be positive for normal brain, skin and prostate and cervix tissues and negative for the tumors of the same tissues. Signs of the spectral slopes were used as a discrimination parameter to differentiate tumor from normal tissues for the three organ tissues. Sensitivity and specificity of the system in differentiation between tumors from normal tissues were 93% and %100 for brain, 87% and 85% for skin, 93.7% and 46.1% for cervix and 98% and 100% for prostate.

Sexual steroids in serum and prostatic tissue of human non-cancerous prostate (STERPROSER trial).

PubMed

Neuzillet, Yann; Raynaud, Jean-Pierre; Radulescu, Camélia; Fiet, Jean; Giton, Franck; Dreyfus, Jean-François; Ghoneim, Tarek P; Lebret, Thierry; Botto, Henry

2017-11-01

The specific involvement of the sex steroids in the growth of the prostatic tissue remains unclear. Sex steroid concentrations in plasma and in fresh surgical samples of benign central prostate were correlated to prostate volume. Monocentric prospective study performed between September 2014 and January 2017. Age, obesity parameters, and both serum and intraprostatic concentrations of sex steroids were collected complying with the latest Endocrine Society guidelines and the steroids assessed by GC/MS. Statistical calculations were adjusted for age and body mass index (BMI). Thirty-two patients, equally divided between normal- and high-volume prostate groups, were included in the analysis. High-volume prostate patients were older, heavier and had higher BMI. Comparison adjusted for age and BMI showed higher DHT concentrations in high-volume prostate. Both normal- and high-volume prostate tissues concentrate sex steroids in a similar way. Comparison of enzymatic activity surrogate marker ratios within tissue highlighted similar TT/E1 and TT/E2 ratios, and higher DHT/E1 ratio and lower DHT/PSA ratio in the high-volume prostates. STERPROSER trial provides evidence for higher DHT concentration in highvolume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase. © 2017 Wiley Periodicals, Inc.

Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer.

PubMed

Kalsbeek, Anton M F; Chan, Eva K F; Grogan, Judith; Petersen, Desiree C; Jaratlerdsiri, Weerachai; Gupta, Ruta; Lyons, Ruth J; Haynes, Anne-Maree; Horvath, Lisa G; Kench, James G; Stricker, Phillip D; Hayes, Vanessa M

2018-01-01

Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Fresh prostate cancer biopsies from 115 patients were obtained at time of surgery. All cores underwent pathological review, followed by isolation of cancer and normal tissue. DNA was extracted and qPCR performed to quantify the total amount of mtDNA as a ratio to genomic DNA. Differences in mtDNA content were compared for prostate cancer pathology features and disease outcomes. We showed a significantly reduced mtDNA content in prostate cancer compared with normal adjacent prostate tissue (mean difference 1.73-fold, P-value <0.001). Prostate cancer with increased mtDNA content showed unfavorable pathologic characteristics including, higher disease stage (PT2 vs PT3 P-value = 0.018), extracapsular extension (P-value = 0.02) and a trend toward an increased Gleason score (P-value = 0.064). No significant association was observed between changes in mtDNA content and biochemical recurrence (median follow up of 107 months). Contrary to other cancer types, prostate cancer tissue shows no universally depleted mtDNA content. Rather, the change in mtDNA content is highly variable, mirroring known prostate cancer genome heterogeneity. Patients with high mtDNA content have an unfavorable pathology, while a high mtDNA content in normal adjacent prostate tissue is associated with worse prognosis. © 2017 Wiley Periodicals, Inc.

FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer.

PubMed

Davidsson, Sabina; Andren, Ove; Ohlson, Anna-Lena; Carlsson, Jessica; Andersson, Swen-Olof; Giunchi, Francesca; Rider, Jennifer R; Fiorentino, Michelangelo

2018-01-01

The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (T regs ). In the present study we evaluated the prevalence of T reg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4 + T regs and CD8 + T regs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of T regs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. In men with prostate cancer, similarly high numbers of stromal CD4 + T regs were identified in PAH and tumor, but CD4 + T regs were less common in PIN. Greater numbers of epithelial CD4+ T regs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4 + T regs in the normal prostatic tissue counterpart. Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4 + T regs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established. © 2017 The Authors. The Prostate Published by Wiley Periodicals Inc.

Photodynamic therapy in prostate cancer: optical dosimetry and response of normal tissue

NASA Astrophysics Data System (ADS)

Chen, Qun; Shetty, Sugandh D.; Heads, Larry; Bolin, Frank; Wilson, Brian C.; Patterson, Michael S.; Sirls, Larry T., II; Schultz, Daniel; Cerny, Joseph C.; Hetzel, Fred W.

1993-06-01

The present study explores the possibility of utilizing photodynamic therapy (PDT) in treating localized prostate carcinoma. Optical properties of ex vivo human prostatectomy specimens, and in vivo and ex vivo dog prostate glands were studied. The size of the PDT induced lesion in dog prostate was pathologically evaluated as a biological endpoint. The data indicate that the human normal and carcinoma prostate tissues have similar optical properties. The average effective attenuation depth is less in vivo than that of ex vivo. The PDT treatment generated a lesion size of up to 16 mm in diameter. The data suggest that PDT is a promising modality in prostate cancer treatment. Multiple fiber system may be required for clinical treatment.

Immunohistochemical expression of interleukin-2 receptor and interleukin-6 in patients with prostate cancer and benign prostatic hyperplasia: association with asymptomatic inflammatory prostatitis NIH category IV.

PubMed

Engelhardt, Paul Friedrich; Seklehner, Stephan; Brustmann, Hermann; Lusuardi, Lukas; Riedl, Claus R

2015-04-01

This study prospectively investigated the immunohistochemical expression of interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6) in patients with prostate cancer and benign prostatic hyperplasia (BPH), and a possible association of these conditions with asymptomatic inflammatory prostatitis National Institutes of Health (NIH) category IV. The study included 139 consecutive patients who underwent transurethral resection of the prostate and transvesical enucleation of the prostate (n = 82) or radical prostatectomy (n = 57). To characterize inflammatory changes the criteria proposed by Irani et al. [J Urol 1997;157:1301-3] were used. IL-2R and IL-6 expression was studied by a standard immunohistochemical method. Results were correlated with tumour, node, metastasis stage, Gleason scores, total prostate-specific antigen, International Prostate Symptom Score and body mass index. IL-2R and IL-6 expression was significantly higher in neoplastic prostate cancer tissue than in normal tissue of prostate cancer patients (p < 0.001 and p < 0.04, respectively). Prostate cancer patients with prostatitis showed significantly higher IL-2R expression than those without inflammation (p < 0.03). In patients with BPH, expression of IL-2R as well as IL-6 was higher in patients with prostatitis than in those without (p < 0.01 and p < 0.02, respectively). IL-2R and IL-6 expression was significantly higher in prostate cancer tissue than in normal tissue. Patients with asymptomatic inflammatory prostatitis NIH category IV showed significantly greater activity.

Gene expression signature of benign prostatic hyperplasia revealed by cDNA microarray analysis.

PubMed

Luo, Jun; Dunn, Thomas; Ewing, Charles; Sauvageot, Jurga; Chen, Yidong; Trent, Jeffrey; Isaacs, William

2002-05-15

Despite the high prevalence of benign prostatic hyperplasia (BPH) in the aging male, little is known regarding the etiology of this disease. A better understanding of the molecular etiology of BPH would be facilitated by a comprehensive analysis of gene expression patterns that are characteristic of benign growth in the prostate gland. Since genes differentially expressed between BPH and normal prostate tissues are likely to reflect underlying pathogenic mechanisms involved in the development of BPH, we performed comparative gene expression analysis using cDNA microarray technology to identify candidate genes associated with BPH. Total RNA was extracted from a set of 9 BPH specimens from men with extensive hyperplasia and a set of 12 histologically normal prostate tissues excised from radical prostatectomy specimens. Each of these 21 RNA samples was labeled with Cy3 in a reverse transcription reaction and cohybridized with a Cy5 labeled common reference sample to a cDNA microarray containing 6,500 human genes. Normalized fluorescent intensity ratios from each hybridization experiment were extracted to represent the relative mRNA abundance for each gene in each sample. Weighted gene and random permutation analyses were performed to generate a subset of genes with statistically significant differences in expression between BPH and normal prostate tissues. Semi-quantitative PCR analysis was performed to validate differential expression. A subset of 76 genes involved in a wide range of cellular functions was identified to be differentially expressed between BPH and normal prostate tissues. Semi-quantitative PCR was performed on 10 genes and 8 were validated. Genes consistently upregulated in BPH when compared to normal prostate tissues included: a restricted set of growth factors and their binding proteins (e.g. IGF-1 and -2, TGF-beta3, BMP5, latent TGF-beta binding protein 1 and -2); hydrolases, proteases, and protease inhibitors (e.g. neuropathy target esterase, MMP2, alpha-2-macroglobulin); stress response enzymes (e.g. COX2, GSTM5); and extracellular matrix molecules (e.g. laminin alpha 4 and beta 1, chondroitin sulfate proteoglycan 2, lumican). Genes consistently expressing less mRNA in BPH than in normal prostate tissues were less commonly observed and included the transcription factor KLF4, thrombospondin 4, nitric oxide synthase 2A, transglutaminase 3, and gastrin releasing peptide. We identified a diverse set of genes that are potentially related to benign prostatic hyperplasia, including genes both previously implicated in BPH pathogenesis as well as others not previously linked to this disease. Further targeted validation and investigations of these genes at the DNA, mRNA, and protein levels are warranted to determine the clinical relevance and possible therapeutic utility of these genes. Copyright 2002 Wiley-Liss, Inc.

Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer.

PubMed

Wen, Simeng; Chang, Hong-Chiang; Tian, Jing; Shang, Zhiqun; Niu, Yuanjie; Chang, Chawnshang

2015-02-01

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Influence of zinc deficiency on AKT-MDM2-P53 signaling axes in normal and malignant human prostate cells

USDA-ARS?s Scientific Manuscript database

With prostate being the highest zinc-accumulating tissue before the onset of cancer, the effects of physiologic levels of zinc on Akt-Mdm2-p53 and Akt-p21 signaling axes in human normal prostate epithelial cells (PrEC) and malignant prostate LNCaP cells were examined. Cells were cultured for 6 d in...

Novel In Vivo Model for Combinatorial Fluorescence Labeling in Mouse Prostate

PubMed Central

Fang, Xiaolan; Gyabaah, Kenneth; Nickkholgh, Bita; Cline, J. Mark; Balaji, K.C.

2015-01-01

BACKGROUND The epithelial layer of prostate glands contains several types of cells, including luminal and basal cells. Yet there is paucity of animal models to study the cellular origin of normal or neoplastic development in the prostate to facilitate the treatment of heterogenous prostate diseases by targeting individual cell lineages. METHODS We developed a mouse model that expresses different types of fluorescent proteins (XFPs) specifically in prostatic cells. Using an in vivo stochastic fluorescent protein combinatorial strategy, XFP signals were expressed specifically in prostate of Protein Kinase D1 (PKD1) knock-out, K-RasG12D knock-in, and Phosphatase and tensin homolog (PTEN) and PKD1 double knock-out mice under the control of PB-Cre promoter. RESULTS In vivo XFP signals were observed in prostate of PKD1 knock-out, K-RasG12D knock-in, and PTEN PKD1 double knock-out mice, which developed normal, hyperplastic, and neoplastic prostate, respectively. The patchy expression pattern of XFPs in neoplasia tissue indicated the clonal origin of cancer cells in the prostate. CONCLUSIONS The transgenic mouse models demonstrate combinatorial fluorescent protein expression in normal and cancerous prostatic tissues. This novel prostate-specific fluorescent labeled mouse model, which we named Prorainbow, could be useful in studying benign and malignant pathology of prostate. PMID:25753731

Novel In Vivo model for combinatorial fluorescence labeling in mouse prostate.

PubMed

Fang, Xiaolan; Gyabaah, Kenneth; Nickkholgh, Bita; Cline, J Mark; Balaji, K C

2015-06-15

The epithelial layer of prostate glands contains several types of cells, including luminal and basal cells. Yet there is paucity of animal models to study the cellular origin of normal or neoplastic development in the prostate to facilitate the treatment of heterogenous prostate diseases by targeting individual cell lineages. We developed a mouse model that expresses different types of fluorescent proteins (XFPs) specifically in prostatic cells. Using an in vivo stochastic fluorescent protein combinatorial strategy, XFP signals were expressed specifically in prostate of Protein Kinase D1 (PKD1) knock-out, K-Ras(G) (12) (D) knock-in, and Phosphatase and tensin homolog (PTEN) and PKD1 double knock-out mice under the control of PB-Cre promoter. In vivo XFP signals were observed in prostate of PKD1 knock-out, K-Ras(G) (12) (D) knock-in, and PTEN PKD1 double knock-out mice, which developed normal, hyperplastic, and neoplastic prostate, respectively. The patchy expression pattern of XFPs in neoplasia tissue indicated the clonal origin of cancer cells in the prostate. The transgenic mouse models demonstrate combinatorial fluorescent protein expression in normal and cancerous prostatic tissues. This novel prostate-specific fluorescent labeled mouse model, which we named Prorainbow, could be useful in studying benign and malignant pathology of prostate. © 2015 Wiley Periodicals, Inc.

Variation of M3 muscarinic receptor expression in different prostate tissues and its significance.

PubMed

Song, Wei; Yuan, Mingzhen; Zhao, Shengtian

2009-08-01

To detect the expression of the muscarinic receptor (M receptor) in different prostate tissues and analyze the role of its subtype in prostatic oncogenesis. Thirty-six cases of normal prostate and benign prostatic hyperplasia, and 8 cases of prostatic tumor, were used in this study from the Shandong University, Shandong, China, between 2003-2006. The protein expressions of M1, M2, and M3 receptors in each group were determined by Western-blotting. The gene expressions of the M3 receptor and vascular endothelial growth factors (VEGF) in each group were determined by reverse transcriptase-polymerase chain reaction. The protein and gene expressions of the M3 receptor in the prostatic carcinoma group were higher than that of benign prostatic hyperplasia group (p=0.0001) and normal prostate group (p=0.0001). The M3 receptor and VEGF showed positive straight-line correlations of gene expressions with the 3 groups (r=0.4999, p=0.0001). The M3 receptor may have a close relationship with prostatic oncogenesis.

Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate

USDA-ARS?s Scientific Manuscript database

Introduction: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (1). The present study evaluates serum and prostate tissue folate levels in men with prostate cancer, compared to histologically normal prostate glands from can...

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

PubMed

Ebot, Ericka M; Gerke, Travis; Labbé, David P; Sinnott, Jennifer A; Zadra, Giorgia; Rider, Jennifer R; Tyekucheva, Svitlana; Wilson, Kathryn M; Kelly, Rachel S; Shui, Irene M; Loda, Massimo; Kantoff, Philip W; Finn, Stephen; Vander Heiden, Matthew G; Brown, Myles; Giovannucci, Edward L; Mucci, Lorelei A

2017-11-01

Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10 -4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. © 2017 American Cancer Society.

Photoacoustic physio-chemical analysis for prostate cancer diagnosis (Conference Presentation)

NASA Astrophysics Data System (ADS)

Xu, Guan; Cheng, Qian; Huang, Shengsong; Qin, Ming; Hopkins, Thomas; Lee, Chang H.; Kopelman, Raoul; Chao, Wan-yu; Keller, Evan T.; Wu, Denglong; Wang, Xueding

2017-03-01

Photoacoustic physio-chemical analysis (PAPCA) is a recently developed technology capable of simultaneously quantifying the content of molecular components and the corresponding microarchitectures in biological tissue. We have successfully quantified the diagnostic information in livers with PAPCA. In this study, we implemented PAPCA to the diagnosis of prostate cancers. 4 human prostates were scanned ex vivo. The PA signals from normal and cancerous regions in the prostates were acquired by an interstitial needle PA probe. A total of 14 interstitial measurements, including 6 within the normal regions and 8 in the cancerous regions, were acquired. The observed changes in molecular components, including lipid, collagen and hemoglobin were consistent with the findings by other research groups. The changes were quantified by PA spectral analysis (PASA) at wavelengths where strong optical absorption of the relevant molecular components was found. Statistically significant differences among the PASA parameters were observed (p=0.025 at significance of 0.05). A support vector machine model for differentiating the normal and cancerous tissue was established. With the limited number of samples, an 85% diagnostic accuracy was found. The diagnostic information in the PCPCA can be further enriched by targeted optical contrast agents visualizing the microarchitecture in PCa tissues. F3 PAA-PEG nanoparticles was employed to stain the PCa cells in a transgenic mouse model, in which the microarchitectures of normal and cancerous prostate tissues are comparable to that in human. Statistically significant differences were observed between the contrast-enhanced normal and cancerous regions (p=0.038 at a significance of 0.05).

PAGE-1, an X chromosome-linked GAGE-like gene that is expressed in normal and neoplastic prostate, testis, and uterus

PubMed Central

Brinkmann, Ulrich; Vasmatzis, George; Lee, Byungkook; Yerushalmi, Noga; Essand, Magnus; Pastan, Ira

1998-01-01

We have used a combination of computerized database mining and experimental expression analyses to identify a gene that is preferentially expressed in normal male and female reproductive tissues, prostate, testis, fallopian tube, uterus, and placenta, as well as in prostate cancer, testicular cancer, and uterine cancer. This gene is located on the human X chromosome, and it is homologous to a family of genes encoding GAGE-like proteins. GAGE proteins are expressed in a variety of tumors and in testis. We designate the novel gene PAGE-1 because the expression pattern in the Cancer Genome Anatomy Project libraries indicates that it is predominantly expressed in normal and neoplastic prostate. Further database analysis indicates the presence of other genes with high homology to PAGE-1, which were found in cDNA libraries derived from testis, pooled libraries (with testis), and in a germ cell tumor library. The expression of PAGE-1 in normal and malignant prostate, testicular, and uterine tissues makes it a possible target for the diagnosis and possibly for the vaccine-based therapy of neoplasms of prostate, testis, and uterus. PMID:9724777

PAGE-1, an X chromosome-linked GAGE-like gene that is expressed in normal and neoplastic prostate, testis, and uterus.

PubMed

Brinkmann, U; Vasmatzis, G; Lee, B; Yerushalmi, N; Essand, M; Pastan, I

1998-09-01

We have used a combination of computerized database mining and experimental expression analyses to identify a gene that is preferentially expressed in normal male and female reproductive tissues, prostate, testis, fallopian tube, uterus, and placenta, as well as in prostate cancer, testicular cancer, and uterine cancer. This gene is located on the human X chromosome, and it is homologous to a family of genes encoding GAGE-like proteins. GAGE proteins are expressed in a variety of tumors and in testis. We designate the novel gene PAGE-1 because the expression pattern in the Cancer Genome Anatomy Project libraries indicates that it is predominantly expressed in normal and neoplastic prostate. Further database analysis indicates the presence of other genes with high homology to PAGE-1, which were found in cDNA libraries derived from testis, pooled libraries (with testis), and in a germ cell tumor library. The expression of PAGE-1 in normal and malignant prostate, testicular, and uterine tissues makes it a possible target for the diagnosis and possibly for the vaccine-based therapy of neoplasms of prostate, testis, and uterus.

Isolation and genome-wide expression and methylation characterization of CD31+ cells from normal and malignant human prostate tissue

PubMed Central

Luo, Wei; Hu, Qiang; Wang, Dan; Deeb, Kristin K.; Ma, Yingyu; Morrison, Carl D.; Liu, Song; Johnson, Candace S.; Trump, Donald L.

2013-01-01

Endothelial cells (ECs) are an important component involved in the angiogenesis. Little is known about the global gene expression and epigenetic regulation in tumor endothelial cells. The identification of gene expression and epigenetic difference between human prostate tumor-derived endothelial cells (TdECs) and those in normal tissues may uncover unique biological features of TdEC and facilitate the discovery of new anti-angiogenic targets. We established a method for isolation of CD31+ endothelial cells from malignant and normal prostate tissues obtained at prostatectomy. TdECs and normal-derived ECs (NdECs) showed >90% enrichment in primary culture and demonstrated microvascular endothelial cell characteristics such as cobblestone morphology in monolayer culture, diI-acetyl-LDL uptake and capillary-tube like formation in Matrigel®. In vitro primary cultures of ECs maintained expression of endothelial markers such as CD31, von Willebrand factor, intercellular adhesion molecule, vascular endothelial growth factor receptor 1, and vascular endothelial growth factor receptor 2. We then conducted a pilot study of transcriptome and methylome analysis of TdECs and matched NdECs from patients with prostate cancer. We observed a wide spectrum of differences in gene expression and methylation patterns in endothelial cells, between malignant and normal prostate tissues. Array-based expression and methylation data were validated by qRT-PCR and bisulfite DNA pyrosequencing. Further analysis of transcriptome and methylome data revealed a number of differentially expressed genes with loci whose methylation change is accompanied by an inverse change in gene expression. Our study demonstrates the feasibility of isolation of ECs from histologically normal prostate and prostate cancer via CD31+ selection. The data, although preliminary, indicates that there exist widespread differences in methylation and transcription between TdECs and NdECs. Interestingly, only a small proportion of perturbed genes were overlapped between American (AA) and Caucasian American (CA) patients with prostate cancer. Our study indicates that identifying gene expression and/or epigenetic differences between TdECs and NdECs may provide us with new anti-angiogenic targets. Future studies will be required to further characterize the isolated ECs and determine the biological features that can be exploited in the prognosis and therapy of prostate cancer. PMID:23978847

Decreased expression of Toll-like receptor 4 and 5 during progression of prostate transformation in transgenic adenocarcinoma of mouse prostate mice.

PubMed

Han, Ju-Hee; Park, Jong-Hwan; Kim, Bo-Yeon; Chang, Seo-Na; Kim, Tae-Hyoun; Park, Jae-Hak; Kim, Dong-Jae

2015-01-01

Chronic inflammation has been considered an important risk factor for development of prostate cancer. Toll-like receptors (TLRs) recognize microbial moieties or endogenous molecules and play an important role in the triggering and promotion of inflammation. In this study, we examined whether expression of TLR4 and TLR5 was associated with progression of prostate transformation in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The expression of TLR4 and TLR5 was evaluated by immunohistochemisty in formalin-fixed paraffin-embedded prostate tissue from wild-type (WT) and TRAMP mice. Normal prostate tissue from WT mice showed strong expression of TLR4 and TLR5. However, TLR4 expression in the prostate tissue from TRAMP mice gradually decreased as pathologic grade became more aggressive. TLR5 expression in the prostate tissue from TRAMP mice also decreased in low-grade prostate intraepithelial neoplasia (PIN), high-grade PIN and poorly differentiated adenocarcinoma. Overall, our results suggest that decreased expression of TLR4 and TLR5 may contribute to prostate tumorigenesis.

Gallium-68 DOTATOC PET/CT In Vivo Characterization of Somatostatin Receptor Expression in the Prostate

PubMed Central

Gajić, Milan M.; Obradović, Vladimir B.; Baum, Richard P.

2014-01-01

Abstract Aim: The aim was to investigate somatostatin receptor (sstr) expression in normal prostate by determining the maximum standardized uptake value (SUVmax) of 68Ga-DOTATOC PET/CT in neuroendocrine tumor (NET) patients, without NET involvement of the prostate gland, for establishing the reference standard. Methods: Sixty-four NET patients underwent 68Ga-DOTATOC PET/CT. SUVmax of the prostate gland, normal liver, testes, and gluteus muscles were evaluated. The prostate gland size was measured. Statistical analysis was performed using dedicated software (SPSS13). Results: Mean/median 68Ga-DOTATOC SUVmax values were as follows: normal prostate 2.6±0.0, slightly enlarged prostate 4.2±1.6, prostatic hypertrophy 4.9±1.6, prostatic hyperplasia 5.0±1.5, prostate cancer 9.5±2.1, normal liver 7.3±1.8, testes 1.8±0.5, and gluteus 1.0±0.2. The normal prostate gland had three times less sstr expression than normal liver tissue. Strong correlation was found between patient age and sstr expression in prostate/prostate size. No significant difference existed in sstr expression between prostatic hypertrophy and hyperplasia. Much higher sstr expression was found in prostatic cancer compared with normal prostate. Conclusion: 68Ga-DOTATOC PET/CT defines the baseline sstr uptake in prostate not affected by NET (significantly lower than in the liver). Higher values were established in prostatic hyperplasia and hypertrophy. Only concomitant prostate cancer was associated with higher SUVmax in comparison with non-neoplastic liver. PMID:24450327

Androgen dynamics in vitro in the human prostate gland. Effect of oestradiol-17β

PubMed Central

Giorgi, Eleonora P.; Stewart, Joan C.; Grant, J. K.; Shirley, I. M.

1972-01-01

Normal, hyperplastic and adenocarcinomatous human prostatic tissue was perfused in vitro with radioactively labelled androstenedione, testosterone and 5α-dihydrotestosterone with and without added oestradiol-17β. Various parameters of tissue–steroid relationship were measured at the steady state. When oestradiol (0.11 or 0.22μmol/l) was added to the perfusing medium, the entry of the steroids into the tissue and their metabolism was increased in the majority of the glands studied. The `uptake' of all the steroids varied, in response to the addition of oestradiol, in both normal and adenocarcinomatous glands in a way differing from the response of hyperplastic glands. As a consequence, the tissue clearance of the steroids, particularly of androstenedione and testosterone, increased in normal and adenocarcinomatous glands in the presence of oestradiol, and decreased in the hyperplastic tissues. At a concentration 0.33μmol/l, oestradiol decreased the entry of the steroids in all the tissues studied, while the clearance of steroids tended to decrease. The significance of these findings in terms of the regulation of androgen dynamics in vivo in the normal and diseased human prostate, with particular regard to the response to oestrogen treatment, is discussed. PMID:5075225

STEAP: A prostate-specific cell-surface antigen highly expressed in human prostate tumors

PubMed Central

Hubert, Rene S.; Vivanco, Igor; Chen, Emily; Rastegar, Shiva; Leong, Kahan; Mitchell, Steve C.; Madraswala, Rashida; Zhou, Yanhong; Kuo, James; Raitano, Arthur B.; Jakobovits, Aya; Saffran, Douglas C.; Afar, Daniel E. H.

1999-01-01

In search of novel genes expressed in metastatic prostate cancer, we subtracted cDNA isolated from benign prostatic hypertrophic tissue from cDNA isolated from a prostate cancer xenograft model that mimics advanced disease. One novel gene that is highly expressed in advanced prostate cancer encodes a 339-amino acid protein with six potential membrane-spanning regions flanked by hydrophilic amino- and carboxyl-terminal domains. This structure suggests a potential function as a channel or transporter protein. This gene, named STEAP for six-transmembrane epithelial antigen of the prostate, is expressed predominantly in human prostate tissue and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. Immunohistochemical analysis of clinical specimens demonstrates significant STEAP expression at the cell–cell junctions of the secretory epithelium of prostate and prostate cancer cells. Little to no staining was detected at the plasma membranes of normal, nonprostate human tissues, except for bladder tissue, which expressed low levels of STEAP at the cell membrane. Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. Our results support STEAP as a cell-surface tumor-antigen target for prostate cancer therapy and diagnostic imaging. PMID:10588738

Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers.

PubMed

Zhang, S; Zhang, H S; Reuter, V E; Slovin, S F; Scher, H I; Livingston, P O

1998-02-01

Defining the expression of tumor-associated antigens on primary and metastatic prostate cancer is the crucial first step in selecting appropriate targets for immune attack. In this study, the distribution of the tumor-associated antigens GM2, Tn, sTn, Thompson-Friedenreich antigen (TF), Globo H, Le(y), MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, carcinoembryonic antigen, beta chain of human chorionic gonadotropin (hCG beta), HER2/neu, PSMA, and KSA on primary and metastatic prostate cancer and 16 types of normal tissues was compared by immunohistochemistry, using a panel of well-characterized monoclonal antibodies. Our results show that GM2, KSA, and MUC2 were strongly expressed on 8 or 9 of 9 metastatic prostate cancer biopsy specimens and, with PSMA, hCG beta, TF, Tn, and sTn, on 8 or more of 11 primary prostate cancer specimens. Tn, MUC1, and PSMA were expressed on 4-6 of 9 metastatic specimens. The remaining antigens were expressed on no more than three of nine metastatic specimens. Normal tissues were also tested with all antibodies. With regard to the eight antigens most widely expressed on prostate cancers, PSMA was not expressed significantly on any of the normal tissues except prostate epithelium. Tn, sTn, hCG beta, and MUC2 were detected on up to 3 of 10 types of normal epithelia. GM2, TF, MUC1, and KSA were more broadly distributed on normal epithelia, all primarily at the secretory borders. STn, KSA, and hCG beta were also detected in the testis, and GM2 was expressed on gray matter of brain. From the 30 antigens that we have screened, this study provides the basis for selecting GM2, TF, Tn, sTn, hCG beta, MUC1, MUC2, KSA, and PSMA as target antigens for specific immunotherapy of prostate cancer.

The endocrine-gland-derived vascular endothelial growth factor (EG-VEGF)/prokineticin 1 and 2 and receptor expression in human prostate: Up-regulation of EG-VEGF/prokineticin 1 with malignancy.

PubMed

Pasquali, Daniela; Rossi, Valentina; Staibano, Stefania; De Rosa, Gaetano; Chieffi, Paolo; Prezioso, Domenico; Mirone, Vincenzo; Mascolo, Massimo; Tramontano, Donatella; Bellastella, Antonio; Sinisi, Antonio Agostino

2006-09-01

A new family of angiogenic factors named endocrine-gland-derived vascular endothelial growth factors (EG-VEGF)/prokineticins (PK) have been recently described as predominantly expressed in steroidogenic tissues. Whether the normal and malignant epithelial prostate cells and tissues express EG-VEGF/PK1 and PK2 and their receptors is still unknown. We studied the expression of EG-VEGF/PK1 and PK2 and their receptors (PK-R1 and PK-R2) in human prostate and their involvement in cancer. Using immunohistochemistry, Western blot, and RT-PCR, we determined the expression of EG-VEGF/PK1 in normal prostate (NP) and malignant prostate tissues (PCa), in epithelial cell primary cultures from normal prostate (NPEC) and malignant prostate (CPEC) and in a panel of prostate cell lines. In NPEC, CPEC, and in EPN, a nontransformed human prostate epithelial cell line, EG-VEGF/PK1, PK2, PK-R1, and PK-R2 mRNA levels were evaluated by quantitative RT-PCR. EG-VEGF/PK1 transcript was found in PCa, in CPEC, in EPN, and in LNCaP, whereas it was detected at low level in NP and in NPEC. EG-VEGF/PK1 was absent in androgen-independent PC3 and DU-145 cell lines. Immunochemistry confirmed that EG-VEGF/PK1 protein expression was restricted to hyperplastic and malignant prostate tissues, localized in the glandular epithelial cells, and progressively increased with the prostate cancer Gleason score advancement. EG-VEGF/PK1 and PK2 were weakly expressed in NPEC and EPN. On the other hand, their transcripts were highly detected in CPEC. PK-R1 and PK-R2 were found in NPEC, EPN, and CPEC. Interestingly, CPEC showed a significantly (P < 0.05) higher expression of EG-VEGF/PK1, PK2, PK-R1, and PK-R2 compared with NPEC and EPN. We demonstrated that PKs and their receptors are expressed in human prostate and that their levels increased with prostate malignancy. It may imply that EG-VEGF/PK1 could be involved in prostate carcinogenesis, probably regulating angiogenesis. Thus, the level of EG-VEGF/PK1 could be useful for prostate cancer outcome evaluation and as a target for prostate cancer treatment in the future.

Ghrelin O-acyltransferase (GOAT) is expressed in prostate cancer tissues and cell lines and expression is differentially regulated in vitro by ghrelin.

PubMed

Seim, Inge; Jeffery, Penny L; de Amorim, Laura; Walpole, Carina M; Fung, Jenny; Whiteside, Eliza J; Lourie, Rohan; Herington, Adrian C; Chopin, Lisa K

2013-07-23

Ghrelin is a 28 amino acid peptide hormone that is expressed in the stomach and a range of peripheral tissues, where it frequently acts as an autocrine/paracrine growth factor. Ghrelin is modified by a unique acylation required for it to activate its cognate receptor, the growth hormone secretagogue receptor (GHSR), which mediates many of the actions of ghrelin. Recently, the enzyme responsible for adding the fatty acid residue (octanoyl/acyl group) to the third amino acid of ghrelin, GOAT (ghrelin O-acyltransferase), was identified. We used cell culture, quantitative real-time reverse transcription (RT)-PCR and immunohistochemistry to demonstrate the expression of GOAT in prostate cancer cell lines and tissues from patients. Real-time RT-PCR was used to demonstrate the expression of prohormone convertase (PC)1/3, PC2 and furin in prostate cancer cell lines. Prostate-derived cell lines were treated with ghrelin and desacyl ghrelin and the effect on GOAT expression was measured using quantitative RT-PCR. We have demonstrated that GOAT mRNA and protein are expressed in the normal prostate and human prostate cancer tissue samples. The RWPE-1 and RWPE-2 normal prostate-derived cell lines and the LNCaP, DU145, and PC3 prostate cancer cell lines express GOAT and at least one other enzyme that is necessary to produce mature, acylated ghrelin from proghrelin (PC1/3, PC2 or furin). Finally, ghrelin, but not desacyl ghrelin (unacylated ghrelin), can directly regulate the expression of GOAT in the RWPE-1 normal prostate derived cell line and the PC3 prostate cancer cell line. Ghrelin treatment (100nM) for 6 hours significantly decreased GOAT mRNA expression two-fold (P < 0.05) in the PC3 prostate cancer cell line, however, ghrelin did not regulate GOAT expression in the DU145 and LNCaP prostate cancer cell lines. This study demonstrates that GOAT is expressed in prostate cancer specimens and cell lines. Ghrelin regulates GOAT expression, however, this is likely to be cell-type specific. The expression of GOAT in prostate cancer supports the hypothesis that the ghrelin axis has autocrine/paracrine roles. We propose that the RWPE-1 prostate cell line and the PC3 prostate cancer cell line may be useful for investigating GOAT regulation and function.

Development of a combined ultrasound and electrical impedance imaging system for prostate cancer detection

NASA Astrophysics Data System (ADS)

Wan, Yuqing

Approximately 240,890 men were diagnosed with prostate cancer and 33,720 men were expected to die from it in the year of 2011 in the United States. Unfortunately, the current clinical diagnostic methods (e.g. prostate-specific antigen (PSA), digital rectal examination, ultrasound guided biopsy) used for detecting and staging prostate cancer are limited. It has been shown that cancerous prostate tissue has significantly different electrical properties when compared to benign tissues. Based on these electrical property findings, a transrectal electrical impedance tomography (TREIT) system is proposed as a novel prostate imaging modality. An ultrasound probe is incorporated with TREIT to achieve anatomic information of the prostate and guide electrical property reconstruction. Without the guidance of the ultrasound, the TREIT system can easily discern high contrast inclusions of 1 cm in diameter at distances centered at two times the radius of the TREIT probe away from the probe surface. Furthermore, we have demonstrated that our system is able to detect low contrast inclusions. With the guidance of the ultrasound, our system is capable of detecting a plastic inclusion embedded in a gelatin phantom, indicating the potential to detect cancer. In addition, the results of preliminary in vivo clinical trials using the imaging system are also presented in the thesis. After collecting data for a total 66 patients, we demonstrated that the in vivo conductivity of cancerous tissue is significantly greater than that of benign tissue (p=0.0015 at 400 Hz) and the conductivity of BPH tissue is significantly lower than that of normal tissue (p=0.0009 at 400 Hz). Additionally at 25.6 kHz, the dual-modal imaging system is able to differentiate cancerous tissue from benign tissue with sensitivity of 0.6012 and specificity of 0.5498, normal tissue from BPH tissue with sensitivity of 0.6085 and specificity of 0.5813 and differentiate cancerous tissue from BPH tissue with sensitivity of 0.6510 and specificity of 0.6539, respectively. This research demonstrated the potential and feasibility of detecting the prostate cancer by measuring electrical properties. We hope to incorporate needle electrodes to improve the system performance in the future.

Tunable cytotoxic aptamer-drug conjugates for the treatment of prostate cancer.

PubMed

Powell Gray, Bethany; Kelly, Linsley; Ahrens, Douglas P; Barry, Ashley P; Kratschmer, Christina; Levy, Matthew; Sullenger, Bruce A

2018-05-01

Therapies that can eliminate both local and metastatic prostate tumor lesions while sparing normal organ tissue are desperately needed. With the goal of developing an improved drug-targeting strategy, we turned to a new class of targeted anticancer therapeutics: aptamers conjugated to highly toxic chemotherapeutics. Cell selection for aptamers with prostate cancer specificity yielded the E3 aptamer, which internalizes into prostate cancer cells without targeting normal prostate cells. Chemical conjugation of E3 to the drugs monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) yields a potent cytotoxic agent that efficiently kills prostate cancer cells in vitro but does not affect normal prostate epithelial cells. Importantly, the E3 aptamer targets tumors in vivo and treatment with the MMAF-E3 conjugate significantly inhibits prostate cancer growth in mice, demonstrating the in vivo utility of aptamer-drug conjugates. Additionally, we report the use of antidotes to block E3 aptamer-drug conjugate cytotoxicity, providing a safety switch in the unexpected event of normal cell killing in vivo.

Comparison of normal tissue pharmacokinetics with {sup 111}In/{sup 9}Y monoclonal antibody m170 for breast and prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lehmann, Joerg; Department of Radiodiagnosis and Therapy, Division of Hematology/Oncology, University of California Davis School of Medicine, Sacramento, CA; DeNardo, Gerald L.

Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: {sup 111}In-DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide (GGGF)-m170 and {sup 111}In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for {sup 9}Y was calculated using {sup 111}In MAb pharmacokinetics from the initial imaging study for eachmore » patient, using reference man- and patient-specific masses. Results: The reference man-specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies.« less

TFDP3 was expressed in coordination with E2F1 to inhibit E2F1-mediated apoptosis in prostate cancer.

PubMed

Ma, Yueyun; Xin, Yijuan; Li, Rui; Wang, Zhe; Yue, Qiaohong; Xiao, Fengjing; Hao, Xiaoke

2014-03-10

TFDP3 has been previously identified as an inhibitor of E2F molecules. It has been shown to suppress E2F1-induced apoptosis dependent P53 and to play a potential role in carcinogenesis. However, whether it indeed helps cancer cells tolerate apoptosis stress in cancer tissues remains unknown. TFDP3 expression was assessed by RT-PCR, in situ hybridization and immunohistochemistry in normal human tissues, cancer tissues and prostate cancer tissues. The association between TFDP3 and E2F1 in prostate cancer development was analyzed in various stages. Apoptosis was evaluated with annexin-V and propidium iodide staining and flow-cytometry. The results show that, in 96 samples of normal human tissues, TFDP3 could be detected in the cerebrum, esophagus, stomach, small intestine, bronchus, breast, ovary, uterus, and skin, but seldom in the lung, muscles, prostate, and liver. In addition, TFDP3 was highly expressed in numerous cancer tissues, such as brain-keratinous, lung squamous cell carcinoma, testicular seminoma, cervical carcinoma, skin squamous cell carcinoma, gastric adenocarcinoma, liver cancer, and prostate cancer. Moreover, TFDP3 was positive in 23 (62.2%) of 37 prostate cancer samples regardless of stage. Furthermore, immunohistochemistry results show that TFDP3 was always expressed in coordination with E2F1 at equivalent expression levels in prostate cancer tissues, and was highly expressed particularly in samples of high stage. When E2F1 was extrogenously expressed in LNCap cells, TFDP3 could be induced, and the apoptosis induced by E2F1 was significantly decreased. It was demonstrated that TFDP3 was a broadly expressed protein corresponding to E2F1 in human tissues, and suggested that TFDP3 is involved in prostate cancer cell survival by suppressing apoptosis induced by E2F1. Copyright © 2013 Elsevier B.V. All rights reserved.

Long non-coding RNA lnc-MX1-1 is associated with poor clinical features and promotes cellular proliferation and invasiveness in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Chen-Yi; Gao, Yuan; Wang, Xing-Jie

Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined bymore » real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer. - Highlights: • LncRNA lnc-MX1-1 is up-regulated in prostate cancer. • Overexpression of lnc-MX1-1 is correlated with poor prostate cancer clinical features. • Knockdown of lnc-MX1-1 reduces proliferation and invasiveness of prostate cancer cells.« less

Spectral grading and Gleason grading of malignant prostate tissue using Stokes shift spectra

NASA Astrophysics Data System (ADS)

Al Salhi, M.; Masilamani, V.; Rabah, D.; Farhat, K.; Liu, C. H.; Pu, Y.; Alfano, R. R.

2012-01-01

Gleason score is the most common method of grading the virulence of prostate malignancy and is based on the pathological assessment of morphology of cellular matrix. Since this involves the excision of the tissue, we are working on a new, minimally invasive, non contact, procedure of spectral diagnosis of prostate malignancy. In this preliminary in vitro study reported here, we have analyzed 27 tissue samples (normal control =7: benign=8: malignant =12) by Stokes' shift spectra (SSS) to establish a one- to- one correlation between spectral grading and Gleason grading.

Analysis of the Human Prostate-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling Identifies TMEM79 and ACOXL as Two Putative, Diagnostic Markers in Prostate Cancer

PubMed Central

O'Hurley, Gillian; Busch, Christer; Fagerberg, Linn; Hallström, Björn M.; Stadler, Charlotte; Tolf, Anna; Lundberg, Emma; Schwenk, Jochen M.; Jirström, Karin; Bjartell, Anders; Gallagher, William M.; Uhlén, Mathias; Pontén, Fredrik

2015-01-01

To better understand prostate function and disease, it is important to define and explore the molecular constituents that signify the prostate gland. The aim of this study was to define the prostate specific transcriptome and proteome, in comparison to 26 other human tissues. Deep sequencing of mRNA (RNA-seq) and immunohistochemistry-based protein profiling were combined to identify prostate specific gene expression patterns and to explore tissue biomarkers for potential clinical use in prostate cancer diagnostics. We identified 203 genes with elevated expression in the prostate, 22 of which showed more than five-fold higher expression levels compared to all other tissue types. In addition to previously well-known proteins we identified two poorly characterized proteins, TMEM79 and ACOXL, with potential to differentiate between benign and cancerous prostatic glands in tissue biopsies. In conclusion, we have applied a genome-wide analysis to identify the prostate specific proteome using transcriptomics and antibody-based protein profiling to identify genes with elevated expression in the prostate. Our data provides a starting point for further functional studies to explore the molecular repertoire of normal and diseased prostate including potential prostate cancer markers such as TMEM79 and ACOXL. PMID:26237329

Whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH) and healthy male inhabitants (HMI) and prostatic tissue selenium levels (PTSL) in patients with PC and BPH.

PubMed

Muecke, Ralph; Klotz, Theodor; Giedl, Josef; Buentzel, Jens; Kundt, Guenther; Kisters, Klaus; Prott, Franz-Josef; Micke, Oliver

2009-01-01

The aim of this exploratory study was to evaluate whether significant differences exist between whole blood selenium levels (WBSL) in patients with prostate cancer (PC), benign prostatic hyperplasia (BPH), healthy male inhabitants (HMI) in northern Bavaria and the normal value. Furthermore, we investigated whether differences exist between prostatic tissue selenium levels (PTSL) in patients with PC, BPH and the benign tissue surrounding the PC. We prospectively evaluated WBSL in 24 patients with PC, 21 patients with BPH, and 21 HMI. Measurements of PTSL were performed in 17 patients with PC and 22 patients with BPH. In 9 cases with PC, measurements were also done in the benign tissue surrounding the carcinoma. Measurements were performed using automated graphite furnace atomic absorption spectrophotometry. In patients with PC, there is a significantly lower WBSL in comparison to HMI (p=0.04). There is no significant difference in WBSL between BPH-patients and HMI (p=0.13) and between PC- and BPH-patients (p=0.67). In all patients and the HMI, there is a significantly lower WBSL in comparison to the recommended normal value of 85-162 microg/l (p<0.01). There is no significant difference in PTSL between PC and BPH (p=0.49), and between PC and the tissue compartment surrounding the PC (p=0.56). PTSL seemed to be reduced in the compartment surrounding the PC in comparison to BPH (p=0.03). In PC-patients, there is no significant correlation between WBSL and prostate specific antigen (PSA) (? = -0.20; p=0.36), Gleason score (? = 0.32, p=0.13), and T-stage (? = 0.22; p=0.23). Since the WBSL measured in all men with PC and BPH, and in HMI participating in our study were significantly lower than the recommended normal range, our findings may support the recommendation of selenium supplementation.

Nc886 is epigenetically repressed in prostate cancer and acts as a tumor suppressor through the inhibition of cell growth.

PubMed

Fort, Rafael Sebastián; Mathó, Cecilia; Geraldo, Murilo Vieira; Ottati, María Carolina; Yamashita, Alex Shimura; Saito, Kelly Cristina; Leite, Katia Ramos Moreira; Méndez, Manuel; Maedo, Noemí; Méndez, Laura; Garat, Beatriz; Kimura, Edna Teruko; Sotelo-Silveira, José Roberto; Duhagon, María Ana

2018-02-02

Nc886 is a 102 bp non-coding RNA transcript initially classified as a microRNA precursor (Pre-miR-886), later as a divergent homologue of the vault RNAs (vtRNA 2-1) and more recently as a novel type of RNA (nc886). Although nc886/vtRNA2-1/Pre-miR-886 identity is still controversial, it was shown to be epigenetically controlled, presenting both tumor suppressor and oncogenic function in different cancers. Here, we study for the first time the role of nc886 in prostate cancer. Nc886 promoter methylation status and its correlation with patient clinical parameters or DNMTs levels were evaluated in TCGA and specific GEO prostate tissue datasets. Nc886 level was measured by RT-qPCR to compare normal/neoplastic prostate cells from radical prostatectomies and cell lines, and to assess nc886 response to demethylating agents. The effect of nc886 recovery in cell proliferation (in vitro and in vivo) and invasion (in vitro) was evaluated using lentiviral transduced DU145 and LNCaP cell lines. The association between the expression of nc886 and selected genes was analyzed in the TCGA-PRAD cohort. Nc886 promoter methylation increases in tumor vs. normal prostate tissue, as well as in metastatic vs. normal prostate tissue. Additionally, nc886 promoter methylation correlates with prostate cancer clinical staging, including biochemical recurrence, Clinical T-value and Gleason score. Nc886 transcript is downregulated in tumor vs. normal tissue -in agreement with its promoter methylation status- and increases upon demethylating treatment. In functional studies, the overexpression of nc886 in the LNCaP and DU145 cell line leads to a decreased in vitro cell proliferation and invasion, as well as a reduced in vivo cell growth in NUDE-mice tumor xenografts. Finally, nc886 expression associates with the prostate cancer cell cycle progression gene signature in TCGA-PRAD. Our data suggest a tumor suppressor role for nc886 in the prostate, whose expression is epigenetically silenced in cancer leading to an increase in cell proliferation and invasion. Nc886 might hold clinical value in prostate cancer due to its association with clinical parameters and with a clinically validated gene signature.

Hypoexpression and epigenetic regulation of candidate tumor suppressor gene CADM-2 in human prostate cancer.

PubMed

Chang, Guimin; Xu, Shuping; Dhir, Rajiv; Chandran, Uma; O'Keefe, Denise S; Greenberg, Norman M; Gingrich, Jeffrey R

2010-11-15

Cell adhesion molecules (CADM) comprise a newly identified protein family whose functions include cell polarity maintenance and tumor suppression. CADM-1, CADM-3, and CADM-4 have been shown to act as tumor suppressor genes in multiple cancers including prostate cancer. However, CADM-2 expression has not been determined in prostate cancer. The CADM-2 gene was cloned and characterized and its expression in human prostatic cell lines and cancer specimens was analyzed by reverse transcription-PCR and an immunohistochemical tissue array, respectively. The effects of adenovirus-mediated CADM-2 expression on prostate cancer cells were also investigated. CADM-2 promoter methylation was evaluated by bisulfite sequencing and methylation-specific PCR. We report the initial characterization of CADM-2 isoforms: CADM-2a and CADM-2b, each with separate promoters, in human chromosome 3p12.1. Prostate cancer cell lines, LNCaP and DU145, expressed negligible CADM-2a relative to primary prostate tissue and cell lines, RWPE-1 and PPC-1, whereas expression of CADM-2b was maintained. Using immunohistochemistry, tissue array results from clinical specimens showed statistically significant decreased expression in prostate carcinoma compared with normal donor prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and normal tissue adjacent to tumor (P < 0.001). Adenovirus-mediated CADM-2a expression suppressed DU145 cell proliferation in vitro and colony formation in soft agar. The decrease in CADM-2a mRNA in cancer cell lines correlated with promoter region hypermethylation as determined by bisulfite sequencing and methylation-specific PCR. Accordingly, treatment of cells with the demethylating agent 5-aza-2'-deoxycytidine alone or in combination with the histone deacetylase inhibitor trichostatin A resulted in the reactivation of CADM-2a expression. CADM-2a protein expression is significantly reduced in prostate cancer. Its expression is regulated in part by promoter methylation and implicates CADM-2 as a previously unrecognized tumor suppressor gene in a proportion of human prostate cancers. ©2010 AACR.

Long term organ culture of human prostate tissue in a NASA-designed rotating wall bioreactor

NASA Technical Reports Server (NTRS)

Margolis, L.; Hatfill, S.; Chuaqui, R.; Vocke, C.; Emmert-Buck, M.; Linehan, W. M.; Duray, P. H.

1999-01-01

PURPOSE: To maintain ex vivo integral prostatic tissue including intact stromal and ductal elements using the NASA-designed Rotating Wall Vessel (RWV) which maintains colocalized cells in an environment that promotes both three-dimensional cellular interactions together with the uniform mass transfer of nutrients and metabolic wastes. MATERIALS AND METHODS: Samples of normal prostate were obtained as a byproduct of transurethral prostatectomy or needle biopsy. Prostatic tissue dissected into small 1 x 1 mm. blocks was cultured in the Rotating Wall Vessel (RWV) Bioreactor for various time periods and analyzed using histological, immunochemical, and total cell RNA assays. RESULTS: We report the long term maintenance of benign explanted human prostate tissue grown in simple culture medium, under the simulated microgravity conditions afforded by the RWV bioreactor. Mesenchymal stromal elements including blood vessels and architecturally preserved tubuloglandular acini were maintained for a minimum of 28 days. Cytokeratins, vimentin and TGF-beta2 receptor and ligand were preserved through the entire culture period as revealed by immunocytochemistry. Prostatic acid phosphatase (PAP) was continuously expressed during the culture period, although somewhat decreased. Prostatic specific antigen (PSA) and its transcript were down regulated over time of culture. Prostatic carcinoma cells from the TSU cell line were able to invade RWV-cultured benign prostate tissue explants. CONCLUSIONS: The RWV bioreactor represents an additional new technology for culturing prostate tissue for further investigations concerning the basic physiology and pathobiology of this clinically important tissue.

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content.

PubMed

Shibata, Yasuhiro; Arai, Seiji; Miyazawa, Yoshiyuki; Shuto, Takahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Ito, Kazuto; Suzuki, Kazuhiro

2017-05-01

The effects of a steroidal antiandrogen (AA) and 5-alpha-reductase inhibitor (5ARI) on prostate tissue hormone content and metabolism are not fully elucidated. The objective of this study is to investigate the hormone content and metabolism of the prostate tissues of patients treated with AA or 5ARI using the ultra-sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Thirty-nine patients with benign prostatic hyperplasia (BPH) undergoing transurethral surgery were included. Serum and prostate tissue hormone and prostate tissue hormone metabolism analyses were performed using LC-MS/MS after 1 month of treatment with chlormadinone acetate (CMA; steroidal AA, 50 mg/day) or dutasteride (DUTA; dual 5ARI, 0.5 mg/day). Serum testosterone (T), dihydrotestosterone (DHT), and adrenal androgen levels were lower in the CMA group than the control group. Prostate tissue T and DHT levels were also lower in the CMA group than the control group. In the DUTA group, only serum and prostate DHT concentrations were reduced compared to the control group; in contrast, those of other hormones, especially T and 4-androstene-3,17-dione in the prostate tissue, showed marked elevations up to 70.4- and 11.4-fold normal levels, respectively. Moreover, the hormone metabolism assay confirmed that the conversion of T to DHT was significantly suppressed while that of T to 4-androstene-3,17-dione was significantly accelerated in the prostate tissue of DUTA-treated patients. Although treatment with AA and 5ARI show similar clinical outcomes, their effect on tissue hormone content and metabolism varied greatly. Prostate 77: 672-680, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Evaluation of the normal-to-diseased apparent diffusion coefficient ratio as an indicator of prostate cancer aggressiveness.

PubMed

Lebovici, Andrei; Sfrangeu, Silviu A; Feier, Diana; Caraiani, Cosmin; Lucan, Ciprian; Suciu, Mihai; Elec, Florin; Iacob, Gheorghita; Buruian, Mircea

2014-05-10

We tested the feasibility of a simple method for assessment of prostate cancer (PCa) aggressiveness using diffusion-weighted magnetic resonance imaging (MRI) to calculate apparent diffusion coefficient (ADC) ratios between prostate cancer and healthy prostatic tissue. The requirement for institutional review board approval was waived. A set of 20 standardized core transperineal saturation biopsy specimens served as the reference standard for placement of regions of interest on ADC maps in tumorous and normal prostatic tissue of 22 men with PCa (median Gleason score: 7; range, 6-9). A total of 128 positive sectors were included for evaluation. Two diagnostic ratios were computed between tumor ADCs and normal sector ADCs: the ADC peripheral ratio (the ratio between tumor ADC and normal peripheral zone tissue, ADC-PR), and the ADC central ratio (the ratio between tumor ADC and normal central zone tissue, ADC-CR). The performance of the two ratios in detecting high-risk tumor foci (Gleason 8 and 9) was assessed using the area under the receiver operating characteristic curve (AUC). Both ADC ratios presented significantly lower values in high-risk tumors (0.48 ± 0.13 for ADC-CR and 0.40 ± 0.09 for ADC-PR) compared with low-risk tumors (0.66 ± 0.17 for ADC-CR and 0.54 ± 0.09 for ADC-PR) (p < 0.001) and had better diagnostic performance (ADC-CR AUC = 0.77, sensitivity = 82.2%, specificity = 66.7% and ADC-PR AUC = 0.90, sensitivity = 93.7%, specificity = 80%) than stand-alone tumor ADCs (AUC of 0.75, sensitivity = 72.7%, specificity = 70.6%) for identifying high-risk lesions. The ADC ratio as an intrapatient-normalized diagnostic tool may be better in detecting high-grade lesions compared with analysis based on tumor ADCs alone, and may reduce the rate of biopsies.

Evaluation of the normal-to-diseased apparent diffusion coefficient ratio as an indicator of prostate cancer aggressiveness

PubMed Central

2014-01-01

Background We tested the feasibility of a simple method for assessment of prostate cancer (PCa) aggressiveness using diffusion-weighted magnetic resonance imaging (MRI) to calculate apparent diffusion coefficient (ADC) ratios between prostate cancer and healthy prostatic tissue. Methods The requirement for institutional review board approval was waived. A set of 20 standardized core transperineal saturation biopsy specimens served as the reference standard for placement of regions of interest on ADC maps in tumorous and normal prostatic tissue of 22 men with PCa (median Gleason score: 7; range, 6–9). A total of 128 positive sectors were included for evaluation. Two diagnostic ratios were computed between tumor ADCs and normal sector ADCs: the ADC peripheral ratio (the ratio between tumor ADC and normal peripheral zone tissue, ADC-PR), and the ADC central ratio (the ratio between tumor ADC and normal central zone tissue, ADC-CR). The performance of the two ratios in detecting high-risk tumor foci (Gleason 8 and 9) was assessed using the area under the receiver operating characteristic curve (AUC). Results Both ADC ratios presented significantly lower values in high-risk tumors (0.48 ± 0.13 for ADC-CR and 0.40 ± 0.09 for ADC-PR) compared with low-risk tumors (0.66 ± 0.17 for ADC-CR and 0.54 ± 0.09 for ADC-PR) (p < 0.001) and had better diagnostic performance (ADC-CR AUC = 0.77, sensitivity = 82.2%, specificity = 66.7% and ADC-PR AUC = 0.90, sensitivity = 93.7%, specificity = 80%) than stand-alone tumor ADCs (AUC of 0.75, sensitivity = 72.7%, specificity = 70.6%) for identifying high-risk lesions. Conclusions The ADC ratio as an intrapatient-normalized diagnostic tool may be better in detecting high-grade lesions compared with analysis based on tumor ADCs alone, and may reduce the rate of biopsies. PMID:24885552

Prostate cancer in native Japanese and Japanese-American men: effects of dietary differences on prostatic tissue.

PubMed

Marks, Leonard S; Kojima, Munekado; Demarzo, Angelo; Heber, David; Bostwick, David G; Qian, Junqi; Dorey, Frederick J; Veltri, Robert W; Mohler, James L; Partin, Alan W

2004-10-01

To investigate the relationship between diet and prostate cancer (CaP) among native Japanese (NJ) and second-generation or third-generation Japanese-American (J-A) men--focusing on the effects of animal fat and soy on prostatic tissues. The subjects were 50 Japanese men undergoing radical prostatectomy, 25 NJ living in Nagoya, Japan and 25 U.S.-born J-A men, living in Los Angeles, California. A priori, the NJ men were believed to be a low-fat, high-soy group and the J-A men, a high-fat, low-soy group. The studies included postoperative measurements of diet (Block questionnaire), body fat (bioimpedance), blood, urine, and prostatic biomarkers in malignant and adjacent normal tissue, using a tissue microarray made from the original paraffin blocks. The NJ and J-A men were similar in age (65 to 70 years old; P <0.05), prostate-specific antigen level (7.1 to 8.6 ng/mL), prostate volume (35 to 38 cm3), and Gleason score (5.6 to 6.6), but their body composition differed. J-A men had more body fat (24% versus 19%), higher serum triglyceride levels (245 versus 106 mg/dL), lower estradiol levels (27 versus 31 ng/mL), and much lower urinary soy-metabolite levels (1:3) than NJ men (P <0.02). In both NJ and J-A groups, expression of numerous tissue biomarkers separated normal from CaP tissue, including markers for apoptosis (Bcl-2, caspase-3), growth factor receptors (epidermal growth factor receptor), racemase, 5-lipoxygenase, kinase inhibition (p27), and cell proliferation (Ki-67; all P <0.02). Furthermore, within both normal and CaP tissues, caspase-3 and 5-lipoxygenase were expressed more in NJ than in J-A men (P <0.01). Nuclear morphometry showed that the chromatin in each of the four groups (normal versus CaP, NJ versus J-A) was different (area under the curve 85% to 94%, P <0.01), despite fundamental genetic homogeneity. NJ and J-A men, products of similar genetics but differing environments, were shown to have differences in body composition that could influence CaP evolution. The CaP specimens from the NJ and J-A men were histologically similar, but tissue biomarker expression, especially of lipoxygenase and the caspase family, suggested differing mechanisms of carcinogenesis. Differences in nuclear morphometry suggested the additional possibility of gene-nutrient interactions.

Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci.

PubMed

Larson, Nicholas B; McDonnell, Shannon K; Fogarty, Zach; Larson, Melissa C; Cheville, John; Riska, Shaun; Baheti, Saurabh; Weber, Alexandra M; Nair, Asha A; Wang, Liang; O'Brien, Daniel; Davila, Jaime; Schaid, Daniel J; Thibodeau, Stephen N

2017-10-17

Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to cis -acting associations due to study limitations. While trans -eQTL scans suffer from high testing dimensionality, recent evidence indicates most trans -eQTL associations are mediated by cis -regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis -mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple trans -eQTL associations that were significantly mediated by cis -regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B , and target trans -genes with known HNF response elements ( MIA2 , SRC , SEMA6A , KIF12 ). We additionally identified evidence of cis -acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1 . The majority of these cis -mediator relationships demonstrated trans -eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer.

Effect of intravenous gadolinium-DTPA on diffusion-weighted imaging for prostate lesions and normal tissue at 3.0-Tesla magnetic resonance imaging.

PubMed

Liu, Xiaohang; Zhou, Liangping; Peng, Weijun; Qian, Min

2011-06-01

Post-contrast diffusion-weighted imaging (DWI) is occasionally necessary when the results of the pre-contrast DWI differ from that of the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), however, the effects of contrast material on DWI image and apparent diffusion coefficient (ADC) values have not been fully examined. To assess whether the administration of gadolinium-DTPA (Gd-DTPA) significantly affects the DWI of prostate lesions or normal tissue at the 3.0 Tesla magnetic resonance imaging (3.0 T MRI). Fifty-one patients with 52 prostate lesions, including 32 prostate cancer (25 in the peripheral zone [PZ] and seven that could not be confidently located) and 20 benign lesions (11 in PZ and nine in central grand [CG]), underwent echo-planar imaging (EPI)-DWI with b values of 0, 1000 s/mm(2) before and after administration of Gd-DTPA at 3.0 T MRI. Regions of interest (ROI) were drawn in all lesions, 42 normal PZ, 44 CG tissue and air to calculate the signal-to-noise ratio (SNR) and ADC values of lesions and normal tissue, and contrast-to-noise ratio (CNR) of lesions for pre- and post-contrast images. Statistical differences between pre- and post-contrast data were assessed by use of a paired t test. No significant differences between pre- and post-contrast images were found in the CNR of lesions and SNR of all the tissue except CG, which showed a statistically significant decline (9.6%, p < 0.0001) in SNR after contrast relative to the pre-contrast images. The post-contrast ADC values were statistically significantly lower than pre-contrast for prostate cancer (0.80 ± 0.11 mm(2)/s Vs 0.89 ± 0.12 mm(2)/s, p < 0.0001) and benign lesions (1.14 ± 0.30 mm(2)/s vs. 1.2 ± 0.29 mm(2)/s, p < 0.0001). No significant differences were detected for normal tissue. The administration of Gd-DTPA can slightly affect the DWI image quality of the prostate and reduce the ADC value of lesions at 3.0T MRI. Applications of post-contrast DWI require caution in interpretation.

Reference-tissue correction of T2-weighted signal intensity for prostate cancer detection

NASA Astrophysics Data System (ADS)

Peng, Yahui; Jiang, Yulei; Oto, Aytekin

2014-03-01

The purpose of this study was to investigate whether correction with respect to reference tissue of T2-weighted MRimage signal intensity (SI) improves its effectiveness for classification of regions of interest (ROIs) as prostate cancer (PCa) or normal prostatic tissue. Two image datasets collected retrospectively were used in this study: 71 cases acquired with GE scanners (dataset A), and 59 cases acquired with Philips scanners (dataset B). Through a consensus histology- MR correlation review, 175 PCa and 108 normal-tissue ROIs were identified and drawn manually. Reference-tissue ROIs were selected in each case from the levator ani muscle, urinary bladder, and pubic bone. T2-weighted image SI was corrected as the ratio of the average T2-weighted image SI within an ROI to that of a reference-tissue ROI. Area under the receiver operating characteristic curve (AUC) was used to evaluate the effectiveness of T2-weighted image SIs for differentiation of PCa from normal-tissue ROIs. AUC (+/- standard error) for uncorrected T2-weighted image SIs was 0.78+/-0.04 (datasets A) and 0.65+/-0.05 (datasets B). AUC for corrected T2-weighted image SIs with respect to muscle, bladder, and bone reference was 0.77+/-0.04 (p=1.0), 0.77+/-0.04 (p=1.0), and 0.75+/-0.04 (p=0.8), respectively, for dataset A; and 0.81+/-0.04 (p=0.002), 0.78+/-0.04 (p<0.001), and 0.79+/-0.04 (p<0.001), respectively, for dataset B. Correction in reference to the levator ani muscle yielded the most consistent results between GE and Phillips images. Correction of T2-weighted image SI in reference to three types of extra-prostatic tissue can improve its effectiveness for differentiation of PCa from normal-tissue ROIs, and correction in reference to the levator ani muscle produces consistent T2-weighted image SIs between GE and Phillips MR images.

Ghrelin O-acyltransferase (GOAT) is expressed in prostate cancer tissues and cell lines and expression is differentially regulated in vitro by ghrelin

PubMed Central

2013-01-01

Background Ghrelin is a 28 amino acid peptide hormone that is expressed in the stomach and a range of peripheral tissues, where it frequently acts as an autocrine/paracrine growth factor. Ghrelin is modified by a unique acylation required for it to activate its cognate receptor, the growth hormone secretagogue receptor (GHSR), which mediates many of the actions of ghrelin. Recently, the enzyme responsible for adding the fatty acid residue (octanoyl/acyl group) to the third amino acid of ghrelin, GOAT (ghrelin O-acyltransferase), was identified. Methods We used cell culture, quantitative real-time reverse transcription (RT)-PCR and immunohistochemistry to demonstrate the expression of GOAT in prostate cancer cell lines and tissues from patients. Real-time RT-PCR was used to demonstrate the expression of prohormone convertase (PC)1/3, PC2 and furin in prostate cancer cell lines. Prostate-derived cell lines were treated with ghrelin and desacyl ghrelin and the effect on GOAT expression was measured using quantitative RT-PCR. Results We have demonstrated that GOAT mRNA and protein are expressed in the normal prostate and human prostate cancer tissue samples. The RWPE-1 and RWPE-2 normal prostate-derived cell lines and the LNCaP, DU145, and PC3 prostate cancer cell lines express GOAT and at least one other enzyme that is necessary to produce mature, acylated ghrelin from proghrelin (PC1/3, PC2 or furin). Finally, ghrelin, but not desacyl ghrelin (unacylated ghrelin), can directly regulate the expression of GOAT in the RWPE-1 normal prostate derived cell line and the PC3 prostate cancer cell line. Ghrelin treatment (100nM) for 6 hours significantly decreased GOAT mRNA expression two-fold (P < 0.05) in the PC3 prostate cancer cell line, however, ghrelin did not regulate GOAT expression in the DU145 and LNCaP prostate cancer cell lines. Conclusions This study demonstrates that GOAT is expressed in prostate cancer specimens and cell lines. Ghrelin regulates GOAT expression, however, this is likely to be cell-type specific. The expression of GOAT in prostate cancer supports the hypothesis that the ghrelin axis has autocrine/paracrine roles. We propose that the RWPE-1 prostate cell line and the PC3 prostate cancer cell line may be useful for investigating GOAT regulation and function. PMID:23879975

Elemental concentration analysis in prostate tissues using total reflection X-ray fluorescence

NASA Astrophysics Data System (ADS)

Leitão, R. G.; Palumbo, A.; Souza, P. A. V. R.; Pereira, G. R.; Canellas, C. G. L.; Anjos, M. J.; Nasciutti, L. E.; Lopes, R. T.

2014-02-01

Prostate cancer (PCa) currently represents the second most prevalent malignant neoplasia in men, representing 21% of all cancer cases. Benign Prostate Hyperplasia (BPH) is an illness prevailing in men above the age of 50, close to 90% after the age of 80. The prostate presents a high zinc concentration, about 10-fold higher than any other body tissue. In this work, samples of human prostate tissues with cancer, BPH and normal tissue were analyzed utilizing total reflection X-ray fluorescence spectroscopy using synchrotron radiation technique (SR-TXRF) to investigate the differences in the elemental concentrations in these tissues. SR-TXRF analyses were performed at the X-ray fluorescence beamline at Brazilian National Synchrotron Light Laboratory (LNLS), in Campinas, São Paulo. It was possible to determine the concentrations of the following elements: P, S, K, Ca, Fe, Cu, Zn and Rb. By using Mann-Whitney U test it was observed that almost all elements presented concentrations with significant differences (α=0.05) between the groups studied.

Rapid Selection of Mesenchymal Stem and Progenitor Cells in Primary Prostate Stromal Cultures

PubMed Central

Brennen, W. Nathaniel; Kisteman, L. Nelleke; Isaacs, John T.

2016-01-01

BACKGROUND Carcinoma-associated fibroblasts (CAFs) are a dominant component of the tumor microenvironment with pro-tumorigenic properties. Despite this knowledge, their physiologic origins remain poorly understood. Mesenchymal stem cells (MSCs) can be recruited from the bone marrow to areas of tissue damage and inflammation, including prostate cancer. MSCs can generate and have many overlapping properties with CAFs in preclinical models. METHODS Multiparameter flow cytometry and multipotent differentiation assays used to define MSCs in primary prostate stromal cultures derived from young (>25 yrs) organ donors and prostate cancer patients compared with bone marrow-derived stromal cultures. Population doubling times, population doublings, cell size, and differentiation potential determined under multiple culture conditions, including normoxia, hypoxia, and a variety of media. TGF-β measured by ELISA. RESULTS MSCs and stromal progenitors are not only present in normal and malignant prostate tissue, but are quickly selected for in primary stromal cultures derived from these tissues; becoming the dominant population within just a few passages. Growth potential inversely associated with TGF-β concentrations. All conditions generated populations with an average cell diameter >15 μm. All cultures tested had the ability to undergo osteogenic and chondrogenic differentiation, but unlike bone marrow-derived MSCs, primary stromal cultures derived from normal prostate tissue lack adipogenic differentiation potential. In contrast, a subset of stromal cultures derived from prostate cancer patients retain the ability to differentiate into adipocytes; a property that is significantly suppressed under hypoxic conditions in both bone marrow- and prostate-derived MSCs. CONCLUSIONS Primary prostate stromal cultures are highly enriched in cells with an MSC or stromal progenitor phenotype. The use of primary cultures such as these to study CAFs raises interesting implications when considering their overlapping properties. The lack of adipogenesis in stromal cultures derived from normal prostates suggests they have a lineage-restricted progenitor phenotype. The retention of adipogenic differentiation in cultures from a subset of prostate cancer patients suggests the active recruitment of less committed progenitors or MSCs from the bone marrow as a function of disease progression. This recruitment can potentially be exploited for prognostic purposes or a cell-based platform for the systemic delivery of cytotoxic agents to sites of prostate cancer. PMID:26732992

Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures.

PubMed

Brennen, W Nathaniel; Kisteman, L Nelleke; Isaacs, John T

2016-05-01

Carcinoma-associated fibroblasts (CAFs) are a dominant component of the tumor microenvironment with pro-tumorigenic properties. Despite this knowledge, their physiologic origins remain poorly understood. Mesenchymal stem cells (MSCs) can be recruited from the bone marrow to areas of tissue damage and inflammation, including prostate cancer. MSCs can generate and have many overlapping properties with CAFs in preclinical models. Multiparameter flow cytometry and multipotent differentiation assays used to define MSCs in primary prostate stromal cultures derived from young (<25 yrs) organ donors and prostate cancer patients compared with bone marrow-derived stromal cultures. Population doubling times, population doublings, cell size, and differentiation potential determined under multiple culture conditions, including normoxia, hypoxia, and a variety of media. TGF-β measured by ELISA. MSCs and stromal progenitors are not only present in normal and malignant prostate tissue, but are quickly selected for in primary stromal cultures derived from these tissues; becoming the dominant population within just a few passages. Growth potential inversely associated with TGF-β concentrations. All conditions generated populations with an average cell diameter >15 µm. All cultures tested had the ability to undergo osteogenic and chondrogenic differentiation, but unlike bone marrow-derived MSCs, primary stromal cultures derived from normal prostate tissue lack adipogenic differentiation potential. In contrast, a subset of stromal cultures derived from prostate cancer patients retain the ability to differentiate into adipocytes; a property that is significantly suppressed under hypoxic conditions in both bone marrow- and prostate-derived MSCs. Primary prostate stromal cultures are highly enriched in cells with an MSC or stromal progenitor phenotype. The use of primary cultures such as these to study CAFs raises interesting implications when considering their overlapping properties. The lack of adipogenesis in stromal cultures derived from normal prostates suggests they have a lineage-restricted progenitor phenotype. The retention of adipogenic differentiation in cultures from a subset of prostate cancer patients suggests the active recruitment of less committed progenitors or MSCs from the bone marrow as a function of disease progression. This recruitment can potentially be exploited for prognostic purposes or a cell-based platform for the systemic delivery of cytotoxic agents to sites of prostate cancer. © 2016 Wiley Periodicals, Inc.

Expression screening of cancer/testis genes in prostate cancer identifies NR6A1 as a novel marker of disease progression and aggressiveness.

PubMed

Mathieu, Romain; Evrard, Bertrand; Fromont, Gaëlle; Rioux-Leclercq, Nathalie; Godet, Julie; Cathelineau, Xavier; Guillé, François; Primig, Michael; Chalmel, Frédéric

2013-07-01

Cancer/Testis (CT) genes are expressed in male gonads, repressed in most healthy somatic tissues and de-repressed in various somatic malignancies including prostate cancers (PCa). Because of their specific expression signature and their associations with tumor aggressiveness and poor outcomes, CT genes are considered to be useful biomarkers and they are also targets for the development of new anti-cancer immunotherapies. The aim of this study was to identify novel CT genes associated with hormone-sensitive prostate cancer (HSPC), and castration-resistant prostate cancer (CRPC). To identify novel CT genes we screened genes for which transcripts were detected by RNA profiling specifically in normal testis and in either HSPC or CRPC as compared to normal prostate and 44 other healthy tissues using GeneChips. The expression and clinicopathological significance of a promising candidate--NR6A1--was examined in HSPC, CRPC, and metastatic site samples using tissue microarrays. We report the identification of 98 genes detected in CRPC, HSPC and testicular samples but not in the normal controls. Among them, cellular levels of NR6A1 were found to be higher in HSPC compared to normal prostate and further increased in metastatic lesions and CRPC. Furthermore, increased NR6A1 immunoreactivity was significantly associated with a high Gleason score, advanced pT stage and cancer cell proliferation. Our results show that cellular levels of NR6A1 are correlated with disease progression in PCa. We suggest that this essential orphan nuclear receptor is a potential therapeutic target as well as a biomarker of PCa aggressiveness. Copyright © 2013 Wiley Periodicals, Inc.

Selection of tumor antigens as targets for immune attack using immunohistochemistry: protein antigens.

PubMed

Zhang, S; Zhang, H S; Cordon-Cardo, C; Ragupathi, G; Livingston, P O

1998-11-01

The relative expression of mucin antigens MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC7 and glycoprotein antigens KSA, carcinoembryonic antigen, prostate-specific membrane antigen (PSMA), HER-2/neu, and human chorionic gonadotropin-beta on different cancers and normal tissues is difficult to determine from available reports. We have compared the distribution of these antigens by immunohistology on a broad range of malignant and normal tissues. MUC1 expression was most intense in cancers of breast, lung, ovarian, and endometrial origin; MUC2 was most intense in cancers of colon and prostate origin; and MUC5AC was most intense in cancers of breast and gastric origin. MUC4 was intensely expressed in 50% of cancers of colon and pancreas origin, and MUC3, MUC5B, and MUC7 were expressed in a variety of epithelial cancers, but not so intensely. KSA was intensely and uniformly expressed on all epithelial cancers; carcinoembryonic antigen was expressed in most cancers of breast, lung, colon, pancreas, and gastric origin; and PSMA was expressed only in cancers of prostate origin. Human chorionic gonadotropin-beta was expressed on the majority of sarcomas and cancers of breast, lung, and pancreas origin, although intense staining was not seen. Staining on normal tissues was restricted to one or many normal epithelial tissues ranging from MUC3, MUC4, and PSMA, which were expressed only on epithelia of pancreas, stomach, and prostate origin, respectively, to MUC1 and KSA, which were expressed on most normal epithelia. Expression was restricted to the secretory borders of these epithelia while stroma and other normal tissues were completely negative. These results plus the results of the two previous papers (S. Zhang et al, Int. J. Cancer, 73: 42-49, 1997; S. Zhang et al., Int. J. Cancer, 73: 50-56, 1997) in this series provide the basis for selection of multiple cell surface antigens as targets for antibody-mediated attack against these cancers.

A Rapid Filter Insert-based 3D Culture System for Primary Prostate Cell Differentiation

PubMed Central

Tricoli, Lucas; Berry, Deborah L.; Albanese, Chris

2018-01-01

Conditionally reprogrammed cells (CRCs) provide a sustainable method for primary cell culture and the ability to develop extensive “living biobanks” of patient derived cell lines. For many types of epithelial cells, various three dimensional (3D) culture approaches have been described that support an improved differentiated state. While CRCs retain their lineage commitment to the tissue from which they are isolated, they fail to express many of the differentiation markers associated with the tissue of origin when grown under normal two dimensional (2D) culture conditions. To enhance the application of patient-derived CRCs for prostate cancer research, a 3D culture format has been defined that enables a rapid (2 weeks total) luminal cell differentiation in both normal and tumor-derived prostate epithelial cells. Herein, a filter insert-based format is described for the culturing and differentiation of both normal and malignant prostate CRCs. A detailed description of the procedures required for cell collection and processing for immunohistochemical and immunofluorescent staining are provided. Collectively the 3D culture format described, combined with the primary CRC lines, provides an important medium- to high- throughput model system for biospecimen-based prostate research. PMID:28287583

Metabolomic signatures of aggressive prostate cancer.

PubMed

McDunn, Jonathan E; Li, Zhen; Adam, Klaus-Peter; Neri, Bruce P; Wolfert, Robert L; Milburn, Michael V; Lotan, Yair; Wheeler, Thomas M

2013-10-01

Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings. A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer-free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement. Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5-year recurrence (AUROC from 0.53 to 0.64). These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests. Copyright © 2013 Wiley Periodicals, Inc.

Androgen Receptor Content of the Normal and Hyperplastic Canine Prostate

PubMed Central

Shain, Sydney A.; Boesel, Robert W.

1978-01-01

A procedure was developed for measurement of androgen receptors in cytoplasmic extracts of prostates from intact dogs. The protocol utilized exchange saturation analysis at 15°C employing the synthetic androgen R1881 (17β-hydroxy-17α-methylestra-4,9,11-trien-3-one) as the ligand probe and quantitatively detected total cytoplasmic androgen receptor (Rc, androgen-free receptor, and RcA, androgen-occupied receptor) present at the initiation of the assay. This protocol was employed in conjunction with a tissue mince saturation analysis procedure (for quantitation of nuclear androgen receptor) to quantitate total androgen receptor content of normal and hyperplastic prostates obtained from young (2.5- or 4.6-yr old) and aged (12.5-yr old) purebred dogs of known birth date. The total cytoplasmic androgen receptor content (picomoles per prostate) of hyperplastic prostates was 4.6-fold greater than that of normal prostates. The total nuclear androgen receptor content of hyperplastic prostates (picomoles per prostate measured in crude nuclear preparations) was either 5.0- (4.6-yr-old dogs) or 7.8-fold (2.5-yr-old dogs) greater than that of normal prostates. However, androgen receptor content per cell was identical for hyperplastic and normal canine prostates, with the exception that nuclear androgen receptor was diminished in prostates from 2.5-yr-old dogs. The cell content per gram dry weight was identical for hyperplastic and normal canine prostates. We conclude that canine prostate hyperplasia is characterized by coordinate proliferation of androgen receptor-positive and androgen receptor-negative cells and is not a consequence of increased accumulation of 5α-dihydrotestosterone due to proliferation of androgen receptors per prostate cell. PMID:76635

Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.

PubMed

Brenner, David J; Martinez, Alvaro A; Edmundson, Gregory K; Mitchell, Christina; Thames, Howard D; Armour, Elwood P

2002-01-01

A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue. Earlier estimates of alpha/beta for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. The estimated value of alpha/beta from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues. This analysis provides strong supporting evidence that alpha/beta values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.

Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT.

PubMed

Kuang, Yu; Wu, Lili; Hirata, Emily; Miyazaki, Kyle; Sato, Miles; Kwee, Sandi A

2015-04-01

This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by (18)F-choline positron emission tomography/computed tomography (PET/CT). Thirty patients with localized prostate cancer underwent (18)F-choline PET/CT before treatment. Two VMAT plans, plan79 Gy and plan100-105 Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) prescription was 79 Gy in both plans, but plan100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on (18)F-choline PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan100-105 Gy had significantly higher TCP than plan79 Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan100-105 Gy. VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a (18)F-choline PET-defined IDL. Copyright © 2015 Elsevier Inc. All rights reserved.

Radiobiological Impact of Reduced Margins and Treatment Technique for Prostate Cancer in Terms of Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensen, Ingelise, E-mail: inje@rn.d; Carl, Jesper; Lund, Bente

2011-07-01

Dose escalation in prostate radiotherapy is limited by normal tissue toxicities. The aim of this study was to assess the impact of margin size on tumor control and side effects for intensity-modulated radiation therapy (IMRT) and 3D conformal radiotherapy (3DCRT) treatment plans with increased dose. Eighteen patients with localized prostate cancer were enrolled. 3DCRT and IMRT plans were compared for a variety of margin sizes. A marker detectable on daily portal images was presupposed for narrow margins. Prescribed dose was 82 Gy within 41 fractions to the prostate clinical target volume (CTV). Tumor control probability (TCP) calculations based on themore » Poisson model including the linear quadratic approach were performed. Normal tissue complication probability (NTCP) was calculated for bladder, rectum and femoral heads according to the Lyman-Kutcher-Burman method. All plan types presented essentially identical TCP values and very low NTCP for bladder and femoral heads. Mean doses for these critical structures reached a minimum for IMRT with reduced margins. Two endpoints for rectal complications were analyzed. A marked decrease in NTCP for IMRT plans with narrow margins was seen for mild RTOG grade 2/3 as well as for proctitis/necrosis/stenosis/fistula, for which NTCP <7% was obtained. For equivalent TCP values, sparing of normal tissue was demonstrated with the narrow margin approach. The effect was more pronounced for IMRT than 3DCRT, with respect to NTCP for mild, as well as severe, rectal complications.« less

Studies of a novel photosensitizer Pd-bacteriopheophorbide (Tookad) for the prostate cancer PDT in canine model

NASA Astrophysics Data System (ADS)

Huang, Zheng; Chen, Qun; Brun, Pierre-Herve; Wilson, Brian C.; Scherz, Avigdor; Salomon, Yoram; Luck, David L.; Beckers, Jill; Hetzel, Fred W.

2003-12-01

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the i.v. infused photosensitizer drug. The effects of two-session PDT were evaluated. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week, post second-session PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. Two-session PDT or one single session PDT induced a similar extent of damage. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Maximum lesion size of over 3 cm in dimension could be achieved with a single 1-cm interstitial treatment, suggesting the therapy is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat prostate cancer.

Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate

PubMed Central

2013-01-01

Background The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate. Methods Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers. Results The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified. Conclusions The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the different zones. MicroRNA signatures that are specific for PZ and TZ tumors could also lead to more accurate prognoses, since tumors arising in the PZ tend to be more aggressive than tumors arising in the TZ. PMID:23890084

Structure and Function of the Splice Variants of TMPRSS2-ERG, a Prevalent Genomic Alteration in Prostate Cancer

DTIC Science & Technology

2011-09-01

the ETS family of transcription factors showing diverse expression patterns in human tissues (Turner and Watson, 2008). ERG, similar to other...and adult mouse tissues . Most striking of these observations was highly selective and abundant expression of erg protein in endothelial cells of...mouse tissues . We for the first time clarified that endogenous ERG was not expressed in normal mouse prostate epithelium (Mohamed et al., 2010

Evaluation of NKX3.1 and C-MYC expression in canine prostatic cancer.

PubMed

Fonseca-Alves, Carlos Eduardo; Kobayashi, Priscila Emiko; Laufer-Amorim, Renée

2018-06-01

NKX3.1/C-MYC cross-regulation has been reported in the normal human prostate, and loss of NKX3.1 and gain of C-MYC seem to be important events in prostate cancer development and progression. The dog can be an interesting model for human prostatic disease, and yet only one previous research study has shown deregulation of NKX3.1 and MYC in the canine prostate. To address the expression of NKX3.1 and C-MYC in different canine prostatic lesions, this study verified the gene and protein expression of NKX3.1 and C-MYC in normal canine prostatic tissues. We identified a 26 kDa band that corresponded to the NKX3.1 protein, while C-MYC showed a 50 kDa band on Western blotting analysis of all prostatic tissues. We observed that NKX3.1 protein and transcript were down-regulated in prostate cancer (PC) samples compared with non-neoplastic samples. We also observed that C-MYC protein was overexpressed in PC samples compared with normal (P = .001) and proliferative inflammatory atrophy (PIA) samples (P = .003). We found a positive correlation between NKX3.1 and C-MYC protein expression in normal and PIA samples. Interestingly, a negative correlation (NKX3.1 downregulation and MYC overexpression) was observed between NKX3.1 and MYC transcripts in PC. Thus, samples with higher C-MYC expression also exhibited higher NKX3.1 expression, which indicates the regulation of C-MYC by NKX3.1 protein. As in humans, these two genes and proteins were found to be related to canine prostate cancer. However, in contrast from what is observed in humans, in canine PC samples, the downregulation of NKX3.1 cannot be explained by DNA hypermethylation. Copyright © 2018 Elsevier Ltd. All rights reserved.

An improved light microscopical histoquantitative method for the stereological analysis of the rat ventral prostate lobe.

PubMed

Romppanen, T; Huttunen, E; Helminen, H J

1980-07-01

An improved light microscopical histoquantitative method for the analysis of the stereologic structure of the ventral lobe of the rat prostate is introduced. From paraffin-embedded tissue sections, volumetric fractions of the acinar parenchyma, the glandular epithelium, the glandular lumen, and the interacinar tissue were determined. The surface density of the glandular epithelium and the length density of the glandular tubules per cubic millimeter of tissue were also calculated. The corresponding total amount/quantity of each tissue compartment was computed for the whole ventral lobe based on the weight of the lobe. Using established stereologic laws, the height of the epithelium, the diameter of the glandular tubules, the free distance between the glandular tubules, and the distance between the glandular centers (means) were determined. The fitness of the method was tested by analyzing, in addition to normal prostates, ventral prostates of rats castrated 30 days before sacrifice.

Optical coherence elastography (OCE) as a method for identifying benign and malignant prostate biopsies

NASA Astrophysics Data System (ADS)

Li, Chunhui; Guan, Guangying; Ling, Yuting; Lang, Stephen; Wang, Ruikang K.; Huang, Zhihong; Nabi, Ghulam

2015-03-01

Objectives. Prostate cancer is the most frequently diagnosed malignancy in men. Digital rectal examination (DRE) - a known clinical tool based on alteration in the mechanical properties of tissues due to cancer has traditionally been used for screening prostate cancer. Essentially, DRE estimates relative stiffness of cancerous and normal prostate tissue. Optical coherence elastography (OCE) are new optical imaging techniques capable of providing cross-sectional imaging of tissue microstructure as well as elastogram in vivo and in real time. In this preliminary study, OCE was used in the setting of the human prostate biopsies ex vivo, and the images acquired were compared with those obtained using standard histopathologic methods. Methods. 120 prostate biopsies were obtained by TRUS guided needle biopsy procedures from 9 patients with clinically suspected cancer of the prostate. The biopsies were approximately 0.8mm in diameter and 12mm in length, and prepared in Formalin solution. Quantitative assessment of biopsy samples using OCE was obtained in kilopascals (kPa) before histopathologic evaluation. The results obtained from OCE and standard histopathologic evaluation were compared provided the cross-validation. Sensitivity, specificity, and positive and negative predictive values were calculated for OCE (histopathology was a reference standard). Results. OCE could provide quantitative elasticity properties of prostate biopsies within benign prostate tissue, prostatic intraepithelial neoplasia, atypical hyperplasia and malignant prostate cancer. Data analysed showed that the sensitivity and specificity of OCE for PCa detection were 1 and 0.91, respectively. PCa had significantly higher stiffness values compared to benign tissues, with a trend of increasing in stiffness with increasing of malignancy. Conclusions. Using OCE, microscopic resolution elastogram is promising in diagnosis of human prostatic diseases. Further studies using this technique to improve the detection and staging of malignant cancer of the prostate are ongoing.

Differences in prostate and adipose tissue basic fibroblast growth factor: analysis of preliminary results.

PubMed

Mydlo, J H; Kral, J G; Macchia, R J

1997-09-01

Basic fibroblast growth factor (bFGF or FGF-2) is mitogenic to human prostate epithelial and stromal cells, and it is reported to be elevated in the serum and urine of patients with various cancers, including prostate cancer. Obesity, with increased body fat, is a risk factor for prostate cancer through unknown mechanisms. Because adipose tissue is a source of FGF-2, we determined the quantity and quality of activity of FGF-2 in omental adipose tissue and compared it with normal and cancerous prostate tissues. Using heparin-Sepharose chromatography, we extracted proteins from human omental adipose tissue, adenocarcinoma of the prostate, and benign prostatic hypertrophic (BPH) tissues. Each of the mitogenic proteins eluted with NaCl concentrations between 1.4 M and 1.8 M, similar to control FGF-2. Using FGF-2 antisera (which inhibited the mitogenic activity of the proteins), we performed Western blot analysis to confirm their homology to FGF-2. We also assessed recovery, mitogenicity, and angiogenicity of each of the proteins using thymidine incorporation into human umbilical vein endothelial cells and the chorioallantoic membrane assay. There was greater recovery of FGF-2 from omental adipose tissue compared with cancerous or BPH homogenates (40 micrograms [2.0 micrograms/g] versus 25 micrograms [1.25 micrograms/g] and 20 micrograms [1.0 microgram/g], respectively). Moreover. FGF-2 from adipose tissue had greater mitogenic activity (96.2% versus 74.8% and 54%; P < 0.05) and a greater angiogenic activity (5.1 vessels versus 2.9 and 1.8 vessels; P < 0.05) on the chorioallantoic assay. We suggest that human omental adipose tissue FGF-2 may demonstrate greater mitogenic and angiogenic activity than either BPH or prostate cancer tissue FGF-2. It is not known whether FGF-2 from adipose tissue qualitatively or quantitatively may underlie the relationship between obesity and prostate cancer.

Expression of proinflammatory cytokine interleukin-6 in tissue samples of human prostate obtained by needle biopsy.

PubMed

Miličević, Nevenka; Mrčela, Milanka; Galić, Josip; Marjanović, Ksenija

2015-11-01

Interleukin-6 (IL-6) has been associated with the development of prostate cancer. The aim of the study was to clarify whether IL-6 expression in prostate tissue could be a useful marker in differentiation of prostate diseases in small foci by pathologist visual scoring. Archival paraffin-embedded specimens of benign prostate hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), prostatitis and prostate adenocarcinoma were studied by immunohistochemistry with a mouse monoclonal antibody IL-6 using the streptavidin-biotin method. Significantly, lower IL-6 immunoreactivity was observed in normal epithelial cells (p=0.000) and basal cells (p=0.000) in the samples of prostate adenocarcinoma in comparison to the samples with BPH, PIN and prostatitis. There was no significant difference in IL-6 expression in malignant and premalignant cells (p=0.814) as well as in stromal cells among the four diagnoses (p=0.22). IL-6 was expressed in normal epithelial cells, premalignant epithelial cells and malignant epithelial cells as well as in stromal cells. However, in our research IL-6 was of limited utility as a single marker for differential diagnosis of the prostate diseases in small foci needle biopsy by pathologist visual scoring. The standardization of immunohistochemical (IHC) staining protocol for IL-6 is required to determine IL-6 expression in order to avoid possible misinterpretation of the IHC results. Copyright © 2015 Elsevier GmbH. All rights reserved.

Low Testosterone Alters the Activity of Mouse Prostate Stem Cells.

PubMed

Zhou, Ye; Copeland, Ben; Otto-Duessel, Maya; He, Miaoling; Markel, Susan; Synold, Tim W; Jones, Jeremy O

2017-04-01

Low serum testosterone (low T) has been repeatedly linked to worse outcomes in men with newly diagnosed prostate cancer (PC). How low T contributes to these outcomes is unknown. Here we demonstrate that exposure to low T causes significant changes in the mouse prostate and prostate stem cells. Mice were castrated and implanted with capsules to achieve castrate, normal, or sub-physiological levels of T. After 6 weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. FACS was used to quantify the percentages of purported prostate stem and transit amplifying (TA) cells in mouse prostates. Prostate tissues were also stained for the presence of CD68+ cells and RNA was extracted from prostate tissue or specific cell populations to measure changes in transcript levels with low T treatment. Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were similar. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining prostate androgen levels. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the mouse prostate can maintain functional levels of androgens despite low serum T levels. Low T increased the frequency of prostate stem and TA cells in adult prostate tissue and caused major transcriptional changes in those cells. Gene ontology analysis suggested that low T caused inflammatory responses and immunofluorescent staining indicated that low T treatment led to the increased presence of CD68+ macrophages in prostate tissue. Low T alters the AR signaling axis which likely leads to maintenance of functional levels of prostate androgens. Low T also induces quantitative and qualitative changes in prostate stem cells which appear to lead to inflammatory macrophage infiltration. These changes are proposed to lead to an aggressive phenotype once cancers develop and may contribute to the poor outcomes in men with low T. Prostate 77:530-541, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells.

PubMed

Vander Griend, Donald J; Karthaus, Wouter L; Dalrymple, Susan; Meeker, Alan; DeMarzo, Angelo M; Isaacs, John T

2008-12-01

Resolving the specific cell of origin for prostate cancer is critical to define rational targets for therapeutic intervention and requires the isolation and characterization of both normal human prostate stem cells and prostate cancer-initiating cells (CIC). Single epithelial cells from fresh normal human prostate tissue and prostate epithelial cell (PrEC) cultures derived from them were evaluated for the presence of subpopulations expressing stem cell markers and exhibiting stem-like growth characteristics. When epithelial cell suspensions containing cells expressing the stem cell marker CD133+ are inoculated in vivo, regeneration of stratified human prostate glands requires inductive prostate stromal cells. PrEC cultures contain a small subpopulation of CD133+ cells, and fluorescence-activated cell sorting-purified CD133+ PrECs self-renew and regenerate cell populations expressing markers of transit-amplifying cells (DeltaNp63), intermediate cells (prostate stem cell antigen), and neuroendocrine cells (CD56). Using a series of CD133 monoclonal antibodies, attachment and growth of CD133+ PrECs requires surface expression of full-length glycosylated CD133 protein. Within a series of androgen receptor-positive (AR+) human prostate cancer cell lines, CD133+ cells are present at a low frequency, self-renew, express AR, generate phenotypically heterogeneous progeny negative for CD133, and possess an unlimited proliferative capacity, consistent with CD133+ cells being CICs. Unlike normal adult prostate stem cells, prostate CICs are AR+ and do not require functional CD133. This suggests that (a) AR-expressing prostate CICs are derived from a malignantly transformed intermediate cell that acquires "stem-like activity" and not from a malignantly transformed normal stem cell and (b) AR signaling pathways are a therapeutic target for prostate CICs.

Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate.

PubMed

Clavijo Jordan, M Veronica; Lo, Su-Tang; Chen, Shiuhwei; Preihs, Christian; Chirayil, Sara; Zhang, Shanrong; Kapur, Payal; Li, Wen-Hong; De Leon-Rodriguez, Luis M; Lubag, Angelo J M; Rofsky, Neil M; Sherry, A Dean

2016-09-13

Many secretory tissues release Zn(II) ions along with other molecules in response to external stimuli. Here we demonstrate that secretion of Zn(II) ions from normal, healthy prostate tissue is stimulated by glucose in fasted mice and that release of Zn(II) can be monitored by MRI. An ∼50% increase in water proton signal enhancement is observed in T1-weighted images of the healthy mouse prostate after infusion of a Gd-based Zn(II) sensor and an i.p. bolus of glucose. Release of Zn(II) from intracellular stores was validated in human epithelial prostate cells in vitro and in surgically exposed prostate tissue in vivo using a Zn(II)-sensitive fluorescent probe known to bind to the extracellular surface of cells. Given the known differences in intracellular Zn(II) stores in healthy versus malignant prostate tissues, the Zn(II) sensor was then evaluated in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model in vivo. The agent proved successful in detecting small malignant lesions as early as 11 wk of age, making this noninvasive MR imaging method potentially useful for identifying prostate cancer in situations where it may be difficult to detect using current multiparametric MRI protocols.

Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer

NASA Astrophysics Data System (ADS)

Hetzel, Fred W.; Chen, Qun; Luck, David; Beckers, Jill; Huang, Zheng

2004-06-01

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the IV infused photosensitizer drug. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week post PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Prostate lesions could be detected by MRI scan as early as 48 h post PDT. Maximum lesion size of 1.5 cm3 and 2.9 cm3 could be achieved at 50 J/cm and 100 J/cm, respectively, with interstitial treatment using a single 1-cm diffuser fiber, suggesting the Tookad-PDT is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat localized prostate cancer.

Differential expression of cytokeratin mRNA and protein in normal prostate, prostatic intraepithelial neoplasia, and invasive carcinoma.

PubMed Central

Yang, Y.; Hao, J.; Liu, X.; Dalkin, B.; Nagle, R. B.

1997-01-01

The expression of cytokeratin (CK) mRNA for CK5, -8, -14, -16, and -19 was investigated in normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and invasive carcinoma using in situ hybridization. Protein localization was carried out in adjacent sections using immunohistochemistry and correlated with mRNA expression. Snap-frozen human prostate samples including 22 examples of normal glands, 20 cases of PIN lesions, and 12 cases of invasive carcinoma were examined. CK5 and -14 mRNA and protein were prominently expressed only in the basal cells of normal glands and PIN lesions. CK14 mRNA was absent in the luminal cells of the most of the PIN lesions but was seen at a low level in some PIN lesions. CK14 protein was not detected in any PIN lesion, suggesting that, if the cell that makes up the PIN lesions is derived from a basal cell, CK14 translation is depressed although a low level of CK14 mRNA may persist. CK8 mRNA and protein were constitutively expressed in all epithelia of normal and abnormal prostate tissues. CK19 mRNA and protein were persistently expressed in both basal and luminal cells of the tubular portion of normal glands as well as PIN lesions, but were expressed heterogeneously in both basal and luminal cells of normal alveoli. CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not detected either in normal or in abnormal prostate tissues. In conclusion, the expression of CK19 in PIN lesions is similar to its tubular expression and would support an origin of PIN lesions from this structure rather than the alveolar portion of the glands. The similar cytokeratin expression between PIN lesions and invasive carcinoma further supports the concept that PIN is a precursor lesion of invasive carcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:9033282

Analysis of spatial heterogeneity in normal epithelium and preneoplastic alterations in mouse prostate tumor models

PubMed Central

Valkonen, Mira; Ruusuvuori, Pekka; Kartasalo, Kimmo; Nykter, Matti; Visakorpi, Tapio; Latonen, Leena

2017-01-01

Cancer involves histological changes in tissue, which is of primary importance in pathological diagnosis and research. Automated histological analysis requires ability to computationally separate pathological alterations from normal tissue with all its variables. On the other hand, understanding connections between genetic alterations and histological attributes requires development of enhanced analysis methods suitable also for small sample sizes. Here, we set out to develop computational methods for early detection and distinction of prostate cancer-related pathological alterations. We use analysis of features from HE stained histological images of normal mouse prostate epithelium, distinguishing the descriptors for variability between ventral, lateral, and dorsal lobes. In addition, we use two common prostate cancer models, Hi-Myc and Pten+/− mice, to build a feature-based machine learning model separating the early pathological lesions provoked by these genetic alterations. This work offers a set of computational methods for separation of early neoplastic lesions in the prostates of model mice, and provides proof-of-principle for linking specific tumor genotypes to quantitative histological characteristics. The results obtained show that separation between different spatial locations within the organ, as well as classification between histologies linked to different genetic backgrounds, can be performed with very high specificity and sensitivity. PMID:28317907

Microlocalization and Quantitation of Risk Associated Elements in Gleason Graded Prostate Tissue

DTIC Science & Technology

2007-03-01

ORGANIZATION: Regents of the University of California Maya Conn Los Angeles CA 90024 REPORT DATE: March 2007 TYPE OF REPORT...California Maya Conn Los Angeles CA 90024 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S...carcinoma of different histological grading in comparison to normal prostate tissue and adenofibromyomatosis (BPH) Uro Res 10:301-303. 5. Feustel A

Radiobiological impact of reduced margins and treatment technique for prostate cancer in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP).

PubMed

Jensen, Ingelise; Carl, Jesper; Lund, Bente; Larsen, Erik H; Nielsen, Jane

2011-01-01

Dose escalation in prostate radiotherapy is limited by normal tissue toxicities. The aim of this study was to assess the impact of margin size on tumor control and side effects for intensity-modulated radiation therapy (IMRT) and 3D conformal radiotherapy (3DCRT) treatment plans with increased dose. Eighteen patients with localized prostate cancer were enrolled. 3DCRT and IMRT plans were compared for a variety of margin sizes. A marker detectable on daily portal images was presupposed for narrow margins. Prescribed dose was 82 Gy within 41 fractions to the prostate clinical target volume (CTV). Tumor control probability (TCP) calculations based on the Poisson model including the linear quadratic approach were performed. Normal tissue complication probability (NTCP) was calculated for bladder, rectum and femoral heads according to the Lyman-Kutcher-Burman method. All plan types presented essentially identical TCP values and very low NTCP for bladder and femoral heads. Mean doses for these critical structures reached a minimum for IMRT with reduced margins. Two endpoints for rectal complications were analyzed. A marked decrease in NTCP for IMRT plans with narrow margins was seen for mild RTOG grade 2/3 as well as for proctitis/necrosis/stenosis/fistula, for which NTCP <7% was obtained. For equivalent TCP values, sparing of normal tissue was demonstrated with the narrow margin approach. The effect was more pronounced for IMRT than 3DCRT, with respect to NTCP for mild, as well as severe, rectal complications. Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Pharmacologic basis for the enhanced efficacy of dutasteride against prostatic cancers.

PubMed

Xu, Yi; Dalrymple, Susan L; Becker, Robyn E; Denmeade, Samuel R; Isaacs, John T

2006-07-01

Prostatic dihydrotestosterone (DHT) concentration is regulated by precursors from systemic circulation and prostatic enzymes of androgen metabolism, particularly 5alpha-reductases (i.e., SRD5A1 and SRD5A2). Therefore, the levels of expression SRD5A1 and SRD5A2 and the antiprostatic cancer growth response to finasteride, a selective SRD5A2 inhibitor, versus the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, were compared. Real-time PCR and enzymatic assays were used to determine the levels of SRD5A1 and SRD5A2 in normal versus malignant rat and human prostatic tissues. Rats bearing the Dunning R-3327H rat prostate cancer and nude mice bearing LNCaP or PC-3 human prostate cancer xenografts were used as model systems. Tissue levels of testosterone and DHT were determined using liquid chromatography-mass spectrometry. Prostate cancer cells express undetectable to low levels of SRD5A2 but elevated levels of SRD5A1 activity compared with nonmalignant prostatic tissue. Daily oral treatment of rats with the SRD5A2 selective inhibitor, finasteride, reduces prostate weight and DHT content but did not inhibit R-3327H rat prostate cancer growth or DHT content in intact (i.e., noncastrated) male rats. In contrast, daily oral treatment with even a low 1 mg/kg/d dose of the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, reduces both normal prostate and H tumor DHT content and weight in intact rats while elevating tissue testosterone. Daily oral treatment with finasteride significantly (P < 0.05) inhibits growth of LNCaP human prostate cancer xenografts in intact male nude mice, but this inhibition is not as great as that by equimolar oral dosing with dutasteride. This anticancer efficacy is not equivalent, however, to that produced by castration. Only combination of dutasteride and castration produces a greater tumor inhibition (P < 0.05) than castration monotherapy against androgen-responsive LNCaP cancers. In contrast, no response was induced by dutasteride in nude mice bearing androgen-independent PC-3 human prostatic cancer xenografts. These results document that testosterone is not as potent as DHT but does stimulate prostate cancer growth, thus combining castration with dutasteride enhances therapeutic efficacy.

A novel shape similarity based elastography system for prostate cancer assessment

NASA Astrophysics Data System (ADS)

Wang, Haisu; Mousavi, Seyed Reza; Samani, Abbas

2012-03-01

Prostate cancer is the second common cancer among men worldwide and remains the second leading cancer-related cause of death in mature men. The disease can be cured if it is detected at early stage. This implies that prostate cancer detection at early stage is very critical for desirable treatment outcome. Conventional techniques of prostate cancer screening and detection, such as Digital Rectal Examination (DRE), Prostate-Specific Antigen (PSA) and Trans Rectal Ultra-Sonography (TRUS), are known to have low sensitivity and specificity. Elastography is an imaging technique that uses tissue stiffness as contrast mechanism. As the association between the degree of prostate tissue stiffness alteration and its pathology is well established, elastography can potentially detect prostate cancer with a high degree of sensitivity and specificity. In this paper, we present a novel elastography technique which, unlike other elastography techniques, does not require displacement data acquisition system. This technique requires the prostate's pre-compression and postcompression transrectal ultrasound images. The conceptual foundation of reconstructing the prostate's normal and pathological tissues elastic moduli is to determine these moduli such that the similarity between calculated and observed shape features of the post compression prostate image is maximized. Results indicate that this technique is highly accurate and robust.

Label free aggressive prostate cancer identification with ultraviolet photoacoustic spectral analysis (Conference Presentation)

NASA Astrophysics Data System (ADS)

Xu, Guan; Davis, Mandy A.; Siddiqui, Javed; Chao, Wan-yu; Tomlins, Scott A.; Wei, John T.; Wang, Xueding

2017-03-01

Prostate cancer (PCa) is the most commonly diagnosed cancer in American men for the past decades. PCa has a relatively low progression rate but the 5 year survival rate decreases dramatically once the cancer has metastasized. Differentiating aggressive from indolent PCa is critical for improving PCa patient outcomes and preventing metastasis and death. Prostate biopsy is the standard procedure for evaluating the presence and aggressiveness of PCa. The microarchitecture of the biopsied tissues visualized by histology process is evaluated by pathologists and assigned a Gleason score as a quantification of the aggressiveness. In our previous study, we have shown that photoacoustic spectral analysis (PASA) is capable of quantifying the Gleason scores of the H&E stained human prostate tissues. In this study, we attempt to assess the Gleason scores without any staining by taking advantage of the strong optical absorption of nucleic acid at ultraviolet wavelengths. PA signals were generated by wide field illumination at 266 nm and received by a hydrophone with a bandwidth of 0-20 MHz. DU145 prostate cancer cells at the concentrations of 0.8, 0.4, 0.05, 0.025 and 0.0125 million per cm3 simulating those in cancerous and normal tissues were first attempted. The measurements were repeated for 10 times at each concentration. A correlation of 0.86 was observed between the PA signal intensities and the cell concentrations. Human PCa tissues with Gleason score 6, 7 and 8 and normal tissues were assessed. With 11 samples, a correlation of 0.89 was found between the Gleason scores and PASA slopes.

MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer

PubMed Central

Suh, Seong O.; Chen, Yi; Zaman, Mohd Saif; Hirata, Hiroshi; Yamamura, Soichiro; Shahryari, Varahram; Liu, Jan; Tabatabai, Z.Laura; Kakar, Sanjay; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir

2011-01-01

MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here, we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared with the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In seven cancer cell lines with miR-145 hypermethylation, 5-aza-2′-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%), whereas in 18 cell lines with wild-type p53 (WT p53), miR-145 levels were downregulated in only 6 lines (33%, P < 0.001). Electrophoretic mobility shift assay showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WT p53 and MUT p53 into PC-3 cells and found that miR-145 is upregulated by WT p53 but not with MUTp53. The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer. PMID:21349819

Clinical implications of prostate-specific antigen in men and women.

PubMed

Yu, H

2000-01-01

Prostate-specific antigen (PSA) is a valuable tumor marker for prostate cancer. Although it is indeed produced at an extremely high level by the prostate, PSA is also expressed in many female tissues, especially those regulated by sex steroid hormones. PSA is detected in both normal and abnormal breast tissue, as well as in various breast fluids, including milk, nipple aspirate, and cyst fluid. Clinical studies suggest that the presence of PSA in breast tissue may indicate a favorable prognosis for breast cancer patients. Levels of PSA in nipple aspirate fluid, however, may be indicative of breast cancer risk. Concentrations of PSA in serum are elevated in pregnant women as well as in women who have excess androgens. More studies are necessary to determine the clinical implications of the presence of PSA in amniotic fluid and female serum.

The use of morphological characteristics and texture analysis in the identification of tissue composition in prostatic neoplasia.

PubMed

Diamond, James; Anderson, Neil H; Bartels, Peter H; Montironi, Rodolfo; Hamilton, Peter W

2004-09-01

Quantitative examination of prostate histology offers clues in the diagnostic classification of lesions and in the prediction of response to treatment and prognosis. To facilitate the collection of quantitative data, the development of machine vision systems is necessary. This study explored the use of imaging for identifying tissue abnormalities in prostate histology. Medium-power histological scenes were recorded from whole-mount radical prostatectomy sections at x 40 objective magnification and assessed by a pathologist as exhibiting stroma, normal tissue (nonneoplastic epithelial component), or prostatic carcinoma (PCa). A machine vision system was developed that divided the scenes into subregions of 100 x 100 pixels and subjected each to image-processing techniques. Analysis of morphological characteristics allowed the identification of normal tissue. Analysis of image texture demonstrated that Haralick feature 4 was the most suitable for discriminating stroma from PCa. Using these morphological and texture measurements, it was possible to define a classification scheme for each subregion. The machine vision system is designed to integrate these classification rules and generate digital maps of tissue composition from the classification of subregions; 79.3% of subregions were correctly classified. Established classification rates have demonstrated the validity of the methodology on small scenes; a logical extension was to apply the methodology to whole slide images via scanning technology. The machine vision system is capable of classifying these images. The machine vision system developed in this project facilitates the exploration of morphological and texture characteristics in quantifying tissue composition. It also illustrates the potential of quantitative methods to provide highly discriminatory information in the automated identification of prostatic lesions using computer vision.

Selective nanoparticle-directed photothermal ablation of the canine prostate

NASA Astrophysics Data System (ADS)

Schwartz, Jon A.; Price, Roger E.; Gill-Sharp, Kelly L.; Sang, Krystina L.; Khorchani, Jennifer D.; Payne, J. Donald; Goodwin, Bradford S.

2011-03-01

This study adapted AuroLase® Therapy, previously reported for the treatment of brain tumors, to the treatment of prostate disease by 1) using normal canine prostate in vivo, directly injected with a solution of nanoparticles as a proxy for prostate tumor and, 2) developing an appropriate laser dosimetry for prostate which is which is subablative in native prostate while simultaneously producing photothermal coagulation in prostate tissue containing therapeutic nanoshells. Healthy, mixed-breed hound dogs were given surgical laparotomies during which nanoshells were injected directly into one or both prostate hemispheres. Laser energy was delivered percutaneously to the parenchyma of the prostate along 1-5 longitudinal tracts via a liquid-cooled optical fiber catheter terminated with a 1-cm isotropic diffuser after which the incision was closed and sutured using standard surgical techniques. The photothermal lesions were permitted to resolve for up to 8 days, after which each animal was euthanized, necropsied, and the prostate taken for histopathological analysis. We developed a laser dosimetry which is sub- to marginally ablative in native prostate and simultaneously ablative of prostate tissue containing nanoshells which would indicate a viable means of treating tumors of the prostate which are known from other studies to accumulate nanoshells. Secondly, we determined that multiple laser treatments of nanoshell-containing prostate tissue could be accomplished while sparing the urethra and prostate capsule thermal damage. Finally, we determined that the extent of damage zone radii correlate positively with nanoshell concentration, and negatively to the length of time between nanoshell injection and laser treatment.

Epithelium percentage estimation facilitates epithelial quantitative protein measurement in tissue specimens.

PubMed

Chen, Jing; Toghi Eshghi, Shadi; Bova, George Steven; Li, Qing Kay; Li, Xingde; Zhang, Hui

2013-12-01

The rapid advancement of high-throughput tools for quantitative measurement of proteins has demonstrated the potential for the identification of proteins associated with cancer. However, the quantitative results on cancer tissue specimens are usually confounded by tissue heterogeneity, e.g. regions with cancer usually have significantly higher epithelium content yet lower stromal content. It is therefore necessary to develop a tool to facilitate the interpretation of the results of protein measurements in tissue specimens. Epithelial cell adhesion molecule (EpCAM) and cathepsin L (CTSL) are two epithelial proteins whose expressions in normal and tumorous prostate tissues were confirmed by measuring staining intensity with immunohistochemical staining (IHC). The expressions of these proteins were measured by ELISA in protein extracts from OCT embedded frozen prostate tissues. To eliminate the influence of tissue heterogeneity on epithelial protein quantification measured by ELISA, a color-based segmentation method was developed in-house for estimation of epithelium content using H&E histology slides from the same prostate tissues and the estimated epithelium percentage was used to normalize the ELISA results. The epithelium contents of the same slides were also estimated by a pathologist and used to normalize the ELISA results. The computer based results were compared with the pathologist's reading. We found that both EpCAM and CTSL levels, measured by ELISA assays itself, were greatly affected by epithelium content in the tissue specimens. Without adjusting for epithelium percentage, both EpCAM and CTSL levels appeared significantly higher in tumor tissues than normal tissues with a p value less than 0.001. However, after normalization by the epithelium percentage, ELISA measurements of both EpCAM and CTSL were in agreement with IHC staining results, showing a significant increase only in EpCAM with no difference in CTSL expression in cancer tissues. These results were obtained with normalization by both the computer estimated and pathologist estimated epithelium percentage. Our results show that estimation of tissue epithelium percentage using our color-based segmentation method correlates well with pathologists' estimation of tissue epithelium percentages. The epithelium contents estimated by color-based segmentation may be useful in immuno-based analysis or clinical proteomic analysis of tumor proteins. The codes used for epithelium estimation as well as the micrographs with estimated epithelium content are available online.

Pharmacodynamic and pharmacokinetic studies and prostatic tissue distribution of fosfomycin tromethamine in bacterial prostatitis or normal rats.

PubMed

Fan, L; Shang, X; Zhu, J; Ma, B; Zhang, Q

2018-05-02

In this study, we assessed the therapeutic effects of fosfomycin tromethamine (FT) in a bacterial prostatitis (BP) rat model. The BP model was induced by Escherichia coli and was demonstrated after 7 days microbiologically and histologically. Then, 25 BP rats selected were randomly divided into five treatment groups: model group, positive group, FT-3 day group, FT-7 day group and FT-14 day group. Ventral lobes of prostate from all animals were removed, and the serum samples were collected at the end of the experiments. Microbiological cultures and histological findings of the prostate samples demonstrated reduced bacterial growth and improved inflammatory responses in FT-treatment groups compared with the model group, indicating that FT against prostatic infection induced by E. coli showed good antibacterial effects. Moreover, plasma pharmacokinetics and prostatic distribution of fosfomycin were studied and compared in BP and normal rats. The concentrations of fosfomycin in samples were analysed by liquid chromatography-tandem mass spectrometry. There were no differences in plasma pharmacokinetic parameters between two groups. But significantly higher penetration of fosfomycin into prostatic tissues was found in BP rats. We therefore suggested that FT had a good therapeutic effect on BP and it might be used in curing masculine reproductive system diseases. © 2018 Blackwell Verlag GmbH.

Symptomatic and asymptomatic benign prostatic hyperplasia: Molecular differentiation by using microarrays

NASA Astrophysics Data System (ADS)

Prakash, Kulkarni; Pirozzi, Gregorio; Elashoff, Michael; Munger, William; Waga, Iwao; Dhir, Rajiv; Kakehi, Yoshiyuki; Getzenberg, Robert H.

2002-05-01

Benign prostatic hyperplasia (BPH) is a disease of unknown etiology that significantly affects the quality of life in aging men. Histologic BPH may present itself either as symptomatic or asymptomatic in nature. To elucidate the molecular differences underlying BPH, gene expression profiles from the prostate transition zone tissue have been analyzed by using microarrays. A set of 511 differentially expressed genes distinguished symptomatic and asymptomatic BPH. This genetic signature separates BPH from normal tissue but does not seem to change with age. These data could provide novel approaches for alleviating symptoms and hyperplasia in BPH.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuang, Yu; Wu, Lili; Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong

Purpose: This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by {sup 18}F-choline positron emission tomography/computed tomography (PET/CT). Methods and Materials: Thirty patients with localized prostate cancer underwent {sup 18}F-choline PET/CT before treatment. Two VMAT plans, plan{sub 79} {sub Gy} and plan{sub 100-105} {sub Gy}, were compared for each patient. The whole-prostate planning target volume (PTV{sub prostate}) prescription was 79 Gy in both plans, but plan{sub 100-105} {sub Gy} added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, definedmore » by 60% and 70% of maximum prostatic uptake on {sup 18}F-choline PET (IDL{sub suv60%} and IDL{sub suv70%}, respectively, with IDL{sub suv70%} nested inside IDL{sub suv60%} to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). Results: Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDL{sub suv60%} adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan{sub 100-105} {sub Gy} had significantly higher TCP than plan{sub 79} {sub Gy} across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade ≥ 2 late toxicity or rectal bleeding) was found for plan{sub 100-105} {sub Gy}. Conclusions: VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a {sup 18}F-choline PET-defined IDL.« less

Prostate cancer region prediction using MALDI mass spectra

NASA Astrophysics Data System (ADS)

Vadlamudi, Ayyappa; Chuang, Shao-Hui; Sun, Xiaoyan; Cazares, Lisa; Nyalwidhe, Julius; Troyer, Dean; Semmes, O. John; Li, Jiang; McKenzie, Frederic D.

2010-03-01

For the early detection of prostate cancer, the analysis of the Prostate-specific antigen (PSA) in serum is currently the most popular approach. However, previous studies show that 15% of men have prostate cancer even their PSA concentrations are low. MALDI Mass Spectrometry (MS) proves to be a better technology to discover molecular tools for early cancer detection. The molecular tools or peptides are termed as biomarkers. Using MALDI MS data from prostate tissue samples, prostate cancer biomarkers can be identified by searching for molecular or molecular combination that can differentiate cancer tissue regions from normal ones. Cancer tissue regions are usually identified by pathologists after examining H&E stained histological microscopy images. Unfortunately, histopathological examination is currently done on an adjacent slice because the H&E staining process will change tissue's protein structure and it will derogate MALDI analysis if the same tissue is used, while the MALDI imaging process will destroy the tissue slice so that it is no longer available for histopathological exam. For this reason, only the most confident cancer region resulting from the histopathological examination on an adjacent slice will be used to guide the biomarker identification. It is obvious that a better cancer boundary delimitation on the MALDI imaging slice would be beneficial. In this paper, we proposed methods to predict the true cancer boundary, using the MALDI MS data, from the most confident cancer region given by pathologists on an adjacent slice.

Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status.

PubMed

Wang, Naitao; Dong, Bai-Jun; Quan, Yizhou; Chen, Qianqian; Chu, Mingliang; Xu, Jin; Xue, Wei; Huang, Yi-Ran; Yang, Ru; Gao, Wei-Qiang

2016-05-10

Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Intraepithelial lymphocytes in relation to NIH category IV prostatitis in autopsy prostate.

PubMed

Dikov, Dorian; Bachurska, Svitlana; Staikov, Dimitri; Sarafian, Victoria

2015-07-01

Quantitative analysis of the number, normal and pathologic ratios between lymphocytes and epithelial cells (ECs), and the significance of intraepithelial lymphocytes (IELs) in normal prostatic epithelium, benign prostatic hyperplasia (BPH), and high grade prostatic intraepithelial neoplasia (PIN) in relation to NIH category IV prostatitis (histologic prostatitis: HP) was studied in autopsy prostate. IELs were analysed in 59 autopsy prostates, which was routinely embedded in paraffin and immunohistochemically stained for CD3. An average of 300-500 ECs were counted per case. The number of IELs was calculated as the mean/100 ECs. Category IV prostatitis was evaluated using NIH consensus grading system in terms of anatomical localization and grade. In healthy individuals the mean number of IELs/100 ECs was 0.61 ± 0.34% or ≤1 lymphocyte/100 ECs, which is considered as the normal basal level of prostate IELs. In category IV prostatitis, the mean number of IELs/100 ECs was 8.53 ± 3.25% or 5-11 lymphocytes/100 ECs. The number of IELs in both around and inside inflammation areas correlated to the grade and location of HP (P < 0.0001 and P < 0.0003), the presence of acute glandular inflammation (P < 0.0001), the scattered stromal lymphocytes (P = 0.029), and BPH and PIN associated prostatic inflammation (P < 0.0001). The study presents the first attempt to examine and score the basic quantitative values of prostatic IELs in normal prostate and in relation to category IV prostatitis. The detected normal upper limit of CD3+ IELs is 1 lymphocyte/100 ECs in the normal prostate epithelium. This is considered as an organ specific characteristic of the prostate-associated lymphoid tissue (PALT). Values >5 IELs/100 ECs indicate the presence of category IV prostatitis. The severity of inflammation correlates to the number of IELs. There is an intimate link between the quantity of the IELs, the degree of the severity and the localization of category IV prostatitis. HP is a chronic and dynamic inflammatory process affecting the whole prostate gland. The increased number of IELs suggests the immune or autoimmune character of category IV prostatitis, BPH and inflammatory preneoplastic (PIN) lesions in the prostatic tumor environment. © 2015 Wiley Periodicals, Inc.

The Androgen-Regulated Calcium-Activated Nucleotidase 1 (CANT1) Is Commonly Overexpressed in Prostate Cancer and Is Tumor-Biologically Relevant in Vitro

PubMed Central

Gerhardt, Josefine; Steinbrech, Corinna; Büchi, Oralea; Behnke, Silvia; Bohnert, Annette; Fritzsche, Florian; Liewen, Heike; Stenner, Frank; Wild, Peter; Hermanns, Thomas; Müntener, Michael; Dietel, Manfred; Jung, Klaus; Stephan, Carsten; Kristiansen, Glen

2011-01-01

Previously, we identified the calcium-activated nucleotidase 1 (CANT1) transcript as up-regulated in prostate cancer. Now, we studied CANT1 protein expression in a large cohort of nearly 1000 prostatic tissue samples including normal tissue, prostatic intraepithelial neoplasia (PIN), primary carcinomas, metastases, and castrate-resistant carcinomas, and further investigated its functional relevance. CANT1 displayed predominantly a Golgi-type immunoreactivity with additional and variable cytoplasmic staining. In comparison to normal tissues, the staining intensity was significantly increased in PIN lesions and cancer. In cancer, high CANT1 levels were associated with a better prognosis, and castrate-resistant carcinomas commonly showed lower CANT1 levels than primary carcinomas. The functional role of CANT1 was investigated using RNA interference in two prostate cancer cell lines with abundant endogenous CANT1 protein. On CANT1 knockdown, a significantly diminished cell number and DNA synthesis rate, a cell cycle arrest in G1 phase, and a strong decrease of cell transmigration rate and wound healing capacity of CANT1 knockdown cells was found. However, on forced CANT1 overexpression, cell proliferation and migration remained unchanged. In summary, CANT1 is commonly overexpressed in the vast majority of primary prostate carcinomas and in the precursor lesion PIN and may represent a novel prognostic biomarker. Moreover, this is the first study to demonstrate a functional involvement of CANT1 in tumor biology. PMID:21435463

Cascaded discrimination of normal, abnormal, and confounder classes in histopathology: Gleason grading of prostate cancer

PubMed Central

2012-01-01

Background Automated classification of histopathology involves identification of multiple classes, including benign, cancerous, and confounder categories. The confounder tissue classes can often mimic and share attributes with both the diseased and normal tissue classes, and can be particularly difficult to identify, both manually and by automated classifiers. In the case of prostate cancer, they may be several confounding tissue types present in a biopsy sample, posing as major sources of diagnostic error for pathologists. Two common multi-class approaches are one-shot classification (OSC), where all classes are identified simultaneously, and one-versus-all (OVA), where a “target” class is distinguished from all “non-target” classes. OSC is typically unable to handle discrimination of classes of varying similarity (e.g. with images of prostate atrophy and high grade cancer), while OVA forces several heterogeneous classes into a single “non-target” class. In this work, we present a cascaded (CAS) approach to classifying prostate biopsy tissue samples, where images from different classes are grouped to maximize intra-group homogeneity while maximizing inter-group heterogeneity. Results We apply the CAS approach to categorize 2000 tissue samples taken from 214 patient studies into seven classes: epithelium, stroma, atrophy, prostatic intraepithelial neoplasia (PIN), and prostate cancer Gleason grades 3, 4, and 5. A series of increasingly granular binary classifiers are used to split the different tissue classes until the images have been categorized into a single unique class. Our automatically-extracted image feature set includes architectural features based on location of the nuclei within the tissue sample as well as texture features extracted on a per-pixel level. The CAS strategy yields a positive predictive value (PPV) of 0.86 in classifying the 2000 tissue images into one of 7 classes, compared with the OVA (0.77 PPV) and OSC approaches (0.76 PPV). Conclusions Use of the CAS strategy increases the PPV for a multi-category classification system over two common alternative strategies. In classification problems such as histopathology, where multiple class groups exist with varying degrees of heterogeneity, the CAS system can intelligently assign class labels to objects by performing multiple binary classifications according to domain knowledge. PMID:23110677

Isolation and Characterization of Prostate Cancer Stem Cells

DTIC Science & Technology

2012-08-01

guidelines. Adjacent prostate tissue was snap frozen in liquid Nitrogen or fixed in formalin and paraffin-embedded to evaluate anatomy and glandular...phenotypically normal and fertile [35]. We examined the prostate at 8 and 20 weeks of age and found no difference in gross anatomy and histology among WT...gross anatomy of the prostate of WT and CD1662/2 mice at 8 weeks of age, scale bar: 2 mm. Bottom: HE staining of DLP section from WT and CD1662/2 mice

Iterative normalization method for improved prostate cancer localization with multispectral magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Liu, Xin; Samil Yetik, Imam

2012-04-01

Use of multispectral magnetic resonance imaging has received a great interest for prostate cancer localization in research and clinical studies. Manual extraction of prostate tumors from multispectral magnetic resonance imaging is inefficient and subjective, while automated segmentation is objective and reproducible. For supervised, automated segmentation approaches, learning is essential to obtain the information from training dataset. However, in this procedure, all patients are assumed to have similar properties for the tumor and normal tissues, and the segmentation performance suffers since the variations across patients are ignored. To conquer this difficulty, we propose a new iterative normalization method based on relative intensity values of tumor and normal tissues to normalize multispectral magnetic resonance images and improve segmentation performance. The idea of relative intensity mimics the manual segmentation performed by human readers, who compare the contrast between regions without knowing the actual intensity values. We compare the segmentation performance of the proposed method with that of z-score normalization followed by support vector machine, local active contours, and fuzzy Markov random field. Our experimental results demonstrate that our method outperforms the three other state-of-the-art algorithms, and was found to have specificity of 0.73, sensitivity of 0.69, and accuracy of 0.79, significantly better than alternative methods.

Long Noncoding RNAs AC009014.3 and Newly Discovered XPLAID Differentiate Aggressive and Indolent Prostate Cancers.

PubMed

Cesnik, Anthony J; Yang, Bing; Truong, Andrew; Etheridge, Tyler; Spiniello, Michele; Steinbrink, Maisie I; Shortreed, Michael R; Frey, Brian L; Jarrard, David F; Smith, Lloyd M

2018-06-01

The molecular mechanisms underlying aggressive versus indolent disease are not fully understood. Recent research has implicated a class of molecules known as long noncoding RNAs (lncRNAs) in tumorigenesis and progression of cancer. Our objective was to discover lncRNAs that differentiate aggressive and indolent prostate cancers. We analyzed paired tumor and normal tissues from six aggressive Gleason score (GS) 8-10 and six indolent GS 6 prostate cancers. Extracted RNA was split for poly(A)+ and ribosomal RNA depletion library preparations, followed byRNA sequencing (RNA-Seq) using an Illumina HiSeq 2000. We developed an RNA-Seq data analysis pipeline to discover and quantify these molecules. Candidate lncRNAs were validated using RT-qPCR on 87 tumor tissue samples: 28 (GS 6), 28 (GS 3+4), 6 (GS 4+3), and 25 (GS 8-10). Statistical correlations between lncRNAs and clinicopathologic variables were tested using ANOVA. The 43 differentially expressed (DE) lncRNAs between aggressive and indolent prostate cancers included 12 annotated and 31 novel lncRNAs. The top six DE lncRNAs were selected based on large, consistent fold-changes in the RNA-Seq results. Three of these candidates passed RT-qPCR validation, including AC009014.3 (P < .001 in tumor tissue) and a newly discovered X-linked lncRNA named XPLAID (P = .049 in tumor tissue and P = .048 in normal tissue). XPLAID and AC009014.3 show promise as prognostic biomarkers. We discovered several dozen lncRNAs that distinguish aggressive and indolent prostate cancers, of which four were validated using RT-qPCR. The investigation into their biology is ongoing. Published by Elsevier Inc.

Bone marrow-derived cells contribute to regeneration of injured prostate epithelium and stroma.

PubMed

Nakata, Wataru; Nakai, Yasutomo; Yoshida, Takahiro; Sato, Mototaka; Hatano, Koji; Nagahara, Akira; Fujita, Kazutoshi; Uemura, Motohide; Nonomura, Norio

2015-06-01

Recent studies have reported that bone marrow-derived cells (BMDCs), which are recruited to sites of tissue injury and inflammation, can differentiate into epithelial cells, such as liver, lung, gastrointestinal tract, and skin cells. We investigated the role of BMDCs in contributing to regeneration of injured prostate epithelium. Using chimera rats that received allogenic bone marrow grafts from green fluorescent protein (GFP) transgenic rats after lethal whole-body irradiation, we investigated the existence of epithelial marker-positive BMDCs in injured prostate tissue caused by transurethral injection of lipopolysaccharide. Prostate tissues were harvested 2 weeks after transurethral lipopolysaccharide injection. Immunofluorescence staining showed that some cells in the stroma co-expressed GFP and pan-cytokeratin, which suggested the existence of epithelial marker-positive BMDCs. To confirm the existence of such cells, we collected bone marrow-derived non-hematopoietic cells (GFP+/CD45- cells) from the prostate by fluorescence-activated cell sorter analysis and analyzed the characteristics of the GFP+/CD45- cells. The number of cells in this population significantly increased from 0.042% to 0.492% compared with normal prostate tissue. We found by immunofluorescent analysis and RT-PCR that GFP+/CD45- cells expressed cytokeratin, which suggested that these cells have some features of epithelial cells. In the prostate obtained from the chimera rats 34 weeks after lipopolysaccharide injection, GFP- and cytokeratin-positive cells were observed in the prostate gland, which suggested that some of the cells in the prostate gland regenerated after prostate inflammation derived from bone marrow. BMDCs might be able to differentiate into prostate epithelial cells after prostatic injury. © 2015 Wiley Periodicals, Inc.

Raman spectroscopy for prostate cancer detection and characterization (Conference Presentation)

NASA Astrophysics Data System (ADS)

Aubertin, Kelly; Trinh, Quoc-Huy; Jermyn, Michael; St-Pierre, Catherine; Vladoiu, Maria-Claudia; Grosset, Andrée.-Anne; Saad, Fred; Trudel, Dominique; Leblond, Frédéric

2017-02-01

Prostate cancer is the most frequent diagnosed cancers among men. When prostate cancer occurs, the cancer does not result in only one or few localized malignant tumor, but is generally spread within the whole prostate. In order to counteract the very high level of heterogeneities exhibited by prostate tissues, we developed a method for high-resolution co-registration of Raman spectroscopy with prostate cancer diagnosis. Raman spectra were acquired on fresh ex vivo prostate within 2 hours after radical prostatectomy using a multi-wavelength hand-held contact probe. After the measurements, the prostate was reintegrated to the usual pathological workflow: formalin fixated and paraffin embedded (FFPE), and prepared for microscope histopathological analyses. The precise reconstruction of the prostate slice with hematoxylin and eosin (H and E) tissue allows the spatial correlation of the measured area (0.2 mm2) with the correspondent histopathological information, for point-by-point diagnosis determination. The tissue was classified into groups (normal/cancer) and subgroups according to the percentage of benign glands, stroma or cancer. Different machine learning algorithms were tested to classify the spectra with increasing levels of categorization. Preliminary results showed that Raman spectroscopy is capable of detecting prostate cancer with an accuracy >90%. In addition, high percentages of stroma (vs. glands) have been correlated with spectral signature of collagen, which is the main constituent of extracellular matrix.

[Influence of Kudou Shencha decotion on INF-gamma, ICAM-1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats].

PubMed

Xia, Li-Ying; Liu, Wei-Jia; Li, Ming-Xi; Ge, Wen-Jin; Gao, Xue-Min; Zhang, Jian-Jun

2014-05-01

To investigate the influence of Kudou Shencha decotion on INF-y, ICAM-1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats. Forty Wistar male rats were divided into 5 groups randomly: Kudou Shencha decotion group with high dosage and low dosage, Qianleitai group, the model control group and normal group. The rat model of chronic nonbacterial prostatitis was established by multiple hypodermical injection of the suspension of prostatic protein purification with Freund's completed adjuvant. The level of intercellular adhesion molecule (ICAM-1), interferon gamma (INF-gamma) and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay (ELISA). The content of ICAM-1 and MCP-1 in the model group was higher than that of the normal group (P < 0.05), the content of ICAM-1 was obviously decreased in Kudou Shencha decotion group with high dosage (P <0.05), the contents of MCP-1 were all obviously decreased in Kudou Shencha decotion groups and Qianlietai group. Compared with the model group, the contents of INF-gamma in all treatment groups were decreased insignificantly. Kudou Shencha decotion has the action of lowering the level of ICAM-1 and MCP-1, which may be one of the mechanisms of Kudou Shencha decotion in the therapy of chronic prostatitis.

A microdissection approach to detect molecular markers during progression of prostate cancer.

PubMed Central

Berthon, P.; Dimitrov, T.; Stower, M.; Cussenot, O.; Maitland, N. J.

1995-01-01

To investigate the underlying mechanisms of carcinogenesis, we have developed a technique to determine the frequency of genetic changes in prostatic carcinoma tissue. We have demonstrated that at a ratio of between 1:4 and 1:9 mutant-normal alleles, the signal from a mutant TP53 allele is not apparent after polymerase chain reaction (PCR) amplification and further direct sequencing or single-strand conformation polymorphism (SSCP) analysis. To bypass this problem, which is inherent in the heterogeneity of the prostate tissue and of the tumour, we selected areas of graded prostate tumours (Gleason score) from cryosectioned preparations and microdissected these cells (20-100 cells). After anionic resin removal of proteins, PCR amplification of TP53 gene exons 5/6 and SSCP analysis, an abnormal SSCP band shift was observed in suspected tumour cells, compared with microdissected stromal cells used as an internal control, while (1) a crude preparation of tissue DNA carrying the tumour did not show any abnormality and (2) immunostaining by a set of monoclonal antibodies against TP53 protein remained negative. Nucleotide sequence analysis of the different bands confirmed the presence of a mutation in the TP53 gene exon 6 position 13,336 in an abnormal band for one specimen, while no mutation was detected in the normal SSCP band. By targeting recognised tumour cells we can find DNA mutations which are undetectable using the standard technique of whole-tissue DNA extraction, particularly in a heterogeneous tumour such as carcinoma of the prostate. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7547246

Several genes encoding ribosomal proteins are over-expressed in prostate-cancer cell lines: confirmation of L7a and L37 over-expression in prostate-cancer tissue samples.

PubMed

Vaarala, M H; Porvari, K S; Kyllönen, A P; Mustonen, M V; Lukkarinen, O; Vihko, P T

1998-09-25

A cDNA library specific for mRNA over-expressed in prostate cancer was generated by subtractive hybridization of transcripts originating from prostatic hyperplasia and cancer tissues. cDNA encoding ribosomal proteins L4, L5, L7a, L23a, L30, L37, S14 and S18 was found to be present among 100 analyzed clones. Levels of ribosomal mRNA were significantly higher at least in one of the prostate-cancer cell lines, LNCaP, DU-145 and PC-3, than in hyperplastic tissue, as determined by slot-blot hybridization. Furthermore, L23a- and S14-transcript levels were significantly elevated in PC-3 cells as compared with those in the normal prostate epithelial cell line PrEC. Generally, dramatic changes in the mRNA content of the ribosomal proteins were not detected, the most evident over-expression being that of L37 mRNA, which was 3.4 times more abundant in LNCaP cells than in hyperplastic prostate tissue. The over-expression of L7a and L37 mRNA was confirmed in prostate-cancer tissue samples by in situ hybridization. Elevated cancer-related expression of L4 and L30 has not been reported, but levels of the other ribosomal proteins are known to be increased in several types of cancers. These results therefore suggest that prostate cancer is comparable with other types of cancers, in that a larger pool of some ribosomal proteins is gained during the transformation process, by an unknown mechanism.

Prostate stem cell antigen is overexpressed in human transitional cell carcinoma.

PubMed

Amara, N; Palapattu, G S; Schrage, M; Gu, Z; Thomas, G V; Dorey, F; Said, J; Reiter, R E

2001-06-15

Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigens, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. In addition to its expression in normal and malignant prostate, we recently reported that PSCA is expressed at low levels in the transitional epithelium of normal bladder. In the present study, we compared the expression of PSCA in normal and malignant urothelial tissues to assess its potential as an immunotherapeutic target in transitional cell carcinoma (TCC). Immunohistochemical analysis of PSCA protein expression was performed on tissue sections from 32 normal bladder specimens, as well as 11 cases of low-grade transitional cell dysplasia, 21 cases of carcinoma in situ (CIS), 38 superficial transitional cell tumors (STCC, stages T(a)-T(1)), 65 muscle-invasive TCCs (ITCCs, stages T(2)-T(4)), and 7 bladder cancer metastases. The level of PSCA protein expression was scored semiquantitatively by assessing both the intensity and frequency (i.e., percentage of positive tumor cells) of staining. We also examined PSCA mRNA expression in a representative sample of normal and malignant human transitional cell tissues. In normal bladder, PSCA immunostaining was weak and confined almost exclusively to the superficial umbrella cell layer. Staining in CIS and STCC was more intense and uniform than that seen in normal bladder epithelium (P < 0.001), with staining detected in 21 (100%) of 21 cases of CIS and 37 (97%) of 38 superficial tumors. PSCA protein was also detected in 42 (65%) of 65 of muscle-invasive and 4 (57%) of 7 metastatic cancers, with the highest levels of PSCA expression (i.e., moderate-strong staining in >50% of tumor cells) seen in 32% of invasive and 43% of metastatic samples. Higher levels of PSCA expression correlated with increasing tumor grade for both STCCs and ITCCs (P < 0.001). Northern blot analysis confirmed the immunohistochemical data, showing a dramatic increase in PSCA mRNA expression in two of five muscle-invasive transitional cell tumors when compared with normal samples. Confocal microscopy demonstrated that PSCA expression in TCC is confined to the cell surface. These data demonstrate that PSCA is overexpressed in a majority of human TCCs, particularly CIS and superficial tumors, and may be a useful target for bladder cancer diagnosis and therapy.

Optimizing the parameters of the Lyman-Kutcher-Burman, Källman, and Logit+EUD models for the rectum - a comparison between normal tissue complication probability and clinical data

NASA Astrophysics Data System (ADS)

Trojková, Darina; Judas, Libor; Trojek, Tomáš

2014-11-01

Minimizing the late rectal toxicity of prostate cancer patients is a very important and widely-discussed topic. Normal tissue complication probability (NTCP) models can be used to evaluate competing treatment plans. In our work, the parameters of the Lyman-Kutcher-Burman (LKB), Källman, and Logit+EUD models are optimized by minimizing the Brier score for a group of 302 prostate cancer patients. The NTCP values are calculated and are compared with the values obtained using previously published values for the parameters. χ2 Statistics were calculated as a check of goodness of optimization.

Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

PubMed

Maund, Sophia Lisette; Nolley, Rosalie; Peehl, Donna Mae

2014-02-01

Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies. Problems encountered include degeneration of differentiated secretory cells, basal cell hyperplasia, and poor survival of PCa. Here, we optimized, characterized, and applied a TSC model of primary human PCa and benign prostate tissue that overcomes many deficiencies of current in vitro models. Tissue cores from fresh prostatectomy specimens were precision-cut at 300 μm and incubated in a rotary culture apparatus. The ability of varied culture conditions to faithfully maintain benign and cancer cell and tissue structure and function over time was evaluated by immunohistological and biochemical assays. After optimization of the culture system, molecular and cellular responses to androgen ablation and to piperlongumine (PL), purported to specifically reduce androgen signaling in PCa, were investigated. Optimized culture conditions successfully maintained the structural and functional fidelity of both benign and PCa TSCs for 5 days. TSCs exhibited androgen dependence, appropriately undergoing ductal degeneration, reduced proliferation, and decreased prostate-specific antigen expression upon androgen ablation. Further, TSCs revealed cancer-specific reduction of androgen receptor and increased apoptosis upon treatment with PL, validating data from cell lines. We demonstrate a TSC model that authentically recapitulates the structural, cellular, and genetic characteristics of the benign and malignant human prostate, androgen dependence of the native tissue, and cancer-specific response to a potentially new therapeutic for PCa. The work described herein provides a basis for advancing the experimental utility of the TSC model.

Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice.

PubMed

Kleinberg, David L; Ruan, Weifeng; Yee, Douglas; Kovacs, Kalman T; Vidal, Sergio

2007-03-01

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.

Noninvasive bioluminescence imaging of normal and spontaneously transformed prostate tissue in mice.

PubMed

Lyons, Scott K; Lim, Ed; Clermont, Anne O; Dusich, Joan; Zhu, Lingyun; Campbell, Kenneth D; Coffee, Richard J; Grass, David S; Hunter, John; Purchio, Tony; Jenkins, Darlene

2006-05-01

Several transgenic mouse models of prostate cancer have been developed recently that are able to recapitulate many key biological features of the human condition. It would, therefore, be desirable to employ these models to test the efficacy of new therapeutics before clinical trial; however, the variable onset and non-visible nature of prostate tumor development limit their use for such applications. We now report the generation of a transgenic reporter mouse that should obviate these limitations by enabling noninvasive in vivo bioluminescence imaging of normal and spontaneously transformed prostate tissue in the mouse. We used an 11-kb fragment of the human prostate-specific antigen (PSA) promoter to achieve specific and robust expression of firefly luciferase in the prostate glands of transgenic mice. Ex vivo bioluminescence imaging and in situ hybridization analysis confirmed that luciferase expression was restricted to the epithelium in all four lobes of the prostate. We also show that PSA-Luc mice exhibit decreased but readily detectable levels of in vivo bioluminescence over extended time periods following androgen ablation. These results suggest that this reporter should enable in vivo imaging of both androgen-dependent and androgen-independent prostate tumor models. As proof-of-principle, we show that we could noninvasively image SV40 T antigen-induced prostate tumorigenesis in mice with PSA-Luc. Furthermore, we show that our noninvasive imaging strategy can be successfully used to image tumor response to androgen ablation in transgenic mice and, as a result, that we can rapidly identify individual animals capable of sustaining tumor growth in the absence of androgen.

Prostate Histotripsy in an Anticoagulated Canine Model

PubMed Central

Wheat, Jeffery C.; Hall, Timothy L.; Hempel, Christopher R.; Cain, Charles A.; Xu, Zhen; Roberts, William W.

2009-01-01

Purpose Histotripsy is a non-invasive ultrasound technology which induces microbubble formation (cavitation) within tissues producing mechanical tissue fractionation. During initial in-vivo feasibility canine studies of prostate ablation, minimal hematuria was observed. In the current study, we sought to further explore this phenomenon by performing extensive prostate histotripsy treatments in anticoagulated canines. Materials and Methods Histotripsy was performed on 9 canine subjects pre-treated with 6 mg of oral warfarin for 3 to 5 days using an extracorporeal 750 kHz therapeutic ultrasound transducer delivering acoustic pulses to the prostatic urethra and periurethral parenchyma. After 7–28 days, the subjects were euthanized, transrectal prostate ultrasound was performed and the prostate was harvested. Serum hemoglobin and International Normalization Ratio (INR) were measured immediately prior to histotripsy treatment and at euthanasia. Results Mean treatment INR was 4.6 (median 2.4, range 1.2 to 11.3). There was no clinically significant change in hemoglobin concentration at euthanasia compared to baseline. At harvest, histologic sections of the prostate revealed a large cavity corresponding to the planned treatment volume incorporating the prostatic urethra and parenchyma in all subjects. Urine was clear within 2 days of treatment and no blood clots were seen. Conclusions Despite therapeutic and supratherapeutic anticoagulation, histotripsy resulted in minimal bleeding despite significant fractionation and tissue debulking of the prostate. These results have prompted further studies to understand the mechanism of non-thermal hemostasis underlying histotripsy. PMID:19931897

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

PubMed Central

Gay, Hiram A.; Barthold, H. Joseph; O’Meara, Elizabeth; Bosch, Walter R.; El Naqa, Issam; Al-Lozi, Rawan; Rosenthal, Seth A.; Lawton, Colleen; Lee, W. Robert; Sandler, Howard; Zietman, Anthony; Myerson, Robert; Dawson, Laura A.; Willett, Christopher; Kachnic, Lisa A.; Jhingran, Anuja; Portelance, Lorraine; Ryu, Janice; Small, William; Gaffney, David; Viswanathan, Akila N.; Michalski, Jeff M.

2012-01-01

Purpose To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. Methods and Materials One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. Results The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. Conclusions Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research. PMID:22483697

Immunohistochemical analysis of RNA-induced silencing complex-related proteins AGO2 and TNRC6A in prostate and esophageal cancers.

PubMed

Yoo, Nam Jin; Hur, Soo Young; Kim, Min Sung; Lee, Ji Youl; Lee, Sug Hyung

2010-04-01

Evidence exists that microRNA (miRNA), which regulates gene expression, is frequently deregulated in cancers. A mature miRNA directs a RNA-induced silencing complex (RISC) to its target messenger RNA, and causes inhibition of gene transcription. Ago proteins and TNRC proteins are main components of the RISC and participate in miRNA-induced gene silencing. However, expression status of Ago and TNRC proteins has not yet been studied in human cancer tissues. In this study, we attempted to explore whether expressions of Ago2 and TNRC6A are altered in prostate carcinomas (PCA) and esophageal squamous cell carcinomas (ESCC). We analyzed the expression of Ago2 and TNRC6A in 107 PCA and 58 ESCC tissues by immunohistochemistry using a tissue microarray (TMA) method. In the prostate, Ago2 was not expressed in normal glandular cells, while it was expressed in 50.0% of prostate intraepithelial neoplasia (PIN) and 57.0% of the PCA. TNRC6A was not expressed in normal prostate cells, while it was expressed in 55.0% of the PIN and 63.6% of the PCA in cytoplasm and nucleus. In the esophagus, neither Ago2 nor TNRC6A was expressed in normal squamous cells, while Ago2 and TNRC6A were expressed in 58.6% and 62.1% of the ESCC, respectively. However, neither the expression of Ago2 or TNRC6A was associated with pathologic characteristics of the cancers, including age, sex, Gleason score (PCA) and stage. The increased expressions of Ago2 and TNRC6A in both PCA and ESCC compared with their normal cells suggested that over-expression of these proteins may be related to miRNA functions and might play a role in tumorigenesis of PCA and ESCC.

Methylation profiling identified novel differentially methylated markers including OPCML and FLRT2 in prostate cancer.

PubMed

Wu, Yu; Davison, Jerry; Qu, Xiaoyu; Morrissey, Colm; Storer, Barry; Brown, Lisha; Vessella, Robert; Nelson, Peter; Fang, Min

2016-04-02

To develop new methods to distinguish indolent from aggressive prostate cancers (PCa), we utilized comprehensive high-throughput array-based relative methylation (CHARM) assay to identify differentially methylated regions (DMRs) throughout the genome, including both CpG island (CGI) and non-CGI regions in PCa patients based on Gleason grade. Initially, 26 samples, including 8 each of low [Gleason score (GS) 6] and high (GS ≥7) grade PCa samples and 10 matched normal prostate tissues, were analyzed as a discovery cohort. We identified 3,567 DMRs between normal and cancer tissues, and 913 DMRs distinguishing low from high-grade cancers. Most of these DMRs were located at CGI shores. The top 5 candidate DMRs from the low vs. high Gleason comparison, including OPCML, ELAVL2, EXT1, IRX5, and FLRT2, were validated by pyrosequencing using the discovery cohort. OPCML and FLRT2 were further validated in an independent cohort consisting of 20 low-Gleason and 33 high-Gleason tissues. We then compared patients with biochemical recurrence (n=70) vs. those without (n=86) in a third cohort, and they showed no difference in methylation at these DMR loci. When GS 3+4 cases and GS 4+3 cases were compared, OPCML-DMR methylation showed a trend of lower methylation in the recurrence group (n=30) than in the no-recurrence (n=52) group. We conclude that whole-genome methylation profiling with CHARM revealed distinct patterns of differential DNA methylation between normal prostate and PCa tissues, as well as between different risk groups of PCa as defined by Gleason scores. A panel of selected DMRs may serve as novel surrogate biomarkers for Gleason score in PCa.

Effects of TOOKAD-PDT on canine prostates pre-treated with ionizing radiation

NASA Astrophysics Data System (ADS)

Chen, Qun; Huang, Zheng; Luck, David L.; Beckers, Jill; Trncic, Nadira; LaRue, Susan M.; Brun, Pierre-Herve; Wilson, Brian C.; Hetzel, Fred W.

2003-06-01

PDT in prostate cancer will likely be implemented clinically with patients who have failed prior ionizing radiation therapy (RT). The current study is to develop an in vivo model to evaluate the effects of PDT on prostatic tissue after RT. To produce a physiological and anatomical environment in prostate similar to that in patients who have failed RT, canine prostates (n=4) were subjected to a definitive course of ionizing radiation therapy (2.7 Gy x 20 fractions) 5 to 6 months prior to PDT. A laparotomy was performed to expose the prostate for PDT. Second generation photosensitizer Tookad (Palladium-Bacteriopheophorbide, Steba Biotech, The Netherlands) acts primarily on tissue vasculature and is very effective in destroying normal prostatic tissue, as shown by our prior studies. Due to the extremely fast clearance of the photosensitizer, interstitial light irradiation (760 nm, 50-200 J/cm, 150 mW/cm from a 1 cm diffuser fiber) was delivered 4 minutes after the onset of Tookad infusion (i.v. 2.5 mg/ml, 2 mg/kg, total infusion time 10 min). The prostates were harvested for histopathology one week after PDT. At one week, the lesions were characterized by acute hemorrhagic necrosis with patchy sub-capsular hyperemia and edema. The maximum lesion diameter for 50, 100 and 200 J/cm PDT was approximately 15, 20 and 28 mm, respectively. The lesion size is well correlated with light fluence and comparable to that in prostates treated with identical PDT doses but without prior-RT. Under light-microscopy, the PDT induced necrosis is clearly distinguishable from the radiation induced fibrosis. No urethral lesions were observed. Dyer"s Verhoeff stain showed the loss of stromal connective tissue and the acinar collagen in the PDT treated area. There was no noticeable damage on the bladder or underlying colon section. In conclusion, Tookad-PDT can effectively destroy prostate tissue with prior-RT induced fibrosis, thus, may provide an alternative modality for those prostate-cancer patients who have failed RT.

Prostate-specific Membrane Antigen PET: Clinical Utility in Prostate Cancer, Normal Patterns, Pearls, and Pitfalls.

PubMed

Hofman, Michael S; Hicks, Rodney J; Maurer, Tobias; Eiber, Matthias

2018-01-01

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in prostate cancer. Radiolabeled small molecules that bind with high affinity to its active extracellular center have emerged as a potential new diagnostic standard of reference for prostate cancer, resulting in images with extraordinary tumor-to-background contrast. Currently, gallium 68 ( 68 Ga)-PSMA-11 (or HBED-PSMA) is the most widely used radiotracer for PSMA positron emission tomography (PET)/computed tomography (CT) or PSMA PET/magnetic resonance (MR) imaging. Evolving evidence demonstrates superior sensitivity and specificity of PSMA PET compared to conventional imaging, with frequent identification of subcentimeter prostate cancer lesions. PSMA PET is effective for imaging disease in the prostate, lymph nodes, soft tissue, and bone in a "one-stop-shop" examination. There is emerging evidence for its clinical value in staging of high-risk primary prostate cancer and localization of disease in biochemical recurrence. The high sensitivity provided by PSMA PET, with frequent identification of small-volume disease, is redefining patterns of disease spread compared with those seen at conventional imaging. In metastatic castration-resistant prostate cancer, PSMA PET is frequently used for theranostic selection (eg, lutetium 177-PSMA radionuclide therapy), but its potential use for therapy monitoring is still under debate. However, evidence on its proper use to improve patient-related outcomes, particularly in the setting of early biochemical recurrence and targeted treatment of oligometastatic disease, is still missing. Despite the term prostate specific, PSMA functions as a folate hydrolase and is expressed in a range of normal tissues and in other benign and malignant processes. Knowledge of its physiologic distribution and other causes of uptake is essential to minimize false-positive imaging findings. © RSNA, 2018.

Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation

PubMed Central

Damodarasamy, Mamatha; Vernon, Robert B.; Chan, Christina K.; Plymate, Stephen R.; Wight, Thomas N.

2015-01-01

The extracellular matrix (ECM) of the prostate, which is comprised primarily of collagen, becomes increasingly disorganized with age, a property that may influence the development of hyperplasia and cancer. Collageous ECM extracted from the tails of aged mice exhibits many characteristics of collagen in aged tissues, including the prostate. When polymerized into a 3-dimensional (3D) gel, these collagen extracts can serve as models for the study of specific cell-ECM interactions. In the present study, we examined the behaviors of human prostatic epithelial cell lines representing normal prostate epithelial cells (PEC), benign prostatic hyperplasia (BPH-1), and adenocarcinoma (LNCaP) cultured in contact with 3D gels made from collagen extracts of young and aged mice. We found that proliferation of PEC, BPH-1, and LNCaP cells were all increased by culture on aged collagen gels relative to young collagen gels. In examining age-associated differences in the composition of the collagen extracts, we found that aged and young collagen had a similar amount of several collagen-associated ECM components, but aged collagen had a much greater content of the glycosaminoglycan hyaluronan (HA) than young collagen. The addition of HA (of similar size and concentration to that found in aged collagen extracts) to cells placed in young collagen elicited significantly increased proliferation in BPH-1 cells, but not in PEC or LNCaP cells, relative to controls not exposed to HA. Of note, histochemical analyses of human prostatic tissues showed significantly higher expression of HA in BPH and prostate cancer stroma relative to stroma of normal prostate. Collectively, these results suggest that changes in ECM involving increased levels of HA contribute to the growth of prostatic epithelium with aging. PMID:25124870

Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.

PubMed

Segawa, Yoshihiro; Yoshimura, Rikio; Hase, Taro; Nakatani, Tatsuya; Wada, Seiji; Kawahito, Yutaka; Kishimoto, Taketoshi; Sano, Hajime

2002-05-01

Recent studies have demonstrated that peroxisome proliferator activator-receptors (PPAR)-gamma is expressed in some cancer cells such as breast, lung, and gastric cancer, and its ligand induces growth arrest of these cancer cells through apoptosis. However, the expression and localization of PPARs in prostate have not been examined. In this study, PPARs expression was investigated in human prostate cancer (PC), prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues. Tumor specimens were obtained from 156 patients with PC, 15 with PIN, 20 with BPH, and 12 patients with NP tissues. The expressions were investigated by RT-PCR and immunohistochemical methods. Immunoreactive PPAR-alpha and -beta were significantly apparent in PC tissues. Marked expressions of PPAR-alpha and -beta were also detected in PIN, BPH, and NP groups. However, very weak or no expression of immunoreactive PPAR-gamma was found in BPH and NP cases. In contrast, we found significant expression of immunoreactive PPAR-gamma in cancer cells in PC group and in PIN group. Our results demonstrated that PPAR-gamma is induced in PC, and suggest that PPAR-gamma ligands may mediate its own potent antiproliferative effect against PC cells through differentiation. Copyright 2002 Wiley-Liss, Inc.

Fusion of Ultrasound Tissue-Typing Images with Multiparametric MRI for Image-guided Prostate Cancer Radiation Therapy

DTIC Science & Technology

2014-10-01

work under the guidance of an outstanding mentor team at Emory Winship Cancer Institute. I took three courses ( Medical Health Physics, Radiation...and Late Normal-Tissue Toxicity in Breast- Cancer Radiotherapy”, Medical Physics, 40(6):379, 2013. 5. Yang X, Liu T, Curran W and Torres M...Analysis for Normal-tissue Toxicity: A Prospective Ultrasound Study of Acute Toxicity in Breast- Cancer Radiotherapy", Medical Physics 41 (6), 482-482

RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH, primary and metastatic prostate cancer disease.

PubMed

Christoph, Frank; König, Frank; Lebentrau, Steffen; Jandrig, Burkhard; Krause, Hans; Strenziok, Romy; Schostak, Martin

2018-02-01

The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level. Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples. The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p < 0.001) as compared to BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (< 7 or ≥ 7, p = 0.028) or PSA level (< 10 or ≥ 10 µg/l, p = 0.004). RANKL and OPG mRNA expression was higher in tumour tissue from patients with metastatic compared to local disease. The RANKL/OPG ratio was low in normal prostate tissue and high tumours with bone metastases (p < 0.05). Expression of all three cytokines was high in BPH tissue but did not exceed as much as in the tumour tissue. We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.

Deregulation of an imprinted gene network in prostate cancer

PubMed Central

Ribarska, Teodora; Goering, Wolfgang; Droop, Johanna; Bastian, Klaus-Marius; Ingenwerth, Marc; Schulz, Wolfgang A

2014-01-01

Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes. PMID:24513574

Deregulation of an imprinted gene network in prostate cancer.

PubMed

Ribarska, Teodora; Goering, Wolfgang; Droop, Johanna; Bastian, Klaus-Marius; Ingenwerth, Marc; Schulz, Wolfgang A

2014-05-01

Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.

Transcriptome instability as a molecular pan-cancer characteristic of carcinomas.

PubMed

Sveen, Anita; Johannessen, Bjarne; Teixeira, Manuel R; Lothe, Ragnhild A; Skotheim, Rolf I

2014-08-10

We have previously proposed transcriptome instability as a genome-wide, pre-mRNA splicing-related characteristic of colorectal cancer. Here, we explore the hypothesis of transcriptome instability being a general characteristic of cancer. Exon-level microarray expression data from ten cancer datasets were analyzed, including breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, neuroblastoma, and prostate cancer (555 samples), as well as paired normal tissue samples from the colon, lung, prostate, and stomach (93 samples). Based on alternative splicing scores across the genomes, we calculated sample-wise relative amounts of aberrant exon skipping and inclusion. Strong and non-random (P < 0.001) correlations between these estimates and the expression levels of splicing factor genes (n = 280) were found in most cancer types analyzed (breast-, cervical-, colorectal-, lung- and prostate cancer). This suggests a biological explanation for the splicing variation. Surprisingly, these associations prevailed in pan-cancer analyses. This is in contrast to the tissue and cancer specific patterns observed in comparisons across healthy tissue samples from the colon, lung, prostate, and stomach, and between paired cancer-normal samples from the same four tissue types. Based on exon-level expression profiling and computational analyses of alternative splicing, we propose transcriptome instability as a molecular pan-cancer characteristic. The affected cancers show strong and non-random associations between low expression levels of splicing factor genes, and high amounts of aberrant exon skipping and inclusion, and vice versa, on a genome-wide scale.

Aurora-A over-expression in high-grade PIN lesions and prostate cancer.

PubMed

Buschhorn, Holly McKlveen; Klein, Robert R; Chambers, Susan M; Hardy, Margaret C; Green, Sylvan; Bearss, David; Nagle, Raymond B

2005-09-01

Over-expression of Aurora-A (Aurora 2 kinase, STK-15), a protein found in centrosomes thought to be associated with genetic instability, has been previously documented in prostate cancer [Pihan et al.: Cancer Res 61(5):2212-2219, 2001]. It is unknown if this protein is also over-expressed in high-grade prostatic intraepithelial neoplasia (PIN) lesions. PIN lesions were examined for increased Aurora-A using immunohistochemical staining on archival paraffin embedded prostatectomy tissue. Aurora-A expression was scored using size, number, and staining intensity. Protein expression was examined and compared between stromal cells, normal glands, high-grade PIN lesions, and invasive cancer. Immunohistochemistry shows an increased expression of Aurora-A in 96% of high-grade PIN cases, and 98% in cancer lesions. Twenty-nine percent of cases of normal glands from cancerous prostates also showed increased Aurora-A expression. Over-expression of Aurora-A is present in some normal and the majority of high-grade PIN lesions indicating that this may be an early event that leads to the genetic instability seen in prostate carcinogenesis. Copyright 2005 Wiley-Liss, Inc.

Infiltrating mast cells enhance benign prostatic hyperplasia through IL-6/STAT3/Cyclin D1 signals

PubMed Central

Ou, Zhenyu; He, Yao; Qi, Lin; Zu, Xiongbin; Wu, Longxiang; Cao, Zhenzhen; Li, Yuan; Liu, Longfei; Dube, Daud Athanasius; Wang, Zhi; Wang, Long

2017-01-01

Early evidences have showed that mast cells could infiltrate into benign prostatic hyperplasia (BPH) tissues, but the exact role of mast cells in BPH development remains unclear. In this study, we identified more mast cells existing in human BPH tissues compared with that in the normal prostate. In the in vitro co-culture system, BPH-1 prostate cells promoted activation and migration of mast cells, and mast cells conversely stimulated BPH-1 cells proliferation significantly. Molecular analysis demonstrated that mast cell-derived interleukin 6 (IL-6) could activate STAT3/Cyclin D1 signals in BPH-1 cells. Blocking IL-6 or STAT3 partially reverse the capacity of mast cells to enhance BPH-1 cell proliferation. Our findings suggest that infiltrating mast cells in BPH tissues could promote BPH development via IL-6/STAT3/Cyclin D1 signals. Therefore, targeting infiltrating mast cells may improve the therapeutic effect of BPH. PMID:28938626

The oncogenic gene fusion TMPRSS2: ERG is not a diagnostic or prognostic marker for ovarian cancer

PubMed Central

Huang, Lillian; Schauer, Isaiah G; Zhang, Jing; Mercado-Uribe, Imelda; Deavers, Michael T; Huang, Jiaoti; Liu, Jinsong

2011-01-01

TMPRSS2:ERG is a gene fusion resulting from the chromosomal rearrangement of the androgen-regulated TMPRSS2 gene and the ETS transcription factor ERG, leading to the over-expression of the oncogenic molecule ERG. This gene rearrangement has been found in approximately half of all prostate cancers and ERG overexpression is considered as a novel diagnostic marker for prostate carcinoma. However, little is known about the role of the TMPRSS2:ERG gene fusion in ovarian cancer. The purpose of this study was to test ERG expression in ovarian cancer and its potential as a diagnostic marker for ovarian carcinoma progression. A tissue microarray containing 180 ovarian cancer tissues of various pathological types and grades were examined by immunohistochemical analysis for expression of ERG. We also used 40 prostate carcinoma tissues and 40 normal tissues for comparison in parallel experiments. ERG-positive expression was detected in 40% of the prostate tumor cancer, as well as in internal positive control endothelial cells, confirming over-expression of ERG in prostate cancer at relatively the same rate observed by others. In contrast, all of the ovarian tumor patient tissues of varying histologic types were ERG-negative, despite some positivity in endothelial cells. These results suggest that the oncogenic gene fusion TMPRSS2:ERG does not occur in ovarian cancer relative to prostate cancer. Therefore, development of ERG expression profile would not be a useful diagnostic or prognostic marker for ovarian cancer patient screening. PMID:22076164

The oncogenic gene fusion TMPRSS2: ERG is not a diagnostic or prognostic marker for ovarian cancer.

PubMed

Huang, Lillian; Schauer, Isaiah G; Zhang, Jing; Mercado-Uribe, Imelda; Deavers, Michael T; Huang, Jiaoti; Liu, Jinsong

2011-01-01

TMPRSS2:ERG is a gene fusion resulting from the chromosomal rearrangement of the androgen-regulated TMPRSS2 gene and the ETS transcription factor ERG, leading to the over-expression of the oncogenic molecule ERG. This gene rearrangement has been found in approximately half of all prostate cancers and ERG overexpression is considered as a novel diagnostic marker for prostate carcinoma. However, little is known about the role of the TMPRSS2:ERG gene fusion in ovarian cancer. The purpose of this study was to test ERG expression in ovarian cancer and its potential as a diagnostic marker for ovarian carcinoma progression. A tissue microarray containing 180 ovarian cancer tissues of various pathological types and grades were examined by immunohistochemical analysis for expression of ERG. We also used 40 prostate carcinoma tissues and 40 normal tissues for comparison in parallel experiments. ERG-positive expression was detected in 40% of the prostate tumor cancer, as well as in internal positive control endothelial cells, confirming over-expression of ERG in prostate cancer at relatively the same rate observed by others. In contrast, all of the ovarian tumor patient tissues of varying histologic types were ERG-negative, despite some positivity in endothelial cells. These results suggest that the oncogenic gene fusion TMPRSS2:ERG does not occur in ovarian cancer relative to prostate cancer. Therefore, development of ERG expression profile would not be a useful diagnostic or prognostic marker for ovarian cancer patient screening.

Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer.

PubMed

Sun, Yue; Du, Chengli; Wang, Bo; Zhang, Yanling; Liu, Xiaoyan; Ren, Guoping

2014-07-18

eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Finasteride Treatment Alters Tissue Specific Androgen Receptor Expression in Prostate Tissues

PubMed Central

Bauman, Tyler M.; Sehgal, Priyanka D.; Johnson, Karen A.; Pier, Thomas; Bruskewitz, Reginald C.; Ricke, William A.; Huang, Wei

2014-01-01

BACKGROUND Normal and pathologic growth of the prostate is dependent on the synthesis of dihydrotestosterone (DHT) from testosterone by 5α-reductase. Finasteride is a selective inhibitor of 5α-reductase 2, one isozyme of 5α-reductase found in abundance in the human prostate. The objective of this study was to investigate the effects of finasteride on androgen receptor expression and tissue morphology in human benign prostatic hyperplasia specimens. METHODS Patients undergoing transurethral resection of the prostate and either treated or not treated with finasteride between 2004 and 2010 at the University of Wisconsin-Hospital were retrospectively identified using an institutional database. Prostate specimens from each patient were triple-stained for androgen receptor, prostate-specific antigen, and basal marker cytokeratin 5. Morphometric analysis was performed using the multispectral imaging, and results were compared between groups of finasteride treated and non-treated patients. RESULTS Epithelial androgen receptor but not stromal androgen receptor expression was significantly lower in patients treated with finasteride than in non-treated patients. Androgen receptor-regulated prostate-specific antigen was not significantly decreased in finasteride-treated patients. Significant luminal epithelial atrophy and basal cell hyperplasia were prevalent in finasteride treated patients. Epithelial androgen receptor expression was highly correlated to the level of luminal epithelial atrophy. CONCLUSIONS In this study, finasteride decreased the expression of epithelial androgen receptor in a tissue specific manner. The correlation between epithelial androgen receptor and the extent of luminal epithelial atrophy suggests that epithelial androgen receptor may be directly regulating the atrophic effects observed with finasteride treatment. PMID:24789081

Elevated levels of the mismatch repair protein PMS2 are associated with prostate cancer.

PubMed

Norris, Alixanna M; Woodruff, R D; D'Agostino, Ralph B; Clodfelter, Jill E; Scarpinato, Karin Drotschmann

2007-02-01

Defects in mismatch repair (MMR) proteins have been identified in various types of cancer. However, an association with prostate cancer has been controversial. Defective MMR results in genome instability with detrimental consequences that significantly contribute to tumorigenesis. This study determined alterations in key MMR protein levels in prostate cancer with the goal to identify prognostic markers. Prostatectomy samples were immunohistochemically stained and the relative presence or absence of key proteins MSH2, MLH1, and PMS2 determined. Cancer tissue of distinct grades was compared with the normal surrounding tissue. Microsatellite instability (MSI) in altered tissues was determined according to NCI guidelines. In contrast to reports that associate a lack of individual MMR proteins with tumorigenesis, a significant increase in PMS2 levels was identified in PIN lesions and prostate cancer tissue. This elevation in PMS2 was independent of changes in levels in its heterodimeric partner, MLH1. Prostate tumors with elevated levels of PMS2 were genetically unstable, which was corrected by MLH1 co-elevation. This is the first documentation of detrimental consequences associated with the increase in a MMR protein in human cancer. This study recognizes PMS2 elevation as a prognostic marker in pre-neoplastic and prostate cancer lesions. This result has significant implications for future diagnostic and treatment measures. (c) 2006 Wiley-Liss, Inc.

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gay, Hiram A., E-mail: hgay@radonc.wustl.edu; Barthold, H. Joseph; Beth Israel Deaconess Medical Center, Boston, MA

2012-07-01

Purpose: To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. Methods and Materials: One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The followingmore » were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. Results: The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa{sub R}, Adnexa{sub L}, Prostate, SeminalVesc, PenileBulb, Femur{sub R}, and Femur{sub L}. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. Conclusions: Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.« less

SU-E-J-181: Effect of Prostate Motion On Combined Brachytherapy and External Beam Dose Based On Daily Motion of the Prostate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Narayana, V; McLaughlin, P; University of Michigan, Ann Arbor, MI

2015-06-15

Purpose: In this study, the adequacy of target expansions on the combined external beam and implant dose was examined based on the measured daily motion of the prostate. Methods: Thirty patients received an I–125 prostate implant prescribed to dose of 90Gy. This was followed by external beam to deliver a dose of 90Gyeq (external beam equivalent) to the prostate over 25 to 30 fractions. An ideal IMRT plan was developed by optimizing the external beam dose based on the delivered implant dose. The implant dose was converted to an equivalent external beam dose using the linear quadratic model. Patients weremore » set up on the treatment table by daily orthogonal imaging and aligning the marker seeds in the prostate. Orthogonal images were obtained at the end of treatment to assess prostate intrafraction motion. Based on the observed motion of the markers between the initial and final images, 5 individual plans showing the actual dose delivered to the patient were calculated. A final true dose distribution was established based on summing the implant dose and the 5 external beam plans. Dose to the prostate, seminal vesicles, lymphnodes and normal tissues, rectal wall, urethra and lower sphincter were calculated and compared to ideal. On 18 patients who were sexually active, dose to the corpus cavernosum and internal pudendal artery was also calculated. Results: The average prostate motion in 3 orthogonal directions was less than 1 mm with a standard deviation of less than +2 mm. Dose and volume parameters showed that there was no decrease in dose to the targets and a marginal decrease in dose to in normal tissues. Conclusion: Dose delivered by seed implant moves with the prostate, decreasing the impact of intrafractions dose movement on actual dose delivered. Combined brachytherapy and external beam dose delivered to the prostate was not sensitive to prostate motion.« less

Expression of hemidesmosomal and extracellular matrix proteins by normal and malignant human prostate tissue.

PubMed Central

Nagle, R. B.; Hao, J.; Knox, J. D.; Dalkin, B. L.; Clark, V.; Cress, A. E.

1995-01-01

The progression of prostate carcinoma may be influenced by the biochemical nature of the basal lamina surrounding the primary carcinoma cells. As a first step toward understanding this process, the composition and structure of the basal lamina in normal prostate, prostatic intraepithelial neoplasia, and human carcinoma were determined. In addition, a comparison was made between the attachments of the normal basal cell to its underlying basal lamina and those made by primary prostate carcinoma. The normal basal cells form both focal adhesions and hemidesmosomal-like structures as observed by transmission electron microscopy. The normal basal cells exhibited a polarized distribution of hemidesmosomal associated proteins including BP180, BP230, HD1, plectin, laminin-gamma 2(B2t), collagen VII, and the corresponding integrin laminin receptors alpha 6 beta 1 and alpha 6 beta 4. The expression and distribution pattern of these proteins were retained in the prostate intraepithelial neoplasia lesions. In contrast, the carcinoma cells uniformly lacked hemidesmosomal structures, the integrin alpha 6 beta 4, BP180, laminin-gamma 2 (B2t), and collagen VII but did express BP230 (30%), plectin, HD1 (15%), and the integrin laminin receptors alpha 3 beta 1 and alpha 6 beta 1. These results suggest that, although a detectable basal lamina structure is present in carcinoma, its composition and cellular attachments are abnormal. The loss of critical cellular attachments may play a role in influencing the progression potential of prostate carcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7778688

Effects of Kangquan Recipe on sex steroids and cell proliferation in rats with benign prostatic hyperplasia.

PubMed

Huang, Yuan-peng; Du, Jian; Hong, Zhen-feng; Chen, Zhi-qing; Wu, Jin-fa; Zhao, Jin-yan

2009-08-01

To investigate the effects of Kangquan Recipe (KQR) on sex steroids and cell proliferation in an experimental benign prostatic hyperplasia (BPH) model in rats. Seventy-two SD rats were randomly divided into six groups: the normal group, the model group, the finasteride group, and the low-, middle-, and high-dose KQR groups, 12 in each group. Except those in the normal group, the rats were injected with testosterone after castration for the establishment of BPH model and then given respectively with normal saline, finasteride, and low-, middle-, and high-dose of KQR for 30 days. The levels of plasma testosterone (T) and estradiol (E(2)) were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA expression ) of proliferating cell nuclear antigen (PCNA) in prostate tissue was detected by reverse transcription-polymerase chain reaction (RT-PCR) after administration. Compared with the model group, the prostate weight, the plasma T, and the mRNA expression of PCNA were significantly lower, and the plasma E(2) and the ratio of E(2)/T were higher in the three KQR groups (P<0.05 or P<0.01). There was no significant difference in the prostate weight, plasma T and E(2), and ratio of E(2)/T among the finasteride group and the three KQR groups (P>0.05). The mRNA expressions of PCNA were significantly higher in the middle- and low-dose of KQR groups than those in the finasteride group (P<0.05). KQR shows multitarget effects on experimental BPH rats, and the mechanism might be related with regulating the balance of plasma T and E(2) and decreasing the PCNAmRNA expression in prostate tissue to restrain cell proliferation in a dose-dependent manner.

Prostate tumor grown in NASA Bioreactor

NASA Technical Reports Server (NTRS)

2001-01-01

This prostate cancer construct was grown during NASA-sponsored bioreactor studies on Earth. Cells are attached to a biodegradable plastic lattice that gives them a head start in growth. Prostate tumor cells are to be grown in a NASA-sponsored Bioreactor experiment aboard the STS-107 Research-1 mission in 2002. Dr. Leland Chung of the University of Virginia is the principal investigator. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: NASA and the University of Virginia.

Six stroma-based RNA markers diagnostic for prostate cancer in European-Americans validated at the RNA and protein levels in patients in China

PubMed Central

Zhu, Jianguo; Pan, Cong; Jiang, Jun; Deng, Mingsen; Gao, Hengjun; Men, Bozhao; McClelland, Michael; Mercola, Dan; Zhong, Wei-De; Jia, Zhenyu

2015-01-01

We previously analyzed human prostate tissue containing stroma near to tumor and from cancer-negative tissues of volunteers. Over 100 candidate gene expression differences were identified and used to develop a classifier that could detect nearby tumor with an accuracy of 97% (sensitivity = 98% and specificity = 88%) based on 364 independent test cases from primarily European American cases. These stroma-based gene signatures have the potential to identify cancer patients among those with negative biopsies. In this study, we used prostate tissues from Chinese cases to validate six of these markers (CAV1, COL4A2, HSPB1, ITGB3, MAP1A and MCAM). In validation by real-time PCR, four genes (COL4A2, HSPB1, ITGB3, and MAP1A) demonstrated significantly lower expression in tumor-adjacent stroma compared to normal stroma (p value ≤ 0.05). Next, we tested whether these expression differences could be extended to the protein level. In IHC assays, all six selected proteins showed lower expression in tumor-adjacent stroma compared to the normal stroma, of which COL4A2, HSPB1 and ITGB3 showed significant differences (p value ≤ 0.05). These results suggest that biomarkers for diagnosing prostate cancer based on tumor microenvironment may be applicable across multiple racial groups. PMID:26158290

Identifying molecular features for prostate cancer with Gleason 7 based on microarray gene expression profiles.

PubMed

Bălăcescu, Loredana; Bălăcescu, O; Crişan, N; Fetica, B; Petruţ, B; Bungărdean, Cătălina; Rus, Meda; Tudoran, Oana; Meurice, G; Irimie, Al; Dragoş, N; Berindan-Neagoe, Ioana

2011-01-01

Prostate cancer represents the first leading cause of cancer among western male population, with different clinical behavior ranging from indolent to metastatic disease. Although many molecules and deregulated pathways are known, the molecular mechanisms involved in the development of prostate cancer are not fully understood. The aim of this study was to explore the molecular variation underlying the prostate cancer, based on microarray analysis and bioinformatics approaches. Normal and prostate cancer tissues were collected by macrodissection from prostatectomy pieces. All prostate cancer specimens used in our study were Gleason score 7. Gene expression microarray (Agilent Technologies) was used for Whole Human Genome evaluation. The bioinformatics and functional analysis were based on Limma and Ingenuity software. The microarray analysis identified 1119 differentially expressed genes between prostate cancer and normal prostate, which were up- or down-regulated at least 2-fold. P-values were adjusted for multiple testing using Benjamini-Hochberg method with a false discovery rate of 0.01. These genes were analyzed with Ingenuity Pathway Analysis software and were established 23 genetic networks. Our microarray results provide new information regarding the molecular networks in prostate cancer stratified as Gleason 7. These data highlighted gene expression profiles for better understanding of prostate cancer progression.

Imaging of Prostate Cancer Using Gallium-68-Labeled Bombesin.

PubMed

Sonni, Ida; Baratto, Lucia; Iagaru, Andrei

2017-04-01

Nuclear medicine can play an important role in evaluating prostate cancer combining anatomical and functional information with hybrid techniques. Various PET radiopharmaceuticals have been used for targeting specific biological markers in prostate cancer. Research is ideally oriented towards the development of radiopharmaceuticals targeting antigens overexpressed in prostate cancer, as opposed to normal prostate tissue. In this regard, gastrin-releasing peptide receptors (GRPR) are excellent candidates. Bombesin analogues targeting the GRPR have been investigated. Gallium-68 ( 68 Ga) is an interesting PET radioisotope due to several advantages, such as availability, ease of radiochemistry, half-life, and costs. The focus of this review is on 68 Ga-labeled bombesin analogues in prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular differences in transition zone and peripheral zone prostate tumors

PubMed Central

Sinnott, Jennifer A.; Rider, Jennifer R.; Carlsson, Jessica; Gerke, Travis; Tyekucheva, Svitlana; Penney, Kathryn L.; Sesso, Howard D.; Loda, Massimo; Fall, Katja; Stampfer, Meir J.; Mucci, Lorelei A.; Pawitan, Yudi; Andersson, Sven-Olof; Andrén, Ove

2015-01-01

Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20–30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research. PMID:25870172

MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer.

PubMed

Cozzi, Paul J; Wang, Jian; Delprado, Warick; Perkins, Alan C; Allen, Barry J; Russell, Pamela J; Li, Yong

2005-01-01

Molecular changes are vital for the development of prognostic markers and therapeutic modalities of prostate cancer (CaP). There is growing interest in mucins as treatment targets in human malignancies, including CaP. The role of their expression in the progression of CaP is however unclear. We examined the expressions MUC1, MUC2, MUC4, MUC5AC and MUC6 in CaP tissues using tissue microarrays (TMAs) to look for tumor-associated antigens (TAAs) for targeted therapy. In this study, 120 paraffin-embedded specimens were selected from patients who underwent radical retro-pubic prostatectomy (RRP) or trans-urethral-resection of the prostate (TURP) for primary, untreated CaP and 10 matched lymph node metastases. A series of MUC monoclonal antibodies (mAbs) was used on TMAs by standard immunohistochemistry. Our results indicate that the over-expression of MUC1 was detected in 58% of primary CaP tissues and 90% of lymph node metastases but not in normal prostate or benign tissues, while the expression of MUC2, MUC4, MUC5AC and MUC6 was found to be negative in both normal and cancer tissues. Of the MUC1 positive tumors 86% were Gleason grade 7 or higher. Over-expression of MUC1 was found in late stage CaP while MUC2, 4, 5AC and 6 were negative in CaP. MUC1 is a TAA that is highly related to tumor progression in CaP patients. This antigen is ideal for targeted therapy to control micrometastases and hormone refractory disease but additional studies are necessary to assess its usefulness in patient biopsies and CaP bone metastases before clinical trial.

Quantitative characterisation of clinically significant intra-prostatic cancer by prostate-specific membrane antigen (PSMA) expression and cell density on PSMA-11.

PubMed

Domachevsky, Liran; Goldberg, Natalia; Bernstine, Hanna; Nidam, Meital; Groshar, David

2018-05-30

To quantitatively characterize clinically significant intra-prostatic cancer (IPC) by prostate-specific membrane antigen (PSMA) expression and cell density on PSMA-11 positron emission tomography/magnetic resonance (PET/MR). Retrospective study approved by the institutional review board with informed written consent obtained. Patients with a solitary, biopsy-proven prostate cancer, Gleason score (GS) ≥7, presenting for initial evaluation by PET/computerised tomography (PET/CT), underwent early prostate PET/MR immediately after PSMA-11 tracer injection. PET/MR [MRI-based attenuation correction (MRAC)] and PET/CT [CT-based AC (CTAC)] maximal standardised uptake value (SUVmax) and minimal and mean apparent diffusion coefficient (ADCmin, ADCmean; respectively) in normal prostatic tissue (NPT) were compared to IPC area. The relationship between SUVmax, ADCmin and ADCmean measurements was obtained. Twenty-two patients (mean age 69.5±5.0 years) were included in the analysis. Forty-four prostate areas were evaluated (22 IPC and 22 NPT). Median MRAC SUVmax of NPT was significantly lower than median MRAC SUVmax of IPC (p < 0.0001). Median ADCmin and ADCmean of NPT was significantly higher than median ADCmin and ADCmean of IPC (p < 0.0001). A very good correlation was found between MRAC SUVmax with CTAC SUVmax (rho = -0.843, p < 0.0001). A good inverse relationship was found between MRAC SUVmax and CTAC SUVmax with ADCmin (rho = -0.717, p < 0.0001 and -0.740, p < 0.0001; respectively; Z = 0.22, p = 0.82, NS) and with MRAC SUVmax and ADCmean (rho = -0.737, p < 0.0001). PET/MR SUVmax, ADCmin and ADCmean are distinct biomarkers able to differentiate between IPC and NPT in naïve prostate cancer patients with GS ≥ 7. • PSMA PET/MR metrics differentiate between normal and tumoural prostatic tissue. • A multi-parametric approach combining molecular and anatomical information might direct prostate biopsy. • PSMA PET/MR metrics are warranted for radiomics analysis.

Ubiquitin ligase CHIP functions as an oncogene and activates the AKT signaling pathway in prostate cancer.

PubMed

Cheng, Li; Zang, Jin; Dai, Han-Jue; Li, Feng; Guo, Feng

2018-07-01

Carboxyl terminus of Hsc-70-interacting protein (CHIP) is an E3 ubiquitin ligase that induces the ubiquitination and degradation of numerous tumor-associated proteins and serves as a suppressor or promoter in tumor progression. To date, the molecular mechanism of CHIP in prostate cancer remains unknown. Therefore, the present study investigated the biological function of CHIP in prostate cancer cells and obtained evidence that CHIP expression is upregulated in prostate cancer tissues. The CHIP vector was introduced into DU145 cancer cells and the cell biological behaviour was examined through a series of experiments, including cell growth, cell apoptosis and migration and invasion assays. The results indicated that the overexpression of CHIP in DU145 prostatic cancer cells promoted cell proliferation through activation of the protein kinase B (AKT) signaling pathway, which subsequently increased cyclin D1 protein levels and decreased p21 and p27 protein levels. The overexpression of CHIP significantly increased the migration and invasion of the DU145 cells, which is possible due to activation of the AKT signaling pathway and upregulation of vimentin. The expression level of CHIP was observed to be increased in human prostate cancer tissues compared with the adjacent normal tissue. Furthermore, the CHIP expression level exhibited a positively association with the Gleason score of the patents. These findings indicate that CHIP functions as an oncogene in prostate cancer.

Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

PubMed Central

Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

2000-01-01

Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

Expression profile of undifferentiated cell transcription factor 1 in normal and cancerous human epithelia.

PubMed

Mouallif, Mustapha; Albert, Adelin; Zeddou, Mustapha; Ennaji, My Mustapha; Delvenne, Philippe; Guenin, Samuel

2014-08-01

Undifferentiated cell Transcription Factor 1 (UTF1) is a chromatin-bound protein involved in stem cell differentiation. It was initially reported to be restricted to stem cells or germinal tissues. However, recent work suggests that UTF1 is also expressed in somatic cells and that its expression may increase during carcinogenesis. To further clarify the expression profile of UTF1, we evaluated UTF1 expression levels immunohistochemically in eight normal human epithelia (from breast, prostate, endometrium, bladder, colon, oesophagus, lung and kidney) and their corresponding tumours as well as in several epithelial cell lines. We showed UTF1 staining in normal and tumour epithelial tissues, but with varying intensities according to the tissue location. In vitro analyses also revealed that UTF1 is expressed in somatic epithelial cell lines even in the absence of Oct4A and Sox2, its two main known regulators. The comparison of UTF1 levels in normal and tumoral tissues revealed significant overexpression in endometrial and prostatic adenocarcinomas, whereas lower intensity of the staining was observed in renal and colic tumours, suggesting a potential tissue-specific function of UTF1. Altogether, these results highlight a potential dual role for UTF1, acting either as an oncogene or as a tumour suppressor depending on the tissue. These findings also question its role as a specific marker for stem cells. © 2014 The Authors. International Journal of Experimental Pathology © 2014 International Journal of Experimental Pathology.

Micro and bulk analysis of prostate tissues classified as hyperplasia

NASA Astrophysics Data System (ADS)

Kwiatek, W. M.; Banaś, A.; Banaś, K.; Cinque, G.; Dyduch, G.; Falkenberg, G.; Kisiel, A.; Marcelli, A.; Podgórczyk, M.

2007-07-01

BPH (Benign Prostatic Hyperplasia) is the most common benign neoplasm (non cancerous enlargement of the prostate gland), whose prevalence increases with age. The gland, when increased in size, exerts pressure on the urethra, causing obstruction to urine flow. The latter may result in severe urinary tract and kidney conditions. In this work prostate samples from patients diagnosed with BPH were analyzed using synchrotron radiation. Micro-analysis of the hyperplastic samples was carried out on the L-beam line at HASYLAB, DESY (Germany), while bulk analysis on selected samples was performed at the DRX2 beamline at LNF, Frascati (Italy). Microanalysis with a mono-energetic beam 15 μm in diameter confirmed that concentrations of certain elements, such as S, Mn, Cu, Fe and Zn, are good indicators of pathological disorders in prostate tissue that may be considered effective tracers of developing compliant. The concentrations of Mn, Cu, Fe and Zn are higher in hyperplastic tissues, as compared to normal ones, while for sulphur the opposite is observed. Additionally, Fe and S K-edge XANES (X-ray Absorption Near Edge Structure) spectroscopy experiments were carried out in order to determine the chemical speciation of these elements in our samples.

Hypothermia and Rewarming Induce Gene Expression and Multiplication of Cells in Healthy Rat Prostate Tissue

PubMed Central

Kaija, Helena; Pakanen, Lasse; Kortelainen, Marja-Leena; Porvari, Katja

2015-01-01

Prostate cancer has been extensively studied, but cellular stress responses in healthy prostate tissue are rarely investigated. Hypothermia is known to cause alterations in mRNA and protein expressions and stability. The aim of this study was to use normal rat prostate as a model in order to find out consequences of cold exposure and rewarming on the expressions of genes which are either members or functionally/structurally related to erythroblastic leukemia viral oncogene B (ErbB) signaling pathway. Relative mRNA expressions of amphiregulin (AMR), cyclin D1 (CyD1), cyclin-dependent kinase inhibitor 1A (p21), transmembrane form of the prostatic acid phosphatase (PAcP), thrombomodulin (TM) and heat shock transcription factor 1 (HSF1) in rat ventral prostate were quantified in mild (2 or 4.5 h at room temperature) and severe (2 or 4.5 h at +10°C) hypothermia and in rewarming after cold exposure (2 h at +10°C followed by 2 h at room temperature or 3 h at +28°C). AMR protein level, apoptotic Bcl-2 associated X protein to B-cell CLL/lymphoma 2 (Bax/Bcl-2) mRNA ratio and proliferative index Ki-67 were determined. 4.5-h mild hypothermia, 2-h severe hypothermia and rewarming increased expression of all these genes. Elevated proliferation index Ki-67 could be seen in 2-h severe hypothermia, and the proliferation index had its highest value in longer rewarming with totally recovered normal body temperature. Pro-apoptotic tendency could be seen in 2-h mild hypothermia while anti-apoptosis was predominant in 4.5-h mild hypothermia and in shorter rewarming with only partly recovered body temperature. Hypothermia and following rewarming promote the proliferation of cells in healthy rat prostate tissue possibly via ErbB signaling pathway. PMID:25996932

The transcriptional programme of the androgen receptor (AR) in prostate cancer.

PubMed

Lamb, Alastair D; Massie, Charlie E; Neal, David E

2014-03-01

The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin-immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors. © 2013 The Authors. BJU International © 2013 BJU International.

Measurements of free and total PSA, tissue polypeptide-specific antigen (TPS), and CYFRA 21-1 in prostate cancer patients under intermittent androgen suppression therapy.

PubMed

Theyer, G; Dürer, A; Theyer, U; Haberl, I; Ulsperger, E; Baumgartner, G; Hamilton, G

1999-10-01

The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays. Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to <0.58 ng/ml), PSA (from 31.2 +/- 4.5 to <1.7 microg/l), and prostatic volume (mean reduction, 22.2 +/- 4.6%), indicating apoptotic regression of the tumors. Upon treatment cessation, testosterone increased to 6.1 +/- 0.56 ng/ml within 2 months, followed by an increase of PSA to 5.8 +/- 0.8 microg/l. The mean percentage of free PSA (15.1 +/- 2.6%) exhibited no significant change during the whole IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml. PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues. Copyright 1999 Wiley-Liss, Inc.

Fluorescence spectroscopy using excitation and emission matrix for quantification of tissue native fluorophores and cancer diagnosis

NASA Astrophysics Data System (ADS)

Wu, Binlin; Gayen, S. K.; Xu, M.

2014-03-01

Native fluorescence spectrum of normal and cancerous human prostate tissues is studied to distinguish between normal and cancerous tissues, and cancerous tissues at different cancer grade. The tissue samples were obtained from Cooperative Human Tissue Network (CHTN) and National Disease Research Interchange(NDRI). An excitation and emission matrix (EEM) was generated for each tissue sample by acquiring native fluorescence spectrum of the sample using multiple excitation wavelengths. The non-negative matrix factorization algorithm was used to generate fluorescence EEMs that correspond to the fluorophores in biological tissues, including tryptophan, collagen, elastin, nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD) and the background paraffin. We hypothesize that, as a consequence of metabolic changes associated with the development of cancer, the concentrations of NADH and FAD are different in normal and cancerous tissues, and also different for different cancer grades. We used the ratio of the abundances of FAD and NADH to distinguish between normal and cancerous tissues, and the tissue cancer grade. The FAD-to-NADH ratio was found to be the highest for normal tissue and decreased as the cancer grade increased.

Quantitative RT-PCR analysis of estrogen receptor gene expression in laser microdissected prostate cancer tissue.

PubMed

Walton, Thomas J; Li, Geng; McCulloch, Thomas A; Seth, Rashmi; Powe, Desmond G; Bishop, Michael C; Rees, Robert C

2009-06-01

Real-time quantitative RT-PCR analysis of laser microdissected tissue is considered the most accurate technique for determining tissue gene expression. The discovery of estrogen receptor beta (ERbeta) has focussed renewed interest on the role of estrogen receptors in prostate cancer, yet few studies have utilized the technique to analyze estrogen receptor gene expression in prostate cancer. Fresh tissue was obtained from 11 radical prostatectomy specimens and from 6 patients with benign prostate hyperplasia. Pure populations of benign and malignant prostate epithelium were laser microdissected, followed by RNA isolation and electrophoresis. Quantitative RT-PCR was performed using primers for androgen receptor (AR), estrogen receptor beta (ERbeta), estrogen receptor alpha (ERalpha), progesterone receptor (PGR) and prostate specific antigen (PSA), with normalization to two housekeeping genes. Differences in gene expression were analyzed using the Mann-Whitney U-test. Correlation coefficients were analyzed using Spearman's test. Significant positive correlations were seen when AR and AR-dependent PSA, and ERalpha and ERalpha-dependent PGR were compared, indicating a representative population of RNA transcripts. ERbeta gene expression was significantly over-expressed in the cancer group compared with benign controls (P < 0.01). In contrast, PGR expression was significantly down-regulated in the cancer group (P < 0.05). There were no significant differences in AR, ERalpha or PSA expression between the groups. This study represents the first to show an upregulation of ERbeta gene expression in laser microdissected prostate cancer specimens. In concert with recent studies the findings suggest differential production of ERbeta splice variants, which may play important roles in the genesis of prostate cancer. (c) 2009 Wiley-Liss, Inc.

Magnetic resonance image guided transurethral ultrasound prostate ablation: a preclinical safety and feasibility study with 28-day followup.

PubMed

Burtnyk, Mathieu; Hill, Tracy; Cadieux-Pitre, Heather; Welch, Ian

2015-05-01

We determine the safety and feasibility of magnetic resonance image guided transurethral ultrasound prostate ablation using active temperature feedback control in a preclinical canine model with 28-day followup. After a long acclimatization period we performed ultrasound treatment in 8 subjects using the magnetic resonance image guided TULSA-PRO™ transurethral ultrasound prostate ablation system. Comprehensive examinations and observations were done before and throughout the 28-day followup, including assessment of clinically significant treatment related adverse events. In addition to gross pathology evaluation, extensive histopathological analysis was done to assess cell kill inside and outside the prostate. We evaluated prostate conformal heating by comparing the spatial difference between the treatment plan and the 55C isotherm measured on magnetic resonance imaging thermometry acquired during treatment. These findings were confirmed on contrast enhanced magnetic resonance imaging immediately after treatment and at 28 days. Clinically there were no adverse events in any of the 8 subjects throughout the 28-day followup. All subjects had normal urinary and bowel function. Gross necropsy and histology confirmed that the intended thermal cell kill was confined to the prostate. No surrounding tissue was damaged, including the rectum and the external urinary sphincter. Conformal heating was achieved with an average -0.9 mm accuracy and 0.9 mm precision. Contrast enhanced magnetic resonance imaging and histological analysis confirmed tissue ablation in targeted areas of the prostate. Urethral tissue was spared from thermal damage. Magnetic resonance image guided transurethral ultrasound is a safe, feasible procedure for accurate and precise conformal thermal ablation of prostate tissue, as demonstrated in a preclinical model with 28-day followup. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

PubMed

Wu, Weijuan; Yang, Qing; Fung, Kar-Ming; Humphreys, Mitchell R; Brame, Lacy S; Cao, Amy; Fang, Yu-Ting; Shih, Pin-Tsen; Kropp, Bradley P; Lin, Hsueh-Kung

2014-03-05

Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α₁ and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α₁ immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α₁ immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A basal stem cell signature identifies aggressive prostate cancer phenotypes

PubMed Central

Smith, Bryan A.; Sokolov, Artem; Uzunangelov, Vladislav; Baertsch, Robert; Newton, Yulia; Graim, Kiley; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M.; Witte, Owen N.

2015-01-01

Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells. PMID:26460041

Glycosylation potential of human prostate cancer cell lines

PubMed Central

Gao, Yin; Chachadi, Vishwanath B.; Cheng, Pi-Wan

2014-01-01

Altered glycosylation is a universal feature of cancer cells and altered glycans can help cancer cells escape immune surveillance, facilitate tumor invasion, and increase malignancy. The goal of this study was to identify specific glycoenzymes, which could distinguish prostate cancer cells from normal prostatic cells. We investigated enzymatic activities and gene expression levels of key glycosyl- and sulfotransferases responsible for the assembly of O- and N-glycans in several prostatic cells. These cells included immortalized RWPE-1 cells derived from normal prostatic tissues, and prostate cancer cells derived from metastasis in bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP). We found that all cells were capable of synthesizing complex N-glycans and O-glycans with the core 1 structure, and each cell line had characteristic bio-synthetic pathways to modify these structures. The in vitro measured activities corresponded well to the mRNA levels of glycosyltransferases and sulfotransferases. Lectin and antibody binding to whole cells supported these results, which form the basis for the development of tumor cell-specific targeting strategies. PMID:22843320

Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential

PubMed Central

Almeida, Mafalda; Costa, Vera L; Costa, Natália R; Ramalho-Carvalho, João; Baptista, Tiago; Ribeiro, Franclim R; Paulo, Paula; Teixeira, Manuel R; Oliveira, Jorge; Lothe, Ragnhild A; Lind, Guro E; Henrique, Rui; Jerónimo, Carmen

2014-01-01

Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1’s role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall–Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis. PMID:25211630

[Prostate specific antigen and NF-kB in prostatic disease: relation with malignancy].

PubMed

Cansino, J R; Vera, R; Rodríguez de Bethencourt, F; Bouraoui, Y; Rodríguez, G; Prieto, A; de la Peña, J; Paniagua, R; Royuela, M

2011-01-01

NF-kB (p50/p65) is a transcription factor involved in TNF-α-induced cell death resistance by promoting several antiapoptotic genes. We intend to relate the expression of NF-kB (p50 and p65) with serum levels of prostate-specific antigen (PSA), both in normal males and in those with pathologic conditions of the prostate. this study was carried out in 5 normal, 24 benign prostatic hyperplastic (BPH) and 19 patients with prostate cancer (PC). Immunohistochemical and Western blot analyses were performed on tissue and serum PSA was assayed by PSA DPC Immulite assays (Diagnostics Products Corporation, Los Angeles, CA). in controls, p65 NF-kB was not found and p50 was scantly detected in 60% normal samples in the cytoplasm of epithelial cells. Both p50 and p65 were expressed in 62.5% of the samples with BPH and in 63.2% of those with PC. Both increased its frequency of expression with higher PSA serum levels. Activation of NF-kB revealed by its nuclear translocation in prostate cancer could be related to cancer progression and elevated seric PSA levels. A better understanding of the biologic mechanism by which circulating PSA levels increase and its relation with NF-kB expression is needed. Possibly, NF-kB blockage could be used as a therapeutic target to counteract proliferation in prostate cancer. Copyright © 2010 AEU. Published by Elsevier Espana. All rights reserved.

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1.

PubMed

Sun, Xianglun; Li, Youkong; Yu, Jie; Pei, Hong; Luo, Pengcheng; Zhang, Jie

2015-05-01

Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

PubMed

Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

2016-04-07

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Monoamine Oxidase Deficiency Causes Prostate Atrophy and Reduces Prostate Progenitor Cell Activity.

PubMed

Yin, Lijuan; Li, Jingjing; Liao, Chun-Peng; Jason Wu, Boyang

2018-04-10

Monoamine oxidases (MAOs) degrade a number of biogenic and dietary amines, including monoamine neurotransmitters, and play an essential role in many biological processes. Neurotransmitters and related neural events have been shown to participate in the development, differentiation, and maintenance of diverse tissues and organs by regulating the specialized cellular function and morphological structures of innervated organs such as the prostate. Here we show that mice lacking both MAO isoforms, MAOA and MAOB, exhibit smaller prostate mass and develop epithelial atrophy in the ventral and dorsolateral prostates. The cellular composition of prostate epithelium showed reduced CK5 + or p63 + basal cells, accompanied by lower Sca-1 expression in p63 + basal cells, but intact differentiated CK8 + luminal cells in MAOA/B-deficient mouse prostates. MAOA/B ablation also decreased epithelial cell proliferation without affecting cell apoptosis in mouse prostates. Using a human prostate epithelial cell line, we found that stable knockdown of MAOA and MAOB impaired the capacity of prostate stem cells to form spheres, coinciding with a reduced CD133 + /CD44 + /CD24 - stem cell population and less expression of CK5 and select stem cell markers, including ALDH1A1, TROP2, and CD166. Alternative pharmacological inhibition of MAOs also repressed prostate cell stemness. In addition, we found elevated expression of MAOA and MAOB in epithelial and/or stromal components of human prostate hyperplasia samples compared with normal prostate tissues. Taken together, our findings reveal critical roles for MAOs in the regulation of prostate basal progenitor cells and prostate maintenance. Stem Cells 2018. © AlphaMed Press 2018.

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression.

PubMed

Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cieślik, Marcin; Niknafs, Yashar S; Tien, Jean C-Y; Hosono, Yasuyuki; Iyer, Matthew K; Yazdani, Sahr; Subramaniam, Shruthi; Shukla, Sudhanshu K; Jiang, Xia; Wang, Lisha; Liu, Tzu-Ying; Uhl, Michael; Gawronski, Alexander R; Qiao, Yuanyuan; Xiao, Lanbo; Dhanasekaran, Saravana M; Juckette, Kristin M; Kunju, Lakshmi P; Cao, Xuhong; Patel, Utsav; Batish, Mona; Shukla, Girish C; Paulsen, Michelle T; Ljungman, Mats; Jiang, Hui; Mehra, Rohit; Backofen, Rolf; Sahinalp, Cenk S; Freier, Susan M; Watt, Andrew T; Guo, Shuling; Wei, John T; Feng, Felix Y; Malik, Rohit; Chinnaiyan, Arul M

2018-06-01

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.

Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer.

PubMed

Kim, Jung H; Dhanasekaran, Saravana M; Prensner, John R; Cao, Xuhong; Robinson, Daniel; Kalyana-Sundaram, Shanker; Huang, Christina; Shankar, Sunita; Jing, Xiaojun; Iyer, Matthew; Hu, Ming; Sam, Lee; Grasso, Catherine; Maher, Christopher A; Palanisamy, Nallasivam; Mehra, Rohit; Kominsky, Hal D; Siddiqui, Javed; Yu, Jindan; Qin, Zhaohui S; Chinnaiyan, Arul M

2011-07-01

Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex-next-generation sequencing (M-NGS). Hidden Markov model-based next-generation sequence analysis identified ∼68,000 methylated regions per sample. While global CpG island (CGI) methylation was not differential between benign adjacent and cancer samples, overall promoter CGI methylation significantly increased from ~12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues, respectively (P-value < 2 × 10(-16)). We found distinct patterns of promoter methylation around transcription start sites, where methylation occurred not only on the CGIs, but also on flanking regions and CGI sparse promoters. Among the 6691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer-specific, including numerous novel DMRs. A novel cancer-specific DMR in the WFDC2 promoter showed frequent methylation in cancer (17/22 tissues, 6/6 cell lines), but not in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested an epigenetic mechanism for alternate transcription start site utilization, and these modifications segregated into distinct regions when present on the same promoter. Finally, we observed differences in repeat element methylation, particularly LINE-1, between ERG gene fusion-positive and -negative cancers, and we confirmed this observation using pyrosequencing on a tissue panel. This comprehensive methylome map will further our understanding of epigenetic regulation in prostate cancer progression.

Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers-An Explorative Concept Study.

PubMed

Neuhaus, Jochen; Schiffer, Eric; Mannello, Ferdinando; Horn, Lars-Christian; Ganzer, Roman; Stolzenburg, Jens-Uwe

2017-05-04

Previously, we described prostate cancer (PCa) detection (83% sensitivity; 67% specificity) in seminal plasma by CE-MS/MS. Moreover, advanced disease was distinguished from organ-confined tumors with 80% sensitivity and 82% specificity. The discovered biomarkers were naturally occurring fragments of larger seminal proteins, predominantly semenogelin 1 and 2, representing endpoints of the ejaculate liquefaction. Here we identified proteases putatively involved in PCa specific protein cleavage, and examined gene expression and tissue protein levels, jointly with cell localization in normal prostate (nP), benign prostate hyperplasia (BPH), seminal vesicles and PCa using qPCR, Western blotting and confocal laser scanning microscopy. We found differential gene expression of chymase (CMA1), matrix metalloproteinases (MMP3, MMP7), and upregulation of MMP14 and tissue inhibitors (TIMP1 and TIMP2) in BPH. In contrast tissue protein levels of MMP14 were downregulated in PCa. MMP3/TIMP1 and MMP7/TIMP1 ratios were decreased in BPH. In seminal vesicles, we found low-level expression of most proteases and, interestingly, we also detected TIMP1 and low levels of TIMP2. We conclude that MMP3 and MMP7 activity is different in PCa compared to BPH due to fine regulation by their inhibitor TIMP1. Our findings support the concept of seminal plasma biomarkers as non-invasive tool for PCa detection and risk stratification.

An integrated view of the role of miR-130b/301b miRNA cluster in prostate cancer.

PubMed

Fort, Rafael Sebastián; Mathó, Cecilia; Oliveira-Rizzo, Carolina; Garat, Beatriz; Sotelo-Silveira, José Roberto; Duhagon, María Ana

2018-01-01

Prostate cancer is a major health problem worldwide due to its high incidence morbidity and mortality. There is currently a need of improved biomarkers, capable to distinguish mild versus aggressive forms of the disease, and thus guide therapeutic decisions. Although miRNAs deregulated in cancer represent exciting candidates as biomarkers, its scientific literature is frequently fragmented in dispersed studies. This problem is aggravated for miRNAs belonging to miRNA gene clusters with shared target genes. The miRNA cluster composed by hsa-mir-130b and hsa-mir-301b precursors was recently involved in prostate cancer pathogenesis, yet different studies assigned it opposite effects on the disease. We sought to elucidate the role of the human miR-130b/301b miRNA cluster in prostate cancer through a comprehensive data analysis of most published clinical cohorts. We interrogated methylomes, transcriptomes and patient clinical data, unifying previous reports and adding original analysis using the largest available cohort (TCGA-PRAD). We found that hsa-miR-130b-3p and hsa-miR-301b-3p are upregulated in neoplastic vs normal prostate tissue, as well as in metastatic vs primary sites. However, this increase in expression is not due to a decrease of the global DNA methylation of the genes in prostate tissues, as the promoter of the gene remains lowly methylated in normal and neoplastic tissue. A comparison of the levels of human miR-130b/301b and all the clinical variables reported for the major available cohorts, yielded positive correlations with malignance, specifically significant for T-stage, residual tumor status and primary therapy outcome. The assessment of the correlations between the hsa-miR-130b-3p and hsa-miR-301b-3p and candidate target genes in clinical samples, supports their repression of tumor suppressor genes in prostate cancer. Altogether, these results favor an oncogenic role of miR-130b/301b cluster in prostate cancer.

De novo steroid biosynthesis in human prostate cell lines and biopsies.

PubMed

Sakai, Monica; Martinez-Arguelles, Daniel B; Aprikian, Armen G; Magliocco, Anthony M; Papadopoulos, Vassilios

2016-05-01

Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we examined the expression of key enzymes and proteins involved in steroid biosynthesis and metabolism. Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with steroid biosynthesis studies in normal and BPH cells. Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydroxymethylglutaryl-CoA reductase (HMGCR), the mitochondrial translocator protein TSPO and cholesterol side chain cleavage enzyme CYP11A1 were only observed in WPMY-1, BPH-1, and LNCaP cells. HSD3B1, HSD3B2, and CYP17A1 are involved in androgen formation and were not found in most cell lines. WPE1-NA22 and BPH-1 cells were unable to synthesize de novo steroids from mevalonate. Moreover, androgen-deprived cells did not have alterations in the expression of enzymes that could lead to de novo steroid formation. All prostate specimens expressed TSPO and CYP11A1. HSD3B1/2, CYP17A1, HSD17B5, and CYP19A1 mRNA expression was distinct to the profile observed in cells lines. The majority of BPH (90.9%) and PCa (83.1%) specimens contained CYP17A1, compared to control (normal) specimens (46.7%). BPH (82%), PCa (59%), normal (40%), and CRPC (34%) specimens expressed the four key enzymes that metabolize cholesterol to androgens. These studies question the use of prostate cell lines to study steroid biosynthesis and demonstrate that human prostate samples contain transcripts encoding for key steroidogenic enzymes and proteins indicating that they have the potential to synthesize de novo steroids. We propose CYP17A1 as a candidate enzyme that can be used for patient stratification and treatment in BPH and PCa. © 2016 Wiley Periodicals, Inc.

A study of T2-weighted MR image texture features and diffusion-weighted MR image features for computer-aided diagnosis of prostate cancer

NASA Astrophysics Data System (ADS)

Peng, Yahui; Jiang, Yulei; Antic, Tatjana; Giger, Maryellen L.; Eggener, Scott; Oto, Aytekin

2013-02-01

The purpose of this study was to study T2-weighted magnetic resonance (MR) image texture features and diffusionweighted (DW) MR image features in distinguishing prostate cancer (PCa) from normal tissue. We collected two image datasets: 23 PCa patients (25 PCa and 23 normal tissue regions of interest [ROIs]) imaged with Philips MR scanners, and 30 PCa patients (41 PCa and 26 normal tissue ROIs) imaged with GE MR scanners. A radiologist drew ROIs manually via consensus histology-MR correlation conference with a pathologist. A number of T2-weighted texture features and apparent diffusion coefficient (ADC) features were investigated, and linear discriminant analysis (LDA) was used to combine select strong image features. Area under the receiver operating characteristic (ROC) curve (AUC) was used to characterize feature effectiveness in distinguishing PCa from normal tissue ROIs. Of the features studied, ADC 10th percentile, ADC average, and T2-weighted sum average yielded AUC values (+/-standard error) of 0.95+/-0.03, 0.94+/-0.03, and 0.85+/-0.05 on the Phillips images, and 0.91+/-0.04, 0.89+/-0.04, and 0.70+/-0.06 on the GE images, respectively. The three-feature combination yielded AUC values of 0.94+/-0.03 and 0.89+/-0.04 on the Phillips and GE images, respectively. ADC 10th percentile, ADC average, and T2-weighted sum average, are effective in distinguishing PCa from normal tissue, and appear robust in images acquired from Phillips and GE MR scanners.

Expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy.

PubMed

Faramarzi, Sepideh; Ghafouri-Fard, Soudeh

2017-09-01

Prostate cancer is a prevalent disorder among men with a heterogeneous etiological background. Several molecular events and signaling perturbations have been found in this disorder. Among genes whose expressions have been altered during the prostate cancer development are cancer-testis antigens (CTAs). This group of antigens has limited expression in the normal adult tissues but aberrant expression in cancers. This property provides them the possibility to be used as cancer biomarkers and immunotherapeutic targets. Several CTAs have been shown to be immunogenic in prostate cancer patients and some of the have entered clinical trials. Based on the preliminary data obtained from these trials, it is expected that CTA-based therapeutic options are beneficial for at least a subset of prostate cancer patients.

Prostate Stem Cell Antigen DNA Vaccination Breaks Tolerance to Self-antigen and Inhibits Prostate Cancer Growth

PubMed Central

Ahmad, Sarfraz; Casey, Garrett; Sweeney, Paul; Tangney, Mark; O'Sullivan, Gerald C

2009-01-01

Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal human prostate and over expressed in prostate cancer. Elevated levels of PSCA protein in prostate cancer correlate with increased tumor stage/grade, with androgen independence and have higher expression in bone metastases. In this study, the PSCA gene was isolated from the transgenic adenocarcinoma mouse prostate cell line (TRAMPC1), and a vaccine plasmid construct was generated. This plasmid PSCA (pmPSCA) was delivered by intramuscular electroporation (EP) and induced effective antitumor immune responses against subcutaneous TRAMPC1 tumors in male C57 BL/6 mice. The pmPSCA vaccination inhibited tumor growth, resulting in cure or prolongation in survival. Similarly, the vaccine inhibited metastases in PSCA expressing B16 F10 tumors. There was activation of Th-1 type immunity against PSCA, indicating the breaking of tolerance to a self-antigen. This immunity was tumor specific and was transferable by adoptive transfer of splenocytes. The mice remained healthy and there was no evidence of collateral autoimmune responses in normal tissues. EP-assisted delivery of the pmPSCA evoked strong specific responses and could, in neoadjuvant or adjuvant settings, provide a safe and effective immune control of prostate cancer, given that there is significant homology between human and mouse PSCA. PMID:19337234

Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer

DTIC Science & Technology

2013-03-01

cell line was derived from primary human prostate epithelial cells by transformation with human papilloma virus. While not tumorigenic, they do...normal cells and tissues has no significant adverse effects. Inhibition of PKCδ in human and murine cells containing an activated Ras protein, however...initiates rapid and profound apoptosis. In this work, we are testing the hypothesis that inhibition or down-regulation of PKCδ in human and murine

Prostate cancer outcome and tissue levels of metal ions

USGS Publications Warehouse

Sarafanov, A.G.; Todorov, T.I.; Centeno, J.A.; MacIas, V.; Gao, W.; Liang, W.-M.; Beam, C.; Gray, Marion A.; Kajdacsy-Balla, A.

2011-01-01

BACKGROUNDThere are several studies examining prostate cancer and exposure to cadmium, iron, selenium, and zinc. Less data are available on the possible influence of these metal ions on prostate cancer outcome. This study measured levels of these ions in prostatectomy samples in order to examine possible associations between metal concentrations and disease outcome.METHODSWe obtained formalin fixed paraffin embedded tissue blocks of prostatectomy samples of 40 patients with PSA recurrence, matched 1:1 (for year of surgery, race, age, Gleason grading, and pathology TNM classification) with tissue blocks from 40 patients without recurrence (n = 80). Case–control pairs were compared for the levels of metals in areas adjacent to tumors. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for quantification of Cd, Fe, Zn, and Se.RESULTSPatients with biochemical (PSA) recurrence of disease had 12% lower median iron (95 µg/g vs. 111 µg/g; P = 0.04) and 21% lower zinc (279 µg/g vs. 346 µg/g; P = 0.04) concentrations in the normal-appearing tissue immediately adjacent to cancer areas. Differences in cadmium (0.489 µg/g vs. 0.439 µg/g; 4% higher) and selenium (1.68 µg/g vs. 1.58 µg/g; 5% higher) levels were not statistically significant in recurrence cases, when compared to non-recurrences (P = 0.40 and 0.21, respectively).CONCLUSIONSThere is an association between low zinc and low iron prostate tissue levels and biochemical recurrence in prostate cancer. Whether these novel findings are a cause or effect of more aggressive tumors, or whether low zinc and iron prostatic levels raise implications for therapy, remains to be investigated. 

Optical biopsy using fluorescence spectroscopy for prostate cancer diagnosis

NASA Astrophysics Data System (ADS)

Wu, Binlin; Gao, Xin; Smith, Jason; Bailin, Jacob

2017-02-01

Native fluorescence spectra are acquired from fresh normal and cancerous human prostate tissues. The fluorescence data are analyzed using a multivariate analysis algorithm such as non-negative matrix factorization. The nonnegative spectral components are retrieved and attributed to the native fluorophores such as collagen, reduced nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FAD) in tissue. The retrieved weights of the components, e.g. NADH and FAD are used to estimate the relative concentrations of the native fluorophores and the redox ratio. A machine learning algorithm such as support vector machine (SVM) is used for classification to distinguish normal and cancerous tissue samples based on either the relative concentrations of NADH and FAD or the redox ratio alone. The classification performance is shown based on statistical measures such as sensitivity, specificity, and accuracy, along with the area under receiver operating characteristic (ROC) curve. A cross validation method such as leave-one-out is used to evaluate the predictive performance of the SVM classifier to avoid bias due to overfitting.

[Expression of SRD5A1 and its prognostic role in prostate cancer: Analysis based on the data-mining of ONCOMINE].

PubMed

Xu, Bin; Liu, Ning; Chen, Shu-Qiu; Jiang, Hua; Zhang, Li-Jie; Zhang, Xiao-Wen; Yang, Yu; Sha, Guo-Zhu; Liu, Jing; Zhu, Wei-Dong; Chen, Ming

2016-09-01

To explore the expression of I-5α-reductase (SRD5A1)and its prognostic role in prostate cancer . Data about SRD5A1 were retrieved from the ONCOMINE database and the role of SRD5A1 in prostate cancer was analyzed. Totally, 992 studies of different types relevant to the expression of SRD5A1 were identified in the ONCOMINE database. The SRD5A1 expression was statistically significant in 239 of the studies, overexpressed in 157 (11 in prostate cancer) and underexpressed in the other 82 (3 in prostate cancer). Eighteen of the studies, with 1 068 samples, addressed the expression of SRD5A1 in prostate cancer and normal tissues, which was significantly higher in the former than in the latter tissue (P<0.05). In 3 of the studies, the SRD5A1 expression was high in primary prostate cancer and increased with its metastasis (P<0.0 5). Two of the studies with prognostic data showed a higher rate of postoperative biochemical recurrence and a higher total mortality rate in the patients with a high than in those with a low expression of SRD5A1 (P<0.05). SRD5A1 is highly expressed in prostate cancer, especially in metastatic and castration-resistant prostate cancer and its expression is associated with the prognosis of prostate cancer, which may be an important target of medication for prostate cancer.

Accumulation of Palmitoylcarnitine and Its Effect on Pro-Inflammatory Pathways and Calcium Influx in Prostate Cancer.

PubMed

Al-Bakheit, Ala'a; Traka, Maria; Saha, Shikha; Mithen, Richard; Melchini, Antonietta

2016-10-01

Acylcarnitines are intermediates of fatty acid oxidation and accumulate as a consequence of the metabolic dysfunction resulting from the insufficient integration between β-oxidation and the tricarboxylic acid (TCA) cycle. The aim of this study was to investigate whether acylcarnitines accumulate in prostate cancer tissue, and whether their biological actions could be similar to those of dihydrotestosterone (DHT), a structurally related compound associated with cancer development. Levels of palmitoylcarnitine (palcar), a C16:00 acylcarnitine, were measured in prostate tissue using LC-MS/MS. The effect of palcar on inflammatory cytokines and calcium (Ca(2+) ) influx was investigated in in vitro models of prostate cancer. We observed a significantly higher level of palcar in prostate cancerous tissue compared to benign tissue. High levels of palcar have been associated with increased gene expression and secretion of the pro-inflammatory cytokine IL-6 in cancerous PC3 cells, compared to normal PNT1A cells. Furthermore, we found that high levels of palcar induced a rapid Ca(2+) influx in PC3 cells, but not in DU145, BPH-1, or PNT1A cells. This pattern of Ca(2+) influx was also observed in response to DHT. Through the use of whole genome arrays we demonstrated that PNT1A cells exposed to palcar or DHT have a similar biological response. This study suggests that palcar might act as a potential mediator for prostate cancer progression through its effect on (i) pro-inflammatory pathways, (ii) Ca(2+) influx, and (iii) DHT-like effects. Further studies need to be undertaken to explore whether this class of compounds has different biological functions at physiological and pathological levels. Prostate 76:1326-1337, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells

PubMed Central

Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antzack, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J.; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

2016-01-01

Abstract The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks in a wide spectrum of biological systems. PMID:27124473

A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells.

PubMed

Trevino, Victor; Cassese, Alberto; Nagy, Zsuzsanna; Zhuang, Xiaodong; Herbert, John; Antczak, Philipp; Clarke, Kim; Davies, Nicholas; Rahman, Ayesha; Campbell, Moray J; Guindani, Michele; Bicknell, Roy; Vannucci, Marina; Falciani, Francesco

2016-04-01

The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks in a wide spectrum of biological systems.

Expression of the cancer-testis antigen BORIS correlates with prostate cancer.

PubMed

Cheema, Zubair; Hari-Gupta, Yukti; Kita, Georgia-Xanthi; Farrar, Dawn; Seddon, Ian; Corr, John; Klenova, Elena

2014-02-01

BORIS, a paralogue of the transcription factor CTCF, is a member of the cancer-testis antigen (CT) family. BORIS is normally present at high levels in the testis; however it is aberrantly expressed in various tumors and cancer cell lines. The main objectives of this study were to investigate BORIS expression together with sub-cellular localization in both prostate cell lines and tumor tissues, and assess correlations between BORIS and clinical/pathological characteristics. We examined BORIS mRNA expression, protein levels and cellular localization in a panel of human prostate tissues, cancer and benign, together with a panel prostate cell lines. We also compared BORIS levels and localization with clinical/pathological characteristics in prostate tumors. BORIS was detected in all inspected prostate cancer cell lines and tumors, but was absent in benign prostatic hyperplasia. Increased levels of BORIS protein positively correlated with Gleason score, T-stage and androgen receptor (AR) protein levels in prostate tumors. The relationship between BORIS and AR was further highlighted in prostate cell lines by the ability of ectopically expressed BORIS to activate the endogenous AR mRNA and protein. BORIS localization in the nucleus plus cytoplasm was also associated with higher BORIS levels and Gleason score. Detection of BORIS in prostate tumors suggests potential applications of BORIS as a biomarker for prostate cancer diagnosis, as an immunotherapy target and, potentially, a prognostic marker of more aggressive prostate cancer. The ability of BORIS to activate the AR gene indicates BORIS involvement in the growth and development of prostate tumors. © 2013 Wiley Periodicals, Inc.

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits.

PubMed

Rhie, Suhn Kyong; Guo, Yu; Tak, Yu Gyoung; Yao, Lijing; Shen, Hui; Coetzee, Gerhard A; Laird, Peter W; Farnham, Peggy J

2016-01-01

Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements. Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors. Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers.

Punctuated Evolution of Prostate Cancer Genomes

PubMed Central

Baca, Sylvan C.; Prandi, Davide; Lawrence, Michael S.; Mosquera, Juan Miguel; Romanel, Alessandro; Drier, Yotam; Park, Kyung; Kitabayashi, Naoki; MacDonald, Theresa Y.; Ghandi, Mahmoud; Van Allen, Eliezer; Kryukov, Gregory V.; Sboner, Andrea; Theurillat, Jean-Philippe; Soong, T. David; Nickerson, Elizabeth; Auclair, Daniel; Tewari, Ashutosh; Beltran, Himisha; Onofrio, Robert C.; Boysen, Gunther; Guiducci, Candace; Barbieri, Christopher E.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Saksena, Gordon; Voet, Douglas; Ramos, Alex H; Winckler, Wendy; Cipicchio, Michelle; Ardlie, Kristin; Kantoff, Philip W.; Berger, Michael F.; Gabriel, Stacey B.; Golub, Todd R.; Meyerson, Matthew; Lander, Eric S.; Elemento, Olivier; Getz, Gad; Demichelis, Francesca; Rubin, Mark A.; Garraway, Levi A.

2013-01-01

SUMMARY The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy”, frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis. PMID:23622249

Punctuated evolution of prostate cancer genomes.

PubMed

Baca, Sylvan C; Prandi, Davide; Lawrence, Michael S; Mosquera, Juan Miguel; Romanel, Alessandro; Drier, Yotam; Park, Kyung; Kitabayashi, Naoki; MacDonald, Theresa Y; Ghandi, Mahmoud; Van Allen, Eliezer; Kryukov, Gregory V; Sboner, Andrea; Theurillat, Jean-Philippe; Soong, T David; Nickerson, Elizabeth; Auclair, Daniel; Tewari, Ashutosh; Beltran, Himisha; Onofrio, Robert C; Boysen, Gunther; Guiducci, Candace; Barbieri, Christopher E; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L; Saksena, Gordon; Voet, Douglas; Ramos, Alex H; Winckler, Wendy; Cipicchio, Michelle; Ardlie, Kristin; Kantoff, Philip W; Berger, Michael F; Gabriel, Stacey B; Golub, Todd R; Meyerson, Matthew; Lander, Eric S; Elemento, Olivier; Getz, Gad; Demichelis, Francesca; Rubin, Mark A; Garraway, Levi A

2013-04-25

The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

Activation of innate anti-viral immune response genes in symptomatic benign prostatic hyperplasia

PubMed Central

Madigan, Allison A.; Sobek, Kathryn M.; Cummings, Jessica L.; Green, William R.; Bacich, Dean J.; O’Keefe, Denise S.

2012-01-01

Benign Prostatic Hyperplasia (BPH)is the most common urologic disease in men over age 50. Symptoms include acute urinary retention, urgency to urinate and nocturia. For patients with severe symptoms, surgical treatment is used to remove the affected tissue. Interestingly, the presence of histologic BPH does not always correlate with symptoms. The molecular basis of symptomatic BPH and how it differs from asymptomatic BPH is unknown. Investigation into the molecular players involved in symptomatic BPH will likely give insight into novel therapeutic, and potentially preventative, targets. We determined the expression of genes involved in the innate anti-viral immune response in tissues from patients undergoing surgery to alleviate the symptoms of BPH, and compared the results to prostate tissue with histologic BPH, but from patients with few urinary issues (asymptomatic BPH). We found that expression of CFI, APOBEC3G, OAS2, and IFIT1, four genes whose protein products are involved in the innate anti-viral immune response, were significantly transcriptionally upregulated in symptomatic BPH. Additionally we observe hypomethylation and concomitant expression of ancient retroviral-like sequences, the LINE-1 retrotransposons, in symptomatic BPH when compared to normal prostate tissue. These findings merit further investigation into the anti-viral immune response in symptomatic BPH. PMID:22952051

[Hormonal and metabolic effects of drinking mineral water and phytoaeronisation in experimental prostatitis].

PubMed

Polushina, N D; Agaev, A A; Shchelkunov, A V; Eseneev, S M

2004-01-01

Prostatitis modelled in 53 Wistar male rats (300-350 body mass) 7 days after its induction was treated with mineral water "Essentuki N 17" (MW) which was taken in a dose 1.5-2 ml per 100 g body mass for 23-24 days. In addition, some animals received phytoaeroionisation (PAI) with solution of essential oils of mint, sage and lavender. Prostatitis is associated with disorders in prostatic tissue, levels of sex hormones (testosterone, prolactin, FSH, LH), a rise in total cholesterol, glucose. Watering of animals with MW and PAI raised blood insulin, hydrocortisone and testosterone, normalized blood glucose and cholesterol. There was a correlation between blood levels of hydrocortisone and testosterone.

Simulations to Evaluate Accuracy and Patient Dose in Neutron-Stimulated, Emission-Computed Tomography (NSECT) for Diagnosis of Breast Cancer

DTIC Science & Technology

2008-04-01

tissues , Cancer 52 (3) (1983) 508. [18] J.O. Ogunlewe, D.N. Osegbe, Zinc and cadmium concentrations in indigenous blacks with normal, hypertrophic...142 (1976) 65. [10] E.J. Margalioth, J.G. Schenker, M. Chevion, Copper and zinc levels in normal and malignant tissues , Cancer 52 (5) (1983) 868. [11...Krajewska, Zinc and cadmium analysis in human prostate neoplasms, Biol. Trace Elem. Res. 59 (1–3) (1997) 145. [22] V.Y. Zaichick, T.V. Sviridova

A new plan-scoring method using normal tissue complication probability for personalized treatment plan decisions in prostate cancer

NASA Astrophysics Data System (ADS)

Kim, Kwang Hyeon; Lee, Suk; Shim, Jang Bo; Yang, Dae Sik; Yoon, Won Sup; Park, Young Je; Kim, Chul Yong; Cao, Yuan Jie; Chang, Kyung Hwan

2018-01-01

The aim of this study was to derive a new plan-scoring index using normal tissue complication probabilities to verify different plans in the selection of personalized treatment. Plans for 12 patients treated with tomotherapy were used to compare scoring for ranking. Dosimetric and biological indexes were analyzed for the plans for a clearly distinguishable group ( n = 7) and a similar group ( n = 12), using treatment plan verification software that we developed. The quality factor ( QF) of our support software for treatment decisions was consistent with the final treatment plan for the clearly distinguishable group (average QF = 1.202, 100% match rate, n = 7) and the similar group (average QF = 1.058, 33% match rate, n = 12). Therefore, we propose a normal tissue complication probability (NTCP) based on the plan scoring index for verification of different plans for personalized treatment-plan selection. Scoring using the new QF showed a 100% match rate (average NTCP QF = 1.0420). The NTCP-based new QF scoring method was adequate for obtaining biological verification quality and organ risk saving using the treatment-planning decision-support software we developed for prostate cancer.

Investigation of prostate cancer cells using NADH and Tryptophan as biomarker: multiphoton FLIM-FRET microscopy

NASA Astrophysics Data System (ADS)

Rehman, Shagufta; O'Melia, Meghan J.; Wallrabe, Horst; Svindrych, Zdenek; Chandra, Dhyan; Periasamy, Ammasi

2016-03-01

Fluorescence Lifetime Imaging (FLIM) can be used to understand the metabolic activity in cancer. Prostate cancer is one of the leading cancers in men in the USA. This research focuses on FLIM measurements of NAD(P)H and Tryptophan, used as biomarkers to understand the metabolic activity in prostate cancer cells. Two prostate cancers and one normal cell line were used for live-cell FLIM measurements on Zeiss780 2P confocal microscope with SPCM FLIM board. Glucose uptake and glycolysis proceeds about ten times faster in cancer than in non-cancerous tissues. Therefore, we assessed the glycolytic activity in the prostate cancer in comparison to the normal cells upon glucose stimulation by analyzing the NAD(P)H and Trp lifetime distribution and efficiency of energy transfer (E%). Furthermore, we treated the prostate cancer cells with 1μM Doxorubicin, a commonly used anti-cancer chemotherapeutic. Increase in NADH a2%, an indicator of increased glycolysis and increased E% between Trp and NAD(P)H were seen upon glucose stimulation for 30min. The magnitude of shift to the right for NAD(P)H a2% and E% distribution was higher in prostate cancer versus the normal cells. Upon treatment with Doxorubicin decrease in cellular metabolism was seen at 15 and 30 minutes. The histogram for NAD(P)H a2% post-treatment for prostate cancer cells showed a left shift compared to the untreated control suggesting decrease in glycolysis and metabolic activity opposite to what was observed after glucose stimulation. Hence, NAD(P)H and Trp lifetimes can be used biomarkers to understand metabolic activity in prostate cancer and upon chemotherapeutic interventions.

Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

DTIC Science & Technology

2015-10-01

antitumor activity in mouse xenografts did not exert toxic effects on normal tissues. BMI-1 targeted therapy when combined with taxotere resulted in...utilizing zebrafish xenografts (Sabaawy Lab) and prostate cancer cell lines (Bertino Lab), and 3) Confirmation of the antitumor activity of C-209...in mouse xenografts alone and upon combination with taxotere (Bertino Lab). The following tasks from the approved SOW were performed to achieve the

Using Human Stem Cells to Study the Role of the Stroma in the Initiation of Prostate Cancer

DTIC Science & Technology

2011-03-01

alterations in the epithelium that drives the pr ogressive transformation of nor mal human cells into highly malignant derivatives. It is evident that...of tumor initiation, we propose to use normal human prostate epithelium generated from human embryonic stem cells (hESCs) in tissue recombination...serum free conditions for 5-8 days into endoderm in vitro. Confirm endoderm phenotype using immunohistochemistry and FACs analysis . We conducted

Targeted Zinc Delivery: A Novel Treatment for Prostate Cancer

DTIC Science & Technology

2010-06-01

aconitase, which normally functions to oxidize citrate during the Krebs cycle . Because citrate is a principle component of seminal fluid, prostate...tissue, likely due to the metabolic effects of zinc in the Krebs cycle . That is, because zinc inhibits m- aconitase, loss of zinc allows for greater...secretory cells do not complete the oxidation of citrate in the mitochondria and the zinc-mediated inhibition of m-aconitase is crucial for the

Apparent diffusion coefficient in the analysis of prostate cancer: determination of optimal b-value pair to differentiate normal from malignant tissue.

PubMed

Adubeiro, Nuno; Nogueira, Maria Luísa; Nunes, Rita G; Ferreira, Hugo Alexandre; Ribeiro, Eduardo; La Fuente, José Maria Ferreira

Determining optimal b-value pair for differentiation between normal and prostate cancer (PCa) tissues. Forty-three patients with diagnosis or PCa symptoms were included. Apparent diffusion coefficient (ADC) was estimated using minimum and maximum b-values of 0, 50, 100, 150, 200, 500s/mm2 and 500, 800, 1100, 1400, 1700 and 2000s/mm2, respectively. Diagnostic performances were evaluated when Area-under-the-curve (AUC)>95%. 15 of the 35 b-values pair surpassed this AUC threshold. The pair (50, 2000s/mm2) provided the highest AUC (96%) with ADC cutoff 0.89×10- 3 mm 2 /s, sensitivity 95.5%, specificity 93.2% and accuracy 94.4%. The best b-value pair was b=50, 2000s/mm2. Copyright © 2017 Elsevier Inc. All rights reserved.

Association and regulation of protein factors of field effect in prostate tissues

PubMed Central

Gabriel, Kristin N.; Jones, Anna C.; Nguyen, Julie P.T.; Antillon, Kresta S.; Janos, Sara N.; Overton, Heidi N.; Jenkins, Shannon M.; Frisch, Emily H.; Trujillo, Kristina A.; Bisoffi, Marco

2016-01-01

Field effect or field cancerization denotes the presence of molecular aberrations in structurally intact cells residing in histologically normal tissues adjacent to solid tumors. Currently, the etiology of prostate field-effect formation is unknown and there is a prominent lack of knowledge of the underlying cellular and molecular pathways. We have previously identified an upregulated expression of several protein factors representative of prostate field effect, i.e., early growth response-1 (EGR-1), platelet-derived growth factor-A (PDGF-A), macrophage inhibitory cytokine-1 (MIC-1), and fatty acid synthase (FASN) in tissues at a distance of 1 cm from the visible margin of intracapsule prostate adenocarcinomas. We have hypothesized that the transcription factor EGR-1 could be a key regulator of prostate field-effect formation by controlling the expression of PDGF-A, MIC-1, and FASN. Taking advantage of our extensive quantitative immunofluorescence data specific for EGR-1, PDGF-A, MIC-1, and FASN generated in disease-free, tumor-adjacent, and cancerous human prostate tissues, we chose comprehensive correlation as our major approach to test this hypothesis. Despite the static nature and sample heterogeneity of association studies, we show here that sophisticated data generation, such as by spectral image acquisition, linear unmixing, and digital quantitative imaging, can provide meaningful indications of molecular regulations in a physiologically relevant in situ environment. Our data suggest that EGR-1 acts as a key regulator of prostate field effect through induction of pro-proliferative (PDGF-A and FASN), and suppression of pro-apoptotic (MIC-1) factors. These findings were corroborated by computational promoter analyses and cell transfection experiments in non-cancerous prostate epithelial cells with ectopically induced and suppressed EGR-1 expression. Among several clinical applications, a detailed knowledge of pathways of field effect may lead to the development of targeted intervention strategies preventing progression from pre-malignancy to cancer. PMID:27634112

Establishment of a rat model of chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) induced by immunization with a novel peptide T2.

PubMed

Ihsan, Awais Ullah; Khan, Farhan Ullah; Nawaz, Waqas; Khan, Muhammad Zahid; Yang, Mengqi; Zhou, Xiaohui

2017-07-01

The exact etiological mechanism of Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unclear however autoimmunity is the most valid theory. We developed a rat model of Chronic Prostatitis/chronic pelvic pain syndrome by using a novel peptide (T2) isolated from TRPM8. This model might be beneficial in elucidating mechanisms involved in the pathogenesis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). 40 male Sprague-Dawley rats with an average weight of 180-220g were equally distributed into five groups. The normal control group was injected with normal saline (.9% NACL), the CFA group with CFA, AL(OH)3 group was given AL(OH)3 injection, T2 group using a novel peptide T2 and T2+AL(OH)3+CFA group was injected with T2+AL(OH)3+CFA. Dosing to all rat groups were injected subcutaneously. Hematoxylin and eosin staining and Immunohistochemistry were used to investigate inflammatory cell infiltration and IL-1β in the prostate tissue respectively. ELISA technique was used to measure the serum level of CRP and TNF-α. T-test was used to analyze the results. Maximum infiltration of inflammatory cells and the highest level of IL-1β in the prostate tissue was observed in T2+AL(OH)3+CFA group as revealed by histopathology and Immunohistochemistry, respectively. Furthermore, T2+AL(OH)3+CFA group attained the peak value of serum TNF-α and CRP as determined by ELISA technique. Our results demonstrated that T2 in combination with AL(OH)3 and CFA induced severe Prostatitis in rats. We believe that our present model will be highly beneficial for investigation of the pathophysiology of Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT Imaging in Localized Prostate Cancer: Correlation With Multiparametric MRI and Histopathology.

PubMed

Turkbey, Baris; Mena, Esther; Lindenberg, Liza; Adler, Stephen; Bednarova, Sandra; Berman, Rose; Ton, Anita T; McKinney, Yolanda; Eclarinal, Philip; Hill, Craig; Afari, George; Bhattacharyya, Sibaprasad; Mease, Ronnie C; Merino, Maria J; Jacobs, Paula M; Wood, Bradford J; Pinto, Peter A; Pomper, Martin G; Choyke, Peter L

2017-10-01

To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F-fluorobenzyl-L-cysteine) (F-DCFBC), a prostate-specific membrane antigen-targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology. This Health Insurance Portability and Accountability Act of 1996-compliant, prospective, institutional review board-approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51-74 years]; median prostate-specific antigen, 37.5 ng/dL [range, 3.26-216 ng/dL]). Patients underwent mpMRI and F-DCFBC PET/CT within a 3 months' window. Lesions seen on mpMRI were biopsied under transrectal ultrasound/MRI fusion-guided biopsy, or a radical prostatectomy was performed. F-DCFBC PET/CT and mpMRI were evaluated blinded and separately for tumor detection on a lesion basis. For PET image analysis, MRI and F-DCFBC PET images were fused by using software registration; imaging findings were correlated with histology, and uptake of F-DCFBC in tumors was compared with uptake in benign prostatic hyperplasia nodules and normal peripheral zone tissue using the 80% threshold SUVmax. A total of 25 tumor foci (mean size, 1.8 cm; median size, 1.5 cm; range, 0.6-4.7 cm) were histopathologically identified in 13 patients. Sensitivity rates of F-DCFBC PET/CT and mpMRI were 36% and 96%, respectively, for all tumors. For index lesions, the largest tumor with highest Gleason score, sensitivity rates of F-DCFBC PET/CT and mpMRI were 61.5% and 92%, respectively. The average SUVmax for primary prostate cancer was higher (5.8 ± 4.4) than that of benign prostatic hyperplasia nodules (2.1 ± 0.3) or that of normal prostate tissue (2.1 ± 0.4) at 1 hour postinjection (P = 0.0033). The majority of index prostate cancers are detected with F-DCFBC PET/CT, and this may be a prognostic indicator based on uptake and staging. However, for detecting prostate cancer with high sensitivity, it is important to combine prostate-specific membrane antigen PET/CT with mpMRI.

Integral radiation dose to normal structures with conformal external beam radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aoyama, Hidefumi; Westerly, David Clark; Mackie, Thomas Rockwell

2006-03-01

Background: This study was designed to evaluate the integral dose (ID) received by normal tissue from intensity-modulated radiotherapy (IMRT) for prostate cancer. Methods and Materials: Twenty-five radiation treatment plans including IMRT using a conventional linac with both 6 MV (6MV-IMRT) and 20 MV (20MV-IMRT), as well as three-dimensional conformal radiotherapy (3DCRT) using 6 MV (6MV-3DCRT) and 20 MV (20MV-3DCRT) and IMRT using tomotherapy (6MV) (Tomo-IMRT), were created for 5 patients with localized prostate cancer. The ID (mean dose x tissue volume) received by normal tissue (NTID) was calculated from dose-volume histograms. Results: The 6MV-IMRT resulted in 5.0% lower NTID thanmore » 6MV-3DCRT; 20 MV beam plans resulted in 7.7%-11.2% lower NTID than 6MV-3DCRT. Tomo-IMRT NTID was comparable to 6MV-IMRT. Compared with 6MV-3DCRT, 6MV-IMRT reduced IDs to the rectal wall and penile bulb by 6.1% and 2.7%, respectively. Tomo-IMRT further reduced these IDs by 11.9% and 16.5%, respectively. The 20 MV did not reduce IDs to those structures. Conclusions: The difference in NTID between 3DCRT and IMRT is small. The 20 MV plans somewhat reduced NTID compared with 6 MV plans. The advantage of tomotherapy over conventional IMRT and 3DCRT for localized prostate cancer was demonstrated in regard to dose sparing of rectal wall and penile bulb while slightly decreasing NTID as compared with 6MV-3DCRT.« less

Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer.

PubMed

Kong, Zhe; Wan, Xuechao; Zhang, Yalong; Zhang, Pu; Zhang, Yingyi; Zhang, Xiaona; Qi, Xiaoxiang; Wu, Hai; Huang, Jianfeng; Li, Yao

2017-11-25

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. Circular RNA (circRNA) is a unique class of RNA transcribed by RNA polymerase II characterized by jointing 3' and 5' ends together via exon or intron circularization. However, the molecular functions of circRNAs in prostate cancer have rarely been explored. In present study, we found circ-SMARCA5 was up-regulated in prostate cancer samples compared to match normal tissues. We also observed circ-SMARCA5 expression was significantly induced after DHT treatment. Functional experiments showed circ-SMARCA5 acted as an oncogene in prostate cancer by promoting cell cycle and inhibiting cell apoptosis. We thought this study provided useful information for exploring circRNAs as potential therapeutic and prognostic targets for prostate cancer. Copyright © 2017. Published by Elsevier Inc.

Interstitial laser prostatectomy

NASA Astrophysics Data System (ADS)

Johnson, Douglas E.; Cromeens, Douglas M.; Price, Roger E.

1994-05-01

Interstitial laser coagulation of the canine prostate using the Sharplan interstitial thermal therapy fiber (Model 25432) was performed in 9 adult dogs and the subsequent gross and histopathologic changes occurring in the prostate were studied at intervals ranging from 1 hour to 5 weeks. A large well-demarcated area of acute coagulative necrosis developed around each fiber tract which in turn was surrounded by a prominent narrow zone of marked tissue disruption and an outer zone of hemorrhage. Liquefaction developed within the coagulative areas within 24 hours and by 4 days, each prostatic lobe contained an irregular cavity which became lined by normal-appearing transitional epithelium and that by 5 weeks, communicated with the prostatic urethra. These changes, similar to those reported following transurethral visual laser ablation of the prostate, suggest that interstitial laser thermal therapy may provide an alternative means for treating selected patients suffering from prostatic enlargement.

Are blood group isoantigens lost from malignant prostatic epithelium? Immunohistochemical support for the preservation of the H isoantigen.

PubMed Central

Vowden, P.; Lowe, A. D.; Lennox, E. S.; Bleehen, N. M.

1986-01-01

Previous studies while demonstrating the presence of blood group isoantigens on normal prostatic epithelium have failed to identify such antigens on malignant prostatic tissue. Using a series of blood group specific monoclonal antibodies directed towards the A, B, H and Y antigens we have reinvestigated blood group isoantigen expression in both benign prostatic hypertrophy and prostatic adenocarcinoma. Results obtained from areas of benign prostatic hypertrophy are in broad agreement with those published however though we were unable to detect either A or B blood group isoantigens Type 2H and Y isoantigens were identified in 10 of the 12 tumours. These findings, while differing from previously reported results, lend support to the suggested connection between ontogenesis, oncogenesis and blood group isoantigen expression and also support the proposed link between Type 2 structures and malignant transformation. Images Figure 1 Figure 2 PMID:2421753

Altered prostate epithelial development in mice lacking the androgen receptor in stromal fibroblasts.

PubMed

Yu, Shengqiang; Yeh, Chiuan-Ren; Niu, Yuanjie; Chang, Hong-Chiang; Tsai, Yu-Chieh; Moses, Harold L; Shyr, Chih-Rong; Chang, Chawnshang; Yeh, Shuyuan

2012-03-01

Androgens and the androgen receptor (AR) play important roles in the development of male urogenital organs. We previously found that mice with total AR knockout (ARKO) and epithelial ARKO failed to develop normal prostate with loss of differentiation. We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate. However, AR roles of stromal fibroblasts in prostate development remain unclear. To further probe the stromal fibroblast AR roles in prostate development, we generated tissue-selective knockout mice with the AR gene deleted in stromal fibroblasts (FSP-ARKO). We also used primary culture stromal cells to confirm the in vivo data and investigate mechanisms related to prostate development. The results showed cellular alterations in the FSP-ARKO mouse prostate with decreased epithelial proliferation, increased apoptosis, and decreased collagen composition. Further mechanistic studies demonstrated that FSP-ARKO mice have defects in the expression of prostate stromal growth factors. To further confirm these in vivo findings, we prepared primary cultured mouse prostate stromal cells and found knocking down the stromal AR could result in growth retardation of prostate stromal cells and co-cultured prostate epithelial cells, as well as decrease of some stromal growth factors. Our FSP-ARKO mice not only provide the first in vivo evidence in Cre-loxP knockout system for the requirement of stromal fibroblast AR to maintain the normal development of the prostate, but may also suggest the selective knockdown of stromal AR might become a potential therapeutic approach to battle prostate hyperplasia and cancer. Copyright © 2011 Wiley Periodicals, Inc.

Expression and Genetic Variation in Neuroendocrine Signaling Pathways in Lethal and Nonlethal Prostate Cancer among Men Diagnosed with Localized Disease.

PubMed

Lu, Donghao; Carlsson, Jessica; Penney, Kathryn L; Davidsson, Sabina; Andersson, Swen-Olof; Mucci, Lorelei A; Valdimarsdóttir, Unnur; Andrén, Ove; Fang, Fang; Fall, Katja

2017-12-01

Background: Recent data suggest that neuroendocrine signaling pathways may play a role in the progression of prostate cancer, particularly for early-stage disease. We aimed to explore whether expression of selected genes in the adrenergic, serotoninergic, glucocorticoid, and dopaminergic pathways differs in prostate tumor tissue from men with lethal disease compared with men with nonlethal disease. Methods: On the basis of the Swedish Watchful Waiting Cohort, we included 511 men diagnosed with incidental prostate cancer through transurethral resection of the prostate during 1977-1998 with follow-up up to 30 years. For those with tumor tissue ( N = 262), we measured mRNA expression of 223 selected genes included in neuroendocrine pathways. Using DNA from normal prostate tissue ( N = 396), we genotyped 36 SNPs from 14 receptor genes. Lethal prostate cancer was the primary outcome in analyses with pathway gene expression and genetic variants. Results: Differential expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer ( P = 0.007); similar but weaker associations were noted for the adrenergic ( P = 0.014) and glucocorticoid ( P = 0.020) pathways. Variants of the HTR2A (rs2296972; P = 0.002) and NR3CI (rs33388; P = 0.035) genes (within the serotoninergic and glucocorticoid pathways) were associated with lethal cancer in overdominant models. These genetic variants were correlated with expression of several genes in corresponding pathways ( P < 0.05). Conclusions: Our findings lend support to hypothesis that the neuroendocrine pathways, particularly serotoninergic pathway, are associated with lethal outcome in the natural course of localized prostate cancer. Impact: This study provides evidence of the role of neuroendocrine pathways in prostate cancer progression that may have clinical utility. Cancer Epidemiol Biomarkers Prev; 26(12); 1781-7. ©2017 AACR . ©2017 American Association for Cancer Research.

Bad seeds produce bad crops: a single stage-process of prostate tumor invasion

PubMed Central

Man, Yan-gao; Gardner, William A.

2008-01-01

It is a commonly held belief that prostate carcinogenesis is a multi-stage process and that tumor invasion is triggered by the overproduction of proteolytic enzymes. This belief is consistent with data from cell cultures and animal models, whereas is hard to interpret several critical facts, including the presence of cancer in “healthy” young men and cancer DNA phenotype in morphologically normal prostate tissues. These facts argue that alternative pathways may exist for prostate tumor invasion in some cases. Since degradation of the basal cell layer is the most distinct sign of invasion, our recent studies have attempted to identify pre-invasive lesions with focal basal cell layer alterations. Our studies revealed that about 30% of prostate cancer patients harbored normal appearing duct or acinar clusters with a high frequency of focal basal cell layer disruptions. These focally disrupted basal cell layers had significantly reduced cell proliferation and tumor suppressor expression, whereas significantly elevated degeneration, apoptosis, and infiltration of immunoreactive cells. In sharp contrast, associated epithelial cell had significantly elevated proliferation, expression of malignancy-signature markers, and physical continuity with invasive lesions. Based on these and other findings, we have proposed that these normal appearing duct or acinar clusters are derived from monoclonal proliferation of genetically damaged stem cells and could progress directly to invasion through two pathways: 1) clonal in situ transformation (CIST) and 2) multi-potential progenitor mediated “budding” (MPMB). These pathways may contribute to early onset of prostate cancer at young ages, and to clinically more aggressive prostate tumors. PMID:18725981

Gene expression profile of mouse prostate tumors reveals dysregulations in major biological processes and identifies potential murine targets for preclinical development of human prostate cancer therapy.

PubMed

Haram, Kerstyn M; Peltier, Heidi J; Lu, Bin; Bhasin, Manoj; Otu, Hasan H; Choy, Bob; Regan, Meredith; Libermann, Towia A; Latham, Gary J; Sanda, Martin G; Arredouani, Mohamed S

2008-10-01

Translation of preclinical studies into effective human cancer therapy is hampered by the lack of defined molecular expression patterns in mouse models that correspond to the human counterpart. We sought to generate an open source TRAMP mouse microarray dataset and to use this array to identify differentially expressed genes from human prostate cancer (PCa) that have concordant expression in TRAMP tumors, and thereby represent lead targets for preclinical therapy development. We performed microarrays on total RNA extracted and amplified from eight TRAMP tumors and nine normal prostates. A subset of differentially expressed genes was validated by QRT-PCR. Differentially expressed TRAMP genes were analyzed for concordant expression in publicly available human prostate array datasets and a subset of resulting genes was analyzed by QRT-PCR. Cross-referencing differentially expressed TRAMP genes to public human prostate array datasets revealed 66 genes with concordant expression in mouse and human PCa; 56 between metastases and normal and 10 between primary tumor and normal tissues. Of these 10 genes, two, Sox4 and Tubb2a, were validated by QRT-PCR. Our analysis also revealed various dysregulations in major biologic pathways in the TRAMP prostates. We report a TRAMP microarray dataset of which a gene subset was validated by QRT-PCR with expression patterns consistent with previous gene-specific TRAMP studies. Concordance analysis between TRAMP and human PCa associated genes supports the utility of the model and suggests several novel molecular targets for preclinical therapy.

Biodistribution of [(68)Ga]PSMA-HBED-CC in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour Lesions.

PubMed

Prasad, Vikas; Steffen, Ingo G; Diederichs, Gerd; Makowski, Marcus R; Wust, Peter; Brenner, Winfried

2016-06-01

The aim of this study was to determine the physiological and pathophysiological biodistribution of [(68)Ga]PSMA-HBED-CC (PSMA-11) ([(68)Ga]PSMA) in patients with prostate cancer (PCA) to establish the range of normal uptake in relevant organs and primary prostate tumours, locally recurrent PCA, lymph and bone metastases and other metastatic lesions. Additionally, we aimed to determine a cut-off uptake value for differentiation of primary tumours from normal prostate tissue. Overall, [(68)Ga]PSMA positron emission tomography/x-ray computed tomography (PET/CT) of 101 patients (mean age 69.1 years) with PCA was analysed retrospectively. For assessment of tracer biodistribution, maximum standardized uptake values (SUVmax) were calculated for various normal organs, as well as for primary tumours (PT) and/or metastases. Results are presented as median, interquartile range (IQR; 25th quantil-75th quantil) and range (minimum-maximum). [(68)Ga]PSMA PET/CT was performed 50 min (range 30-126) after injection of 109 MBq (range 84-158). Regarding biodistribution, highest uptake (median/IQR/range) of the tracer was found in the kidneys (49.6/40.7-57.6/2.7-97.0) followed by the submandibular glands (17.3/13.7-21.2/7.5-30.4), parotid glands (16.1/12.2-19.8/5.5-30.9) and duodenum (13.8/10.5-17.2/5.8-26.9). The best cut-off value for differentiating physiological uptake in the primary tumour from that in the prostate was found to be an SUVmax of 3.2. The median SUVmax in the PT (n = 35), locally recurrent PCA (n = 8), lymph node (n = 166), bone (n = 157) and other metastases (n = 3) were 10.2, 5.9, 6.2, 7.4 and 3.8, respectively. The best cut-off values for differentiating non-pathological uptake in lymph nodes and bones from tumour uptake were found to be SUVmax of 3.2 and 1.9, respectively. Patients with PSA <2 had significantly lower SUVmax in bone metastases as compared to patients with PSA ≥2 (p < 0.01). This biodistribution study provided a broad range of uptake data of [(68)Ga]PSMA-11 for normal organs/tissues, primary prostate tumours and metastatic lesions based on a large patient cohort. Both PT and small metastatic lesions were detectable due to their high tracer uptake. Four-times-higher median uptake in PT in comparison to normal prostate stroma resulted in a high diagnostic accuracy that could potentially be used for multimodal image-guided biopsy with dedicated reconstruction software.

p62 as a therapeutic target for inhibition of autophagy in prostate cancer.

PubMed

Wang, Lei; Kim, Donghern; Wise, James T F; Shi, Xianglin; Zhang, Zhuo; DiPaola, Robert S

2018-04-01

To test the hypothesis that p62 is an optimal target for autophagy inhibition and Verteporfin, a clinically available drug approved by FDA to treat macular degeneration that inhibits autophagy by targeting p62 protein, can be developed clinically to improve therapy for advanced prostate cancer. Forced expression of p62 in PC-3 cells and normal prostate epithelial cells, RWPE-1 and PZ-HPV7, were carried out by transfection of these cells with pcDNA3.1/p62 or p62 shRNA plasmid. Autophagosomes and autophagic flux were measured by transfection of tandem fluorescence protein mCherry-GFP-LC3 construct. Apoptosis was measured by Annexin V/PI staining. Tumorigenesis was measured by a xenograft tumor growth model. Verteporfin inhibited cell growth and colony formation in PC-3 cells. Verteporfin generated crosslinked p62 oligomers, resulting in inhibition of autophagy and constitutive activation of Nrf2 as well as its target genes, Bcl-2 and TNF-α. In normal prostate epithelial cells, forced expression of p62 caused constitutive Nrf2 activation, development of apoptosis resistance, and Verteporfin treatment exhibited inhibitory effects. Verteporfin treatment also inhibited starvation-induced autophagic flux of these cells. Verteporfin inhibited tumorigenesis of both normal prostate epithelial cells with p62 expression and prostate cancer cells and decreased p62, constitutive Nrf2, and Bcl-xL in xenograft tumor tissues, indicating that p62 can be developed as a drug target against prostate cancer. p62 has a high potential to be developed as a therapeutic target. Verteporfin represents a prototypical agent with therapeutic potential against prostate cancer through inhibition of autophagy by a novel mechanism of p62 inhibition. © 2018 Wiley Periodicals, Inc.

Biotechnology

NASA Image and Video Library

2001-05-15

This prostate cancer construct was grown during NASA-sponsored bioreactor studies on Earth. Cells are attached to a biodegradable plastic lattice that gives them a head start in growth. Prostate tumor cells are to be grown in a NASA-sponsored Bioreactor experiment aboard the STS-107 Research-1 mission in 2002. Dr. Leland Chung of the University of Virginia is the principal investigator. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: NASA and the University of Virginia.

[Prostate cancer detection by assessing stiffness of different tissues using shear wave ultrasound elastog- raphy].

PubMed

Glybochko, P V; Alyaev, Yu G; Amosov, A V; Krupinov, G E; Ganzha, T M; Vorobev, A V; Lumpov, I S; Semendyaev, R I

2016-08-01

Early detection of prostate cancer (PCa) remains a challenging issue. There are studies underway aimed to develop and implement new methods for prostate cancer screening by tumor imaging and obtaining tissue samples from suspicious areas for morphological examination. One of these new methods is shear wave ultrasound elastography (SWUE). The current literature is lacking sufficient coverage of informativeness and specificity of SWUE in the prostate cancer detection, there is no clear criteria for assessing tissue stiffness at different values of PSA and tumor grade, and in prostate hyperplasia and prostatitis. To evaluate the informativeness and specificity of SWUE compared with other diagnostic methods. SWUE has been used in the Clinic of Urology of Sechenov First MSMU since October 2015. During this period, 302 patients were examined using SWUE. SWUE was performed with Aixplorer ultrasound system (Super Sonic Imagine), which provides a single-stage SWUE imaging with both B-mode and real-time mode. The first group (prospective study) included 134 men aged 47 to 81 years with suspected prostate cancer scheduled to either initial or repeat prostate biopsy. PSA levels ranged from 4 to 24 ng/ml. The second group (retrospective study) comprised 120 men with confirmed prostate cancer and PSA levels between 4 and 90 ng/ml. The third group (the control group), comprised 48 healthy men whose PSA level did not exceed 3 ng/ml. All patients of the groups 1 and 2 underwent a standard comprehensive examination. Patients in group 1 were subsequently subjected to transrectal prostate biopsy guided by localization of areas with abnormal tissue stiffness. PCa was detected in 100 of 134 patients. 217 patients of groups 1 and 2 underwent radical prostatectomy. In 28 of them, the match between the cancer location and differentiation in the removed prostate and SWUE findings before surgery was examined. Contrast-enhanced magnetic resonance imaging of pelvic organs was performed in 63 patients of groups 1 and 2. Threshold values of stiffness (Emean) were determined, which normally range from 0 to 23 kPa, from 23.4 to 50 kPa in prostatic hyperplasia and 50.5 kPa and greater in prostate cancer. A total of 220 patients in groups 1 and 2 were found to have prostate cancer. The findings showed increased stiffness of prostate tissue depending on tumor differentiation, Gleason score, and hence, cancer risk. The sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) were calculated for SWUE, biopsy based on 6 peripheral points used during SWUE, and for histologic findings from prostate cross sections. When compared to needle biopsy, Se, Sp, PPV, NPV for SWUE were 90.8, 94.6, 56.6 and 97.9%, respectively. The study findings suggest a high diagnostic performance of SWUE in detecting prostate cancer.

Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples

PubMed Central

2011-01-01

Background Readthrough fusions across adjacent genes in the genome, or transcription-induced chimeras (TICs), have been estimated using expressed sequence tag (EST) libraries to involve 4-6% of all genes. Deep transcriptional sequencing (RNA-Seq) now makes it possible to study the occurrence and expression levels of TICs in individual samples across the genome. Methods We performed single-end RNA-Seq on three human prostate adenocarcinoma samples and their corresponding normal tissues, as well as brain and universal reference samples. We developed two bioinformatics methods to specifically identify TIC events: a targeted alignment method using artificial exon-exon junctions within 200,000 bp from adjacent genes, and genomic alignment allowing splicing within individual reads. We performed further experimental verification and characterization of selected TIC and fusion events using quantitative RT-PCR and comparative genomic hybridization microarrays. Results Targeted alignment against artificial exon-exon junctions yielded 339 distinct TIC events, including 32 gene pairs with multiple isoforms. The false discovery rate was estimated to be 1.5%. Spliced alignment to the genome was less sensitive, finding only 18% of those found by targeted alignment in 33-nt reads and 59% of those in 50-nt reads. However, spliced alignment revealed 30 cases of TICs with intervening exons, in addition to distant inversions, scrambled genes, and translocations. Our findings increase the catalog of observed TIC gene pairs by 66%. We verified 6 of 6 predicted TICs in all prostate samples, and 2 of 5 predicted novel distant gene fusions, both private events among 54 prostate tumor samples tested. Expression of TICs correlates with that of the upstream gene, which can explain the prostate-specific pattern of some TIC events and the restriction of the SLC45A3-ELK4 e4-e2 TIC to ERG-negative prostate samples, as confirmed in 20 matched prostate tumor and normal samples and 9 lung cancer cell lines. Conclusions Deep transcriptional sequencing and analysis with targeted and spliced alignment methods can effectively identify TIC events across the genome in individual tissues. Prostate and reference samples exhibit a wide range of TIC events, involving more genes than estimated previously using ESTs. Tissue specificity of TIC events is correlated with expression patterns of the upstream gene. Some TIC events, such as MSMB-NCOA4, may play functional roles in cancer. PMID:21261984

Clinical significance of CXCL16/CXCR6 expression in patients with prostate cancer.

PubMed

Ha, Hong Koo; Lee, Wan; Park, Hyun Jun; Lee, Sang Don; Lee, Jeong Zoo; Chung, Moon Kee

2011-01-01

We hypothesized that the CXCL16-CXCR6 ligand-receptor system may play an important role in prostate cancer progression. Levels of CXCL16 and CXCR6 expression were evaluated in prostate cancer cell lines (PC-3 and LNCaP) and normal prostate epithelial cells (PrEC), as well as in tissues from 354 patients. The immunohistochemical expression of CXCL16/CXCR6 was greater in the PC-3/LNCaP cells than in the PrEC cell line. The expression of CXCL16/CXCR6 was significantly higher in prostate cancer than in benign prostatic hypertrophy. Using RT-PCR, the expression of CXCL16/CXCR6 was found to be greater in the PC-3/LNCaP cells than in the PrEC cell line. CXCL16/CXCR6 was weakly detected in lung and liver tissues, whereas CXCL16 was highly expressed in specimens of bone metastasis. CXCL16 immunostaining was related to Gleason score, T stage, tumor volume, perineural invasion and lymph node metastasis. However, biochemical PSA recurrence was not related to the expression of CXCL16/CXCR6. High CXCL16/CXCR6 expression may be related to aggressive cancer behavior, and high CXCL16 expression to bone metastases.

Prostate cancer diagnosis with fluorescence lifetime imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sridharan, Shamira; Gandour-Edwards, Regina F.; Dall'Era, Marc; Marcu, Laura

2017-02-01

More than 1 million men in the United States undergo a prostate biopsy procedure annually and approximately 200,000 men receive a diagnosis of prostate cancer. 5-10% of these men have to undergo a repeat biopsy due to insufficient tissue sampling. We are studying the utility of a multi-spectral time resolved fluorescence spectroscopy (MS-TRFS) technique for real-time prostate cancer diagnosis. The MS-TRFS imaging setup, which includes a fiberoptic set-up with a 355nm excitation light source coupled with a blue (450nm) aiming beam, was used to image ex-vivo prostatectomy specimen. The prostate tissue from 11 patients was sectioned at 2mm thickness and the fluorescence lifetime information was overlaid spatially for histology and thus, diagnostic co-registration. Initial results show that fluorescence lifetime in the 390±40nm channel, which measures collagen and elastin signatures, is longer for glandular regions than in the stromal regions. Additionally, lifetime in the 452±45nm channel, corresponding to NAD redox state, is longer in the cancerous glandular region in comparison with the normal glandular regions. Current work is focused on developing real-time quantitative algorithms to combine the fluorescence signatures from the two channels for performing prostate cancer diagnosis on biopsies.

Evaluation of high intensity focused ultrasound ablation of prostate tumor with hyperpolarized 13C imaging biomarkers

NASA Astrophysics Data System (ADS)

Lee, Jessie E.; Diederich, Chris J.; Salgaonkar, Vasant A.; Bok, Robert; Taylor, Andrew G.; Kurhanewicz, John

2015-03-01

Real-time hyperpolarized (HP) 13C MR can be utilized during high-intensity focal ultrasound (HIFU) therapy to improve treatment delivery strategies, provide treatment verification, and thus reduce the need for more radical therapies for lowand intermediate-risk prostate cancers. The goal is to develop imaging biomarkers specific to thermal therapies of prostate cancer using HIFU, and to predict the success of thermal coagulation and identify tissues potentially sensitized to adjuvant treatment by sub-ablative hyperthermic heat doses. Mice with solid prostate tumors received HIFU treatment (5.6 MHz, 160W/cm2, 60 s), and the MR imaging follow-ups were performed on a wide-bore 14T microimaging system. 13C-labeled pyruvate and urea were used to monitor tumor metabolism and perfusion accordingly. After treatment, the ablated tumor tissue had a loss in metabolism and perfusion. In the regions receiving sub-ablative heat dose, a timedependent change in metabolism and perfusion was observed. The untreated regions behaved as a normal untreated TRAMP prostate tumor would. This promising preliminary study shows the potential of using 13C MR imaging as biomarkers of HIFU/thermal therapies.

Microgravity

NASA Image and Video Library

1996-06-01

The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues currently being cultured in rotating bioreactors by investigators

Microgravity

NASA Image and Video Library

1988-07-14

The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues currently being cultured in rotating bioreactors by investigators.

Bioreactor

NASA Technical Reports Server (NTRS)

1996-01-01

The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues currently being cultured in rotating bioreactors by investigators

Rotating Bioreactor

NASA Technical Reports Server (NTRS)

1988-01-01

The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues currently being cultured in rotating bioreactors by investigators.

Dual action of high estradiol doses on MNU-induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment.

PubMed

Gonçalves, Bianca F; de Campos, Silvana G P; Góes, Rejane M; Scarano, Wellerson R; Taboga, Sebastião R; Vilamaior, Patricia S L

2017-06-01

Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms. We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues. Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns. Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time. © 2017 Wiley Periodicals, Inc.

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor

PubMed Central

Guo, W; Liu, R; Bhardwaj, G; Yang, J C; Changou, C; Ma, A-H; Mazloom, A; Chintapalli, S; Xiao, K; Xiao, W; Kumaresan, P; Sanchez, E; Yeh, C-T; Evans, C P; Patterson, R; Lam, K S; Kung, H-J

2014-01-01

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a ‘wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model. PMID:25188519

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor.

PubMed

Guo, W; Liu, R; Bhardwaj, G; Yang, J C; Changou, C; Ma, A-H; Mazloom, A; Chintapalli, S; Xiao, K; Xiao, W; Kumaresan, P; Sanchez, E; Yeh, C-T; Evans, C P; Patterson, R; Lam, K S; Kung, H-J

2014-09-04

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a 'wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model.

Gold Nanoconstructs for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy

NASA Astrophysics Data System (ADS)

Coughlin, Andrew James

Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.

Interphase cytogenetics of prostatic carcinoma in fine needle aspirate smears of radical prostatectomy specimens: A practical screening tool?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, R.Y.; Troncoso, P.; El-Naggar, A.K.

1994-09-01

Identification of chromosomal aberrations that may be used for diagnostic or prognostic evaluation of prostatic adenocarcinoma has been the subject of great interest. In a previous study, we applied the fluorescence in situ hybridization (FISH) method on paraffin-embedded material to show that trisomy 7 was associated with the progression of human prostate cancer. In this study, we attempted to assess the utility of the FISH technique in detecting aneuploidy in fine needle aspirate (FNA) smears of prostatic tissues and to compare FISH results with that of DNA flow cytometry (FCM). Paired samples of normal and tumor FNA smears were obtainedmore » from 10 radical prostatectomy specimens. Dual-color chromosomes 7 and 9-specific centromeric DNA probes were used for FISH. FISH analysis demonstrated increased frequencies of trisomy 7 cells in all 10 tumors studied when compared with the paired normals. In contrast, 6 of 10 tumors were determined to be diploid by FCM. Our results show that FNA of radical prostatectomy specimens is a practical method for obtaining suitable material for both FISH and FCM analyses of prostate carcinoma. Thus, interphase FISH may be a practical screening tool to determine aneuploidy in FNA smears of prostatic carcinoma.« less

Highly sensitive molecular diagnosis of prostate cancer using surplus material washed off from biopsy needles

PubMed Central

Bermudo, R; Abia, D; Mozos, A; García-Cruz, E; Alcaraz, A; Ortiz, Á R; Thomson, T M; Fernández, P L

2011-01-01

Introduction: Currently, final diagnosis of prostate cancer (PCa) is based on histopathological analysis of needle biopsies, but this process often bears uncertainties due to small sample size, tumour focality and pathologist's subjective assessment. Methods: Prostate cancer diagnostic signatures were generated by applying linear discriminant analysis to microarray and real-time RT–PCR (qRT–PCR) data from normal and tumoural prostate tissue samples. Additionally, after removal of biopsy tissues, material washed off from transrectal biopsy needles was used for molecular profiling and discriminant analysis. Results: Linear discriminant analysis applied to microarray data for a set of 318 genes differentially expressed between non-tumoural and tumoural prostate samples produced 26 gene signatures, which classified the 84 samples used with 100% accuracy. To identify signatures potentially useful for the diagnosis of prostate biopsies, surplus material washed off from routine biopsy needles from 53 patients was used to generate qRT–PCR data for a subset of 11 genes. This analysis identified a six-gene signature that correctly assigned the biopsies as benign or tumoural in 92.6% of the cases, with 88.8% sensitivity and 96.1% specificity. Conclusion: Surplus material from prostate needle biopsies can be used for minimal-size gene signature analysis for sensitive and accurate discrimination between non-tumoural and tumoural prostates, without interference with current diagnostic procedures. This approach could be a useful adjunct to current procedures in PCa diagnosis. PMID:22009027

Prostate volumetric‐modulated arc therapy: dosimetry and radiobiological model variation between the single‐arc and double‐arc technique

PubMed Central

Jiang, Runqing

2013-01-01

This study investigates the dosimetry and radiobiological model variation when a second photon arc was added to prostate volumetric‐modulated arc therapy (VMAT) using the single‐arc technique. Dosimetry and radiobiological model comparison between the single‐arc and double‐arc prostate VMAT plans were performed on five patients with prostate volumes ranging from 29−68.1 cm3. The prescription dose was 78 Gy/39 fractions and the photon beam energy was 6 MV. Dose‐volume histogram, mean and maximum dose of targets (planning and clinical target volume) and normal tissues (rectum, bladder and femoral heads), dose‐volume criteria in the treatment plan (D99% of PTV; D30%,D50%,V17Gy and V35Gy of rectum and bladder; D5% of femoral heads), and dose profiles along the vertical and horizontal axis crossing the isocenter were determined using the single‐arc and double‐arc VMAT technique. For comparison, the monitor unit based on the RapidArc delivery method, prostate tumor control probability (TCP), and rectal normal tissue complication probability (NTCP) based on the Lyman‐Burman‐Kutcher algorithm were calculated. It was found that though the double‐arc technique required almost double the treatment time than the single‐arc, the double‐arc plan provided a better rectal and bladder dose‐volume criteria by shifting the delivered dose in the patient from the anterior–posterior direction to the lateral. As the femoral head was less radiosensitive than the rectum and bladder, the double‐arc technique resulted in a prostate VMAT plan with better prostate coverage and rectal dose‐volume criteria compared to the single‐arc. The prostate TCP of the double‐arc plan was found slightly increased (0.16%) compared to the single‐arc. Therefore, when the rectal dose‐volume criteria are very difficult to achieve in a single‐arc prostate VMAT plan, it is worthwhile to consider the double‐arc technique. PACS number: 87.55.D‐, 87.55.dk, 87.55.K‐, 87.55.Qr

Identification of Potential Prostate Cancer-Related Pseudogenes Based on Competitive Endogenous RNA Network Hypothesis.

PubMed

Jiang, Tao; Guo, Junjie; Hu, Zhongchun; Zhao, Ming; Gu, Zhenggang; Miao, Shu

2018-06-20

BACKGROUND Long noncoding RNAs (lncRNAs) have been revealed to function as competing endogenous RNAs (ceRNAs), which can seclude the common microRNAs (miRNAs) and hence prevent the miRNAs from binding to their ancestral gene. Nonetheless, the role of lncRNA-mediated ceRNAs in prostate cancer has not yet been elucidated. MATERIAL AND METHODS Using The Cancer Genome Atlas (TCGA) database, lncRNA, miRNA, and mRNA profiles from 499 prostate cancer tissues and 52 normal prostate tissues were analyzed with the R package "DESeq" to identify the differentially expressed RNAs. GO and KEGG pathway analyses were performed using "DAVID6.8" and R packages "Clusterprofile." The ceRNA network in prostate cancer was constructed using miRDB, miRTarBase, and TargetScan databases. Survival analysis was performed with Kaplan-Meier analysis. RESULTS A total of 376 lncRNAs, 33 miRNAs, and 687 mRNAs were identified as significant factors in tumorigenesis. Based on the hypothesis that the ceRNA network (lncRNA-miRNA-mRNA regulatory axis) is involved in prostate cancer and forms competitive interrelations between miRNA and mRNA or lncRNA, we constructed a ceRNA network that included 23 lncRNAs, 6 miRNAs, and 2 mRNAs that were differentially expressed in prostate cancer. Only 3 lncRNAs (LINC00308, LINC00355, and OSTN-AS1) had a significant association with survival (P<0.05). The 3 prostate cancer-specific lncRNA were validated in prostate cancer cell lines PC3 and DU145 using qRT-PCR. CONCLUSIONS We demonstrated the differential lncRNA expression profiles in prostate cancer, which provides new insights for future studies of the ceRNA network and its regulatory mechanisms in prostate cancer.

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

PubMed Central

Thysell, Elin; Halin Bergström, Sofia; Bergh, Anders

2017-01-01

In order to grow and spread tumors need to interact with adjacent tissues. We therefore hypothesized that small but aggressive prostate cancers influence the rest of the prostate and regional lymph nodes differently than tumors that are more indolent. Poorly metastatic (Dunning AT1) or highly metastatic (Dunning MLL) rat prostate tumor cells were injected into the ventral prostate lobe of immunocompetent rats. After 10 days—when the tumors occupied about 30% of the prostate lobe and lymph node metastases were undetectable—the global gene expression in tumors, benign parts of the prostate, and regional iliac lymph nodes were examined to define tumor-induced changes related to preparation for future metastasis. The tumors induced profound effects on the gene expression profiles in the benign parts of the prostate and these were strikingly different in the two tumor models. Gene ontology enrichment analysis suggested that tumors with high metastatic capacity were more successful than less metastatic tumors in inducing tumor-promoting changes and suppressing anti-tumor immune responses in the entire prostate. Some of these differences such as altered angiogenesis, nerve density, accumulation of T-cells and macrophages were verified by immunohistochemistry. Gene expression alterations in the regional lymph nodes suggested decreased quantity and activation of immune cells in MLL-lymph nodes that were also verified by immunostaining. In summary, even when small highly metastatic prostate tumors can affect the entire tumor-bearing organ and pre-metastatic lymph nodes differently than less metastatic tumors. When the kinetics of these extratumoral influences (by us named TINT = tumor instructed normal tissue) are more precisely defined they could potentially be used as markers of disease aggressiveness and become therapeutic targets. PMID:28472073

Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate

PubMed Central

Chung, Ivy; Montecinos, Viviana P.; Buttyan, Ralph; Johnson, Candace S.; Smith, Gary J.

2013-01-01

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients. PMID:23548616

Ghrelin O-acyltransferase (GOAT) enzyme is overexpressed in prostate cancer, and its levels are associated with patient's metabolic status: Potential value as a non-invasive biomarker.

PubMed

Hormaechea-Agulla, Daniel; Gómez-Gómez, Enrique; Ibáñez-Costa, Alejandro; Carrasco-Valiente, Julia; Rivero-Cortés, Esther; L-López, Fernando; Pedraza-Arevalo, Sergio; Valero-Rosa, José; Sánchez-Sánchez, Rafael; Ortega-Salas, Rosa; Moreno, María M; Gahete, Manuel D; López-Miranda, José; Requena, María J; Castaño, Justo P; Luque, Raúl M

2016-12-01

Ghrelin-O-acyltransferase (GOAT) is the key enzyme regulating ghrelin activity, and has been proposed as a potential therapeutic target for obesity/diabetes and as a biomarker in some endocrine-related cancers. However, GOAT presence and putative role in prostate-cancer (PCa) is largely unknown. Here, we demonstrate, for the first time, that GOAT is overexpressed (mRNA/protein-level) in prostatic tissues (n = 52) and plasma/urine-samples (n = 85) of PCa-patients, compared with matched controls [healthy prostate tissues (n = 12) and plasma/urine-samples from BMI-matched controls (n = 28), respectively]. Interestingly, GOAT levels in PCa-patients correlated with aggressiveness and metabolic conditions (i.e. diabetes). Actually, GOAT expression was regulated by metabolic inputs (i.e. In1-ghrelin, insulin/IGF-I) in cultured normal prostate cells and PCa-cell lines. Importantly, ROC-curve analysis unveiled a valuable diagnostic potential for GOAT to discriminate PCa at the tissue/plasma/urine-level with high sensitivity/specificity, particularly in non-diabetic individuals. Moreover, we discovered that GOAT is secreted by PCa-cells, and that its levels are higher in urine samples from a stimulated post-massage vs. pre-massage prostate-test. In conclusion, plasmatic GOAT levels exhibit high specificity/sensitivity to predict PCa-presence compared with other PCa-biomarkers, especially in non-diabetic individuals, suggesting that GOAT holds potential as a novel non-invasive PCa-biomarker. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epigenetics-related genes in prostate cancer: expression profile in prostate cancer tissues, androgen-sensitive and -insensitive cell lines.

PubMed

Shaikhibrahim, Zaki; Lindstrot, Andreas; Ochsenfahrt, Jacqueline; Fuchs, Kerstin; Wernert, Nicolas

2013-01-01

Epigenetic changes have been suggested to drive prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to identify novel epigenetics-related genes in PCa tissues, and to examine their expression in metastatic PCa cell lines. We analyzed the expression of epigenetics-related genes via a clustering analysis based on gene function in moderately and poorly differentiated PCa glands compared to normal glands of the peripheral zone (prostate proper) from PCa patients using Whole Human Genome Oligo Microarrays. Our analysis identified 12 epigenetics-related genes with a more than 2-fold increase or decrease in expression and a p-value <0.01. In modera-tely differentiated tumors compared to normal glands of the peripheral zone, we found the genes, TDRD1, IGF2, DICER1, ADARB1, HILS1, GLMN and TRIM27, to be upregulated, whereas TNRC6A and DGCR8 were found to be downregulated. In poorly differentiated tumors, we found TDRD1, ADARB and RBM3 to be upregulated, whereas DGCR8, PIWIL2 and BC069781 were downregulated. Our analysis of the expression level for each gene in the metastatic androgen-sensitive VCaP and LNCaP, and -insensitive PC3 and DU-145 PCa cell lines revealed differences in expression among the cell lines which may reflect the different biological properties of each cell line, and the potential role of each gene at different metastatic sites. The novel epigenetics-related genes that we identified in primary PCa tissues may provide further insight into the role that epigenetic changes play in PCa. Moreover, some of the genes that we identified may play important roles in primary PCa and metastasis, in primary PCa only, or in metastasis only. Follow-up studies are required to investigate the functional role and the role that the expression of these genes play in the outcome and progression of PCa using tissue microarrays.

Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells.

PubMed

Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K

2011-10-01

Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

Epidermal Growth Factor Increases LRF/Pokemon Expression in Human Prostate Cancer Cells

PubMed Central

Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K.

2011-01-01

Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. PMID:21640721

Autonomic nerve development contributes to prostate cancer progression.

PubMed

Magnon, Claire; Hall, Simon J; Lin, Juan; Xue, Xiaonan; Gerber, Leah; Freedland, Stephen J; Frenette, Paul S

2013-07-12

Nerves are a common feature of the microenvironment, but their role in tumor growth and progression remains unclear. We found that the formation of autonomic nerve fibers in the prostate gland regulates prostate cancer development and dissemination in mouse models. The early phases of tumor development were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal β2- and β3-adrenergic receptors. Tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor, leading to improved survival of the mice. A retrospective blinded analysis of prostate adenocarcinoma specimens from 43 patients revealed that the densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding normal tissue, respectively, were associated with poor clinical outcomes. These findings may lead to novel therapeutic approaches for prostate cancer.

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution.

PubMed

Denoyer, Delphine; Pearson, Helen B; Clatworthy, Sharnel A S; Smith, Zoe M; Francis, Paul S; Llanos, Roxana M; Volitakis, Irene; Phillips, Wayne A; Meggyesy, Peter M; Masaldan, Shashank; Cater, Michael A

2016-06-14

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed.

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

PubMed Central

Denoyer, Delphine; Pearson, Helen B.; Clatworthy, Sharnel A.S.; Smith, Zoe M.; Francis, Paul S.; Llanos, Roxana M.; Volitakis, Irene; Phillips, Wayne A.; Meggyesy, Peter M.; Masaldan, Shashank; Cater, Michael A.

2016-01-01

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed. PMID:27175597

Fully automated prostate segmentation in 3D MR based on normalized gradient fields cross-correlation initialization and LOGISMOS refinement

NASA Astrophysics Data System (ADS)

Yin, Yin; Fotin, Sergei V.; Periaswamy, Senthil; Kunz, Justin; Haldankar, Hrishikesh; Muradyan, Naira; Cornud, François; Turkbey, Baris; Choyke, Peter

2012-02-01

Manual delineation of the prostate is a challenging task for a clinician due to its complex and irregular shape. Furthermore, the need for precisely targeting the prostate boundary continues to grow. Planning for radiation therapy, MR-ultrasound fusion for image-guided biopsy, multi-parametric MRI tissue characterization, and context-based organ retrieval are examples where accurate prostate delineation can play a critical role in a successful patient outcome. Therefore, a robust automated full prostate segmentation system is desired. In this paper, we present an automated prostate segmentation system for 3D MR images. In this system, the prostate is segmented in two steps: the prostate displacement and size are first detected, and then the boundary is refined by a shape model. The detection approach is based on normalized gradient fields cross-correlation. This approach is fast, robust to intensity variation and provides good accuracy to initialize a prostate mean shape model. The refinement model is based on a graph-search based framework, which contains both shape and topology information during deformation. We generated the graph cost using trained classifiers and used coarse-to-fine search and region-specific classifier training. The proposed algorithm was developed using 261 training images and tested on another 290 cases. The segmentation performance using mean DSC ranging from 0.89 to 0.91 depending on the evaluation subset demonstrates state of the art performance. Running time for the system is about 20 to 40 seconds depending on image size and resolution.

Mitochondrial β-Carotene 9',10' Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function.

PubMed

Gong, Xiaoming; Marisiddaiah, Raju; Zaripheh, Susan; Wiener, Doris; Rubin, Lewis P

2016-10-01

Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme β-carotene 9',10'-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in prostate cancer cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in prostate cancer cells reduced NF-κB activity and decreased NF-κB nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism. This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-κB signaling implies BCO2 status is important in prostate cancer progression. Mol Cancer Res; 14(10); 966-75. ©2016 AACR. ©2016 American Association for Cancer Research.

Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation

PubMed Central

2011-01-01

Background We have previously reported significant downregulation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in prostate cancer (PCa) compared to the surrounding benign tissue. UCHL1 plays an important role in ubiquitin system and different cellular processes such as cell proliferation and differentiation. We now show that the underlying mechanism of UCHL1 downregulation in PCa is linked to its promoter hypermethylation. Furthermore, we present evidences that UCHL1 expression can affect the behavior of prostate cancer cells in different ways. Results Methylation specific PCR analysis results showed a highly methylated promoter region for UCHL1 in 90% (18/20) of tumor tissue compared to 15% (3/20) of normal tissues from PCa patients. Pyrosequencing results confirmed a mean methylation of 41.4% in PCa whereas only 8.6% in normal tissues. To conduct functional analysis of UCHL1 in PCa, UCHL1 is overexpressed in LNCaP cells whose UCHL1 expression is normally suppressed by promoter methylation and found that UCHL1 has the ability to decrease the rate of cell proliferation and suppresses anchorage-independent growth of these cells. In further analysis, we found evidence that exogenous expression of UCHL1 suppress LNCaP cells growth probably via p53-mediated inhibition of Akt/PKB phosphorylation and also via accumulation of p27kip1 a cyclin dependant kinase inhibitor of cell cycle regulating proteins. Notably, we also observed that exogenous expression of UCHL1 induced a senescent phenotype that was detected by using the SA-ß-gal assay and might be due to increased p14ARF, p53, p27kip1 and decreased MDM2. Conclusion From these results, we propose that UCHL1 downregulation via promoter hypermethylation plays an important role in various molecular aspects of PCa biology, such as morphological diversification and regulation of proliferation. PMID:21999842

Big Data Analytics for Prostate Radiotherapy.

PubMed

Coates, James; Souhami, Luis; El Naqa, Issam

2016-01-01

Radiation therapy is a first-line treatment option for localized prostate cancer and radiation-induced normal tissue damage are often the main limiting factor for modern radiotherapy regimens. Conversely, under-dosing of target volumes in an attempt to spare adjacent healthy tissues limits the likelihood of achieving local, long-term control. Thus, the ability to generate personalized data-driven risk profiles for radiotherapy outcomes would provide valuable prognostic information to help guide both clinicians and patients alike. Big data applied to radiation oncology promises to deliver better understanding of outcomes by harvesting and integrating heterogeneous data types, including patient-specific clinical parameters, treatment-related dose-volume metrics, and biological risk factors. When taken together, such variables make up the basis for a multi-dimensional space (the "RadoncSpace") in which the presented modeling techniques search in order to identify significant predictors. Herein, we review outcome modeling and big data-mining techniques for both tumor control and radiotherapy-induced normal tissue effects. We apply many of the presented modeling approaches onto a cohort of hypofractionated prostate cancer patients taking into account different data types and a large heterogeneous mix of physical and biological parameters. Cross-validation techniques are also reviewed for the refinement of the proposed framework architecture and checking individual model performance. We conclude by considering advanced modeling techniques that borrow concepts from big data analytics, such as machine learning and artificial intelligence, before discussing the potential future impact of systems radiobiology approaches.

Big Data Analytics for Prostate Radiotherapy

PubMed Central

Coates, James; Souhami, Luis; El Naqa, Issam

2016-01-01

Radiation therapy is a first-line treatment option for localized prostate cancer and radiation-induced normal tissue damage are often the main limiting factor for modern radiotherapy regimens. Conversely, under-dosing of target volumes in an attempt to spare adjacent healthy tissues limits the likelihood of achieving local, long-term control. Thus, the ability to generate personalized data-driven risk profiles for radiotherapy outcomes would provide valuable prognostic information to help guide both clinicians and patients alike. Big data applied to radiation oncology promises to deliver better understanding of outcomes by harvesting and integrating heterogeneous data types, including patient-specific clinical parameters, treatment-related dose–volume metrics, and biological risk factors. When taken together, such variables make up the basis for a multi-dimensional space (the “RadoncSpace”) in which the presented modeling techniques search in order to identify significant predictors. Herein, we review outcome modeling and big data-mining techniques for both tumor control and radiotherapy-induced normal tissue effects. We apply many of the presented modeling approaches onto a cohort of hypofractionated prostate cancer patients taking into account different data types and a large heterogeneous mix of physical and biological parameters. Cross-validation techniques are also reviewed for the refinement of the proposed framework architecture and checking individual model performance. We conclude by considering advanced modeling techniques that borrow concepts from big data analytics, such as machine learning and artificial intelligence, before discussing the potential future impact of systems radiobiology approaches. PMID:27379211

Profile of cell proliferation and apoptosis activated by the intrinsic and extrinsic pathways in the prostate of aging rats.

PubMed

Gonzaga, Amanda C R; Campolina-Silva, Gabriel H; Werneck-Gomes, Hipácia; Moura-Cordeiro, Júnia D; Santos, Letícia C; Mahecha, Germán A B; Morais-Santos, Mônica; Oliveira, Cleida A

2017-06-01

Estrogens acting through the receptors ERα and ERβ participate in prostate normal growth and cancer. ERβ is highly expressed in the prostate epithelium, playing pro-apoptotic, anti-proliferative, and pro-differentiation roles. Apoptosis is activated by the intrinsic pathway after castration and by the extrinsic pathway after ERβ agonist treatment. This differential activation of apoptotic pathways is important since a major problem in the treatment of prostate cancer is the recurrence of tumors after androgen withdrawal. However, a comprehensive study about the pattern of apoptosis in the aging prostate is lacking, a knowledge gap that we aimed to address herein. Cellular age-related proliferative and apoptotic profiles of prostate tissue obtained from aging Wistar rats were evaluated. Cell death (caspase-3, -8, -9, TNFα) was assessed by immunohistochemistry, immunofluorescence, and TUNEL. Cell proliferation (MCM7) and cell survival factors (ERK1/2, p-ERK1/2, p-Akt, and NF-κB) were determined by immunohistochemistry. As the rats aged, the number of proliferating cells gradually reduced in the normal epithelium of all prostate lobes, while increasing in focal areas of intraepithelial proliferation. Interestingly, in areas of intraepithelial proliferation, we observed a reduction in the number of cells positive for caspase-3, -8, and -9. Regardless the animal's age, few prostate epithelial cells were positive for caspase-3, caspase-9, and TUNEL. In contrast, a progressive increase was seen in the positivity for caspase-8, especially in the atrophic epithelium of ventral prostate, which coincided with a reduction in TNFα immunoreaction. However, morphology of most caspase-8 positive cells suggests that they were not apoptotic. We also found reduced ERβ expression in the same areas. Possibly, low levels of the pro-apoptotic inductors TNFα and ERβ direct caspase-8 activity to an alternative pro-survival role in the atrophic epithelium. This hypothesis is supported by the increased expression of the key survival factors (ERK1/2, p-ERK1/2, p-Akt, and NF-κB) in these areas. Our findings reveal that, as the animals age, there is an increase of proliferation in restricted areas of the prostate epithelium, and a concomitant reduction of the apoptosis rate with an increase in cell survival induced by caspase-8, indicating a focused and spontaneous disruption of tissue homeostasis. © 2017 Wiley Periodicals, Inc.

MR Elastography and Diffusion-Weighted Imaging of ex-vivo Prostate Cancer: quantitative comparison to histopathology

PubMed Central

Nir, Guy; Gagnon, Louis O.; Ischia, Joseph; Jones, Edward C.; Chang, Silvia; Yung, Andrew; Honarvar, Mohammad; Fazli, Ladan; Goldenberg, Larry; Rohling, Robert; Sinkus, Ralph; Kozlowski, Piotr

2017-01-01

Purpose 1) to develop a Magnetic Resonance Elastography (MRE) system for imaging of the ex-vivo human prostate, 2) to assess the diagnostic power of mono-frequency and multi-frequency MRE and diffusion weighted imaging (DWI) alone and combined as correlated with histopathology in a patient study. Materials and Methods An electromagnetic driver was designed specifically for MRE studies in small-bore MR scanners. Ex-vivo prostate specimens (post-fixation) of fourteen patients who underwent radical prostatectomy were imaged with MRE at 7 T (nine cases had DWI). In six patients, the MRE examination was performed at three frequencies (600, 800, 1000 Hz) to extract the power-law exponent Gamma. The images were registered to wholemount pathology slides marked with the Gleason score. The areas under the Receiver-Operator-Characteristic curves (AUC) were calculated. Results The methods were validated in a phantom study and demonstrated that (i) the driver does not interfere with the acquisition process, (ii) the driver can generate amplitudes greater than 100 μm for frequencies <1kHz. In the quantitative study, cancerous tissue with Gleason score at least 3+3 was distinguished from normal tissue in the peripheral zone with an average AUC of 0.75 (Gd), 0.75 (Gl), 0.70 (Gamma-Gd), 0.68 (ADC), and 0.82 (Gd+Gl+ADC). The differentiation between PZ and CG was modest for Gd (p<0.07), Gl (p<0.06) but not significant for Gamma (p<0.2). A correlation of 0.4 kPa/h was found between fixation time of the prostate specimen to the stiffness of the tissue which could affect the diagnostic power results. Conclusion DWI and MRE may provide complementary information; in fact MRE performed better than ADC in distinguishing normal from cancerous tissue in some cases. Multi-frequency (Gamma) analysis did not appear to improve the results. However, in light of effect of tissue fixation, the clinical implication of our results may be inconclusive and more experiments are needed. PMID:25382459

Paleoandrology and prostatic hyperplasia in Italian mummies (XV-XIX century).

PubMed

Fornaciari, G; Ciranni, R; Ventura, L

2001-01-01

Prostatic hyperplasia, a very common condition today, was well known in the past as cause for bladder distension. The difficulty to identify, at autopsy of natural or artificial mummies, even a normal-sized prostate is probably the result of putrefaction processes and its usually dramatic size reduction as well. We report two ancient cases of prostatic hyperplasia recently observed in natural mummies from Italy. The first case regards Pandolfo III Malatesta (1370-1427), a leading figure of the Italian Renaissance. He was a valiant soldier and horseman with a very active life style. The tomb, containing his naturally mummified body, has recently been discovered in Fano (Marche, Central Italy). After careful X-ray and videographic examination, the autopsy showed good preservation of the skeletal muscles, cartilage, internal and external organs, included prostate gland and penis. Macroscopic examination revealed a staghorn calculus (calcium urate) of the left kidney and a severe enlargement of the prostate, with calcifications detectable by X-ray and large nodules protruding in the lumen of an ectatic urethra. Histology shows fibrous brands of connective and muscular tissue surrounding circular and oblong lacunae, with no preservation of epithelial structures. The macroscopic and histological picture allowed us to diagnose prostatic nodular hyperplasia. The second case (XIX century) concerns the natural mummy of an anonymous 50-60 years old man, found in ancient friary near L'Aquila (central Italy), which underwent computed tomography and a complete autopsy. Pelvic CT scans showed distended urinary bladder and a ring of dense tissue at the site of the prostate. At autopsy the bladder measured 7 x 6 x 5 cm and the prostate was 4 x 5 x 3 cm; prostatic urethra had a diameter of x 2 cm. Histology revealed dense fibrous tissue containing muscular fibers and roundish cavities of variable size, filled with eosinophil, PAS-positive material. Concretions were also present in some of these spaces. Strong immunohistochemical reactivy for PSA was observed in this material. The existence of glandular structures containing eosinophil, PAS-positive material, immunoreactive for PSA, confirmed the prostatic nature of the specimen, already suspected after CT scan and gross examination. The presence itself of the prostate, its histological picture, the preserved and distended urinary bladder, in addition to the age of the subject, supported the diagnosis of prostatic hyperplasia.

Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases

PubMed Central

Böttcher, René; Dulla, Kalyan; van Strijp, Dianne; Dits, Natasja; Verhoef, Esther I.; Baillie, George S.; van Leenders, Geert J.L.H.; Houslay, Miles D.; Jenster, Guido; Hoffmann, Ralf

2016-01-01

Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions. We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription. We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated. Disease progression is marked by an overall down-regulation of long PDE4D isoforms, while short isoforms (PDE4D1/2) appear to be relatively unaffected. While these alterations seem to be independent of copy number alterations in the PDE4D locus and driven by AR and ERG binding, we also observed increased DNA methylation in the promoter region of PDE4D5, indicating a long lasting alteration of the isoform composition in prostate cancer tissues. We propose two independent metrics that may serve as diagnostic and prognostic markers for prostate disease: (PDE4D7 - PDE4D5) provides an effective means for distinguishing PCa from normal adjacent prostate, whereas PDE4D1/2 - (PDE4D5 + PDE4D7 + PDE4D9) offers strong prognostic potential to detect aggressive forms of PCa and is associated with metastasis free survival. Overall, our findings highlight the relevance of PDE4D as prostate cancer biomarker and potential drug target. PMID:27683107

Quantitative volumetric imaging of normal, neoplastic and hyperplastic mouse prostate using ultrasound.

PubMed

Singh, Shalini; Pan, Chunliu; Wood, Ronald; Yeh, Chiuan-Ren; Yeh, Shuyuan; Sha, Kai; Krolewski, John J; Nastiuk, Kent L

2015-09-21

Genetically engineered mouse models are essential to the investigation of the molecular mechanisms underlying human prostate pathology and the effects of therapy on the diseased prostate. Serial in vivo volumetric imaging expands the scope and accuracy of experimental investigations of models of normal prostate physiology, benign prostatic hyperplasia and prostate cancer, which are otherwise limited by the anatomy of the mouse prostate. Moreover, accurate imaging of hyperplastic and tumorigenic prostates is now recognized as essential to rigorous pre-clinical trials of new therapies. Bioluminescent imaging has been widely used to determine prostate tumor size, but is semi-quantitative at best. Magnetic resonance imaging can determine prostate volume very accurately, but is expensive and has low throughput. We therefore sought to develop and implement a high throughput, low cost, and accurate serial imaging protocol for the mouse prostate. We developed a high frequency ultrasound imaging technique employing 3D reconstruction that allows rapid and precise assessment of mouse prostate volume. Wild-type mouse prostates were examined (n = 4) for reproducible baseline imaging, and treatment effects on volume were compared, and blinded data analyzed for intra- and inter-operator assessments of reproducibility by correlation and for Bland-Altman analysis. Examples of benign prostatic hyperplasia mouse model prostate (n = 2) and mouse prostate implantation of orthotopic human prostate cancer tumor and its growth (n =  ) are also demonstrated. Serial measurement volume of the mouse prostate revealed that high frequency ultrasound was very precise. Following endocrine manipulation, regression and regrowth of the prostate could be monitored with very low intra- and interobserver variability. This technique was also valuable to monitor the development of prostate growth in a model of benign prostatic hyperplasia. Additionally, we demonstrate accurate ultrasound image-guided implantation of orthotopic tumor xenografts and monitoring of subsequent tumor growth from ~10 to ~750 mm(3) volume. High frequency ultrasound imaging allows precise determination of normal, neoplastic and hyperplastic mouse prostate. Low cost and small image size allows incorporation of this imaging modality inside clean animal facilities, and thereby imaging of immunocompromised models. 3D reconstruction for volume determination is easily mastered, and both small and large relative changes in volume are accurately visualized. Ultrasound imaging does not rely on penetration of exogenous imaging agents, and so may therefore better measure poorly vascularized or necrotic diseased tissue, relative to bioluminescent imaging (IVIS). Our method is precise and reproducible with very low inter- and intra-observer variability. Because it is non-invasive, mouse models of prostatic disease states can be imaged serially, reducing inter-animal variability, and enhancing the power to detect small volume changes following therapeutic intervention.

Identification of the G protein-coupled estrogen receptor (GPER) in human prostate: expression site of the estrogen receptor in the benign and neoplastic gland.

PubMed

Rago, V; Romeo, F; Giordano, F; Ferraro, A; Carpino, A

2016-01-01

Estrogens are involved in growth, differentiation and pathogenesis of human prostate through the mediation of the classical estrogen receptors ERα and ERβ. The G protein-coupled estrogen receptor (GPER) is a 'novel' mediator of estrogen signaling which has been recently recognized in some human reproductive tissues, but its expression in the prostate gland is still unknown. Here, we investigated GPER in benign (from 5 patients) and neoplastic prostatic tissues (from 50 patients) by immunohistochemical analysis and Western blotting. Normal areas of benign prostates revealed a strong GPER immunoreactivity in the basal epithelial cells while luminal epithelial cells were unreactive and stromal cells were weakly immunostained. GPER was also immunolocalized in adenocarcinoma samples but the immunoreactivity of tumoral areas decreased from Gleason pattern 2 to Gleason pattern 4. Furthermore, a strong GPER immunostaining was also revealed in cells of pre-neoplastic lesions (high-grade prostatic intra-epithelial neoplasia). Western blot analysis of benign and tumor protein extracts showed the presence of a ~42 kDa band, consistent with the GPER molecular weight. An increase in both pAkt and p cAMP-response-binding protein (pCREB) levels was also observed in poorly differentiated PCa samples. Finally, this work identified GPER in the epithelial basal cells of benign human prostate, with a different localization with respect to the classical estrogen receptors. Furthermore, the expression of GPER in prostatic adenocarcinoma cells was also observed but with a modulation of the immunoreactivity according to tumor cell arrangements. © 2015 American Society of Andrology and European Academy of Andrology.

Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers.

PubMed

Stumm, Laura; Burkhardt, Lia; Steurer, Stefan; Simon, Ronald; Adam, Meike; Becker, Andreas; Sauter, Guido; Minner, Sarah; Schlomm, Thorsten; Sirma, Hüseyin; Michl, Uwe

2013-07-01

Transcription factors of the forkhead box P (FOXP1-4) family have been implicated in various human cancer types before. The relevance and role of neuronal transcription factor FOXP2 in prostate cancer is unknown. A tissue microarray containing samples from more than 11 000 prostate cancers from radical prostatectomy specimens with clinical follow-up data was analysed for FOXP2 expression by immunohistochemistry. FOXP2 data were also compared with pre-existing ERG fusion (by fluorescence in situ hybridisation and immunohistochemistry) and cell proliferation (Ki67 labelling index) data. There was a moderate to strong FOXP2 protein expression in basal and secretory cells of normal prostatic glands. As compared with normal cells, FOXP2 expression was lost or reduced in 25% of cancers. Strong FOXP2 expression was linked to advanced tumour stage, high Gleason score, presence of lymph node metastases and early tumour recurrence (p<0.0001; each) in ERG fusion-negative, but not in ERG fusion-positive cancers. High FOXP2 expression was linked to high Ki67 labelling index (p<0.0001) in all cancers irrespective of ERG fusion status. These data demonstrate that similar high FOXP2 protein levels as in normal prostate epithelium exert a 'paradoxical' oncogenic role in 'non fusion-type' prostate cancer. It may be speculated that interaction of FOXP2 with members of pathways that are specifically activated in 'non fusion-type' cancers may be responsible for this phenomenon.

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

PubMed Central

Miao, Lu; Holley, Aaron K.; Zhao, Yanming; St. Clair, William H.

2014-01-01

Abstract Significance: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. Recent Advances: Ionizing radiation (IR)–generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. Critical Issues: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. Future Directions: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues. Antioxid. Redox Signal. 20, 1481–1500. PMID:24093432

Study of NGEP expression in androgen sensitive prostate cancer cells: A potential target for immunotherapy

PubMed Central

Mohsenzadegan, Monireh; Tajik, Nader; Madjd, Zahra; Shekarabi, Mehdi; Farajollahi, Mohammad M

2015-01-01

Background: Prostate cancer is one of the leading causes of cancer deaths among men. New gene expressed in prostate (NGEP), is a prostate-specific gene expressed only in normal prostate and prostate cancer tissue. Because of its selective expression in prostate cancer cell surface, NGEP is a potential immunotherapeutic target. To target the NGEP in prostate cancer, it is essential to investigate its expression in prostate cancer cells. Methods: In the present study, we investigated NGEP expression in LNCaP and DU145 cells by real time and RT-PCR, flow cytometric and immunocytochemical analyses. Results: Real time and RT-PCR analyses of NGEP expression showed that NGEP was expressed in the LNCaP cells but not in DU145 cells. The detection of NGEP protein by flow cytometric and immunocytochemistry analyses indicated that NGEP protein was weakly expressed only in LNCaP cell membrane. Conclusion: Our results demonstrate that LNCaP cell line is more suitable than DU145 for NGEP expression studies; however, its low-level expression is a limiting issue. NGEP expression may be increased by androgen supplementation of LNCaP cell culture medium. PMID:26000254

Optimizing heat shock protein expression induced by prostate cancer laser therapy through predictive computational models

NASA Astrophysics Data System (ADS)

Rylander, Marissa N.; Feng, Yusheng; Zhang, Yongjie; Bass, Jon; Stafford, Roger J.; Hazle, John D.; Diller, Kenneth R.

2006-07-01

Thermal therapy efficacy can be diminished due to heat shock protein (HSP) induction in regions of a tumor where temperatures are insufficient to coagulate proteins. HSP expression enhances tumor cell viability and imparts resistance to chemotherapy and radiation treatments, which are generally employed in conjunction with hyperthermia. Therefore, an understanding of the thermally induced HSP expression within the targeted tumor must be incorporated into the treatment plan to optimize the thermal dose delivery and permit prediction of the overall tissue response. A treatment planning computational model capable of predicting the temperature, HSP27 and HSP70 expression, and damage fraction distributions associated with laser heating in healthy prostate tissue and tumors is presented. Measured thermally induced HSP27 and HSP70 expression kinetics and injury data for normal and cancerous prostate cells and prostate tumors are employed to create the first HSP expression predictive model and formulate an Arrhenius damage model. The correlation coefficients between measured and model predicted temperature, HSP27, and HSP70 were 0.98, 0.99, and 0.99, respectively, confirming the accuracy of the model. Utilization of the treatment planning model in the design of prostate cancer thermal therapies can enable optimization of the treatment outcome by controlling HSP expression and injury.

Conditionally reprogrammed normal and primary tumor prostate epithelial cells: a novel patient-derived cell model for studies of human prostate cancer

PubMed Central

Timofeeva, Olga A.; Palechor-Ceron, Nancy; Li, Guanglei; Yuan, Hang; Krawczyk, Ewa; Zhong, Xiaogang; Liu, Geng; Upadhyay, Geeta; Dakic, Aleksandra; Yu, Songtao; Fang, Shuang; Choudhury, Sujata; Zhang, Xueping; Ju, Andrew; Lee, Myeong-Seon; Dan, Han C.; Ji, Youngmi; Hou, Yong; Zheng, Yun-Ling; Albanese, Chris; Rhim, Johng; Schlegel, Richard; Dritschilo, Anatoly; Liu, Xuefeng

2017-01-01

Our previous study demonstrated that conditional reprogramming (CR) allows the establishment of patient-derived normal and tumor epithelial cell cultures from a variety of tissue types including breast, lung, colon and prostate. Using CR, we have established matched normal and tumor cultures, GUMC-29 and GUMC-30 respectively, from a patient's prostatectomy specimen. These CR cells proliferate indefinitely in vitro and retain stable karyotypes. Most importantly, only tumor-derived CR cells (GUMC-30) produced tumors in xenografted SCID mice, demonstrating maintenance of the critical tumor phenotype. Characterization of cells with DNA fingerprinting demonstrated identical patterns in normal and tumor CR cells as well as in xenografted tumors. By flow cytometry, both normal and tumor CR cells expressed basal, luminal, and stem cell markers, with the majority of the normal and tumor CR cells expressing prostate basal cell markers, CD44 and Trop2, as well as luminal marker, CD13, suggesting a transit-amplifying phenotype. Consistent with this phenotype, real time RT-PCR analyses demonstrated that CR cells predominantly expressed high levels of basal cell markers (KRT5, KRT14 and p63), and low levels of luminal markers. When the CR tumor cells were injected into SCID mice, the expression of luminal markers (AR, NKX3.1) increased significantly, while basal cell markers dramatically decreased. These data suggest that CR cells maintain high levels of proliferation and low levels of differentiation in the presence of feeder cells and ROCK inhibitor, but undergo differentiation once injected into SCID mice. Genomic analyses, including SNP and INDEL, identified genes mutated in tumor cells, including components of apoptosis, cell attachment, and hypoxia pathways. The use of matched patient-derived cells provides a unique in vitro model for studies of early prostate cancer. PMID:28009986

IL‑8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF‑κB pathway in prostate cancer.

PubMed

Guo, Yidi; Zang, Ying; Lv, Lianzheng; Cai, Feng; Qian, Tingting; Zhang, Guoying; Feng, Quancheng

2017-12-01

Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties, and is overexpressed in many human cancer types. However, only few studies have demonstrated the mechanisms of action of IL‑8 regarding the ability to promote proliferation and to inhibit apoptosis in prostate cancer. Here, the aim of the present study was to investigate the effects of IL‑8 on the prostate cancer cell line and determine possible mechanisms underlying its effect. In this study, IL‑8 was shown to be significantly upregulated in prostate cancer compared with paired normal control tissues. The data showed that IL‑8 exhibits direct oncogenicity, which significantly induced cell proliferation, invasion and attenuated apoptosis in prostate cancer cells via signal transducer and activator of transcription 3/protein kinase B/nuclear factor‑κB signaling pathways. In conclusion, modulation of IL‑8 expression or its associated signaling pathway may provide a novel working mechanism of IL‑8 in prostate cancer, and a promising strategy for controlling the progression and metastasis of prostate cancer.

Can Apparent Diffusion Coefficient Values Assist PI-RADS Version 2 DWI Scoring? A Correlation Study Using the PI-RADSv2 and International Society of Urological Pathology Systems.

PubMed

Gaur, Sonia; Harmon, Stephanie; Rosenblum, Lauren; Greer, Matthew D; Mehralivand, Sherif; Coskun, Mehmet; Merino, Maria J; Wood, Bradford J; Shih, Joanna H; Pinto, Peter A; Choyke, Peter L; Turkbey, Baris

2018-05-07

The purposes of this study were to assess correlation of apparent diffusion coefficient (ADC) and normalized ADC (ratio of tumor to nontumor tissue) with the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and updated International Society of Urological Pathology (ISUP) categories and to determine how to optimally use ADC metrics for objective assistance in categorizing lesions within PI-RADSv2 guidelines. In this retrospective study, 100 patients (median age, 62 years; range, 44-75 years; prostate-specific antigen level, 7.18 ng/mL; range, 1.70-84.56 ng/mL) underwent 3-T multiparametric MRI of the prostate with an endorectal coil. Mean ADC was extracted from ROIs based on subsequent prostatectomy specimens. Histopathologic analysis revealed 172 lesions (113 peripheral, 59 transition zone). Two radiologists blinded to histopathologic outcome assigned PI-RADSv2 categories. Kendall tau was used to correlate ADC metrics with PI-RADSv2 and ISUP categories. ROC curves were used to assess the utility of ADC metrics in differentiating each reader's PI-RADSv2 DWI category 4 or 5 assessment in the whole prostate and by zone. ADC metrics negatively correlated with ISUP category in the whole prostate (ADC, τ = -0.21, p = 0.0002; normalized ADC, τ = -0.21, p = 0.0001). Moderate negative correlation was found in expert PI-RADSv2 DWI categories (ADC, τ = -0.34; normalized ADC, τ = -0.31; each p < 0.0001) maintained across zones. In the whole prostate, AUCs of ADC and normalized ADC were 87% and 82% for predicting expert PI-RADSv2 DWI category 4 or 5. A derived optimal cutoff ADC less than 1061 and normalized ADC less than 0.65 achieved positive predictive values of 83% and 84% for correct classification of PI-RADSv2 DWI category 4 or 5 by an expert reader. Consistent relations and predictive values were found by an independent novice reader. ADC and normalized ADC inversely correlate with PI-RADSv2 and ISUP categories and can serve as quantitative metrics to assist with assigning PI-RADSv2 DWI category 4 or 5.

Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns.

PubMed

Kirby, Marie K; Ramaker, Ryne C; Roberts, Brian S; Lasseigne, Brittany N; Gunther, David S; Burwell, Todd C; Davis, Nicholas S; Gulzar, Zulfiqar G; Absher, Devin M; Cooper, Sara J; Brooks, James D; Myers, Richard M

2017-04-17

Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer. We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models. We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues. DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.

Radium-223 in metastatic castration resistant prostate cancer

PubMed Central

Vuong, Winston; Sartor, Oliver; Pal, Sumanta K

2014-01-01

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation. PMID:24713838

Investigating the cell death mechanisms in primary prostate cancer cells using low-temperature plasma treatment

NASA Astrophysics Data System (ADS)

O'Connell, Deborah; Hirst, A. M.; Packer, J. R.; Simms, M. S.; Mann, V. M.; Frame, F. M.; Maitland, N. J.

2016-09-01

Atmospheric pressure plasmas have shown considerable promise as a potential cancer therapy. An atmospheric pressure plasma driven with kHz kV excitation, operated with helium and oxygen admixtures is used to investigate the interaction with prostate cancer cells. The cytopathic effect was verified first in two commonly used prostate cancer cell lines (BPH-1 and PC-3 cells) and further extended to examine the effects in paired normal and tumour prostate epithelial cells cultured directly from patient tissues. Through the formation of reactive species in cell culture media, and potentially other plasma components, we observed high levels of DNA damage, together with reduced cell viability and colony-forming ability. We observed differences in response between the prostate cell lines and primary cells, particularly in terms of the mechanism of cell death. The primary cells ultimately undergo necrotic cell death in both the normal and tumour samples, in the complete absence of apoptosis. In addition, we provide the first evidence of an autophagic response in primary cells. This work highlights the importance of studying primary cultures in order to gain a more realistic insight into patient efficacy. EPSRC EP/H003797/1 & EP/K018388/1, Yorkshire Cancer Research: YCR Y257PA.

Prostate seed implant quality assessment using MR and CT image fusion.

PubMed

Amdur, R J; Gladstone, D; Leopold, K A; Harris, R D

1999-01-01

After a seed implant of the prostate, computerized tomography (CT) is ideal for determining seed distribution but soft tissue anatomy is frequently not well visualized. Magnetic resonance (MR) images soft tissue anatomy well but seed visualization is problematic. We describe a method of fusing CT and MR images to exploit the advantages of both of these modalities when assessing the quality of a prostate seed implant. Eleven consecutive prostate seed implant patients were imaged with axial MR and CT scans. MR and CT images were fused in three dimensions using the Pinnacle 3.0 version of the ADAC treatment planning system. The urethra and bladder base were used to "line up" MR and CT image sets during image fusion. Alignment was accomplished using translation and rotation in the three ortho-normal planes. Accuracy of image fusion was evaluated by calculating the maximum deviation in millimeters between the center of the urethra on axial MR versus CT images. Implant quality was determined by comparing dosimetric results to previously set parameters. Image fusion was performed with a high degree of accuracy. When lining up the urethra and base of bladder, the maximum difference in axial position of the urethra between MR and CT averaged 2.5 mm (range 1.3-4.0 mm, SD 0.9 mm). By projecting CT-derived dose distributions over MR images of soft tissue structures, qualitative and quantitative evaluation of implant quality is straightforward. The image-fusion process we describe provides a sophisticated way of assessing the quality of a prostate seed implant. Commercial software makes the process time-efficient and available to any clinical practice with a high-quality treatment planning system. While we use MR to image soft tissue structures, the process could be used with any imaging modality that is able to visualize the prostatic urethra (e.g., ultrasound).

BCL-2 and BCL-XL expression are down-regulated in benign prostate hyperplasia nodules and not affected by finasteride and/or celecoxib

PubMed Central

Li, Feng; Pascal, Laura E; Zhou, Jianhua; Zhou, Yibin; Wang, Ke; Parwani, Anil V; Dhir, Rajiv; Guo, Peng; He, Dalin; Nelson, Joel B; Wang, Zhou

2018-01-01

The mechanisms involved in the development of benign prostatic hyperplasia (BPH) are poorly understood. One potential mechanism involved in BPH pathogenesis may involve altered expression of genes related to apoptosis and proliferation because reduced cell death and increased proliferation are thought to contribute to prostatic enlargement. This study examined the expression of B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra large (BCL-XL), two important anti-apoptosis factors that are also capable of inhibiting cell proliferation via accelerated G1 arrest or delayed G1/S transition, using immunostaining in simple prostatectomy BPH specimens from patients naïve to androgen manipulation. Since androgens and inflammation are thought to play important roles in BPH pathogenesis, we tested the effect of inhibiting 5a-reductase and/or COX-2 on the expression of BCL-2 and BCL-XL in BPH specimens from prostate cancer patients with BPH. These patients had no prior use of chronic NSAIDs and/or 5a-reductase inhibitors and were treated with celecoxib, finasteride, celecoxib plus finasteride or no treatment for 28 consecutive days prior to surgery. In all specimens, BCL-2 and BCL-XL staining was evident in both luminal and basal epithelial cells, with more intense staining in basal cells. Both luminal and basal cells exhibited decreased BCL-2 and BCL-XL staining in BPH nodules compared to the surrounding normal prostatic tissues. In prostate cancer patients with BPH, celecoxib and/or finasteride did not affect the expression of BCL-2 and BCL-XL in luminal or basal cells in BPH nodules and normal adjacent tissues. These results suggest that BCL-2 and BCL-XL may act as anti-proliferative factors in BPH pathogenesis, and the effect of celecoxib and/or finasteride on BPH is unlikely mediated through modulating BCL-2 and BCL-XL signaling. PMID:29531971

Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC-recommended NTCP model.

PubMed

Liu, Mitchell; Moiseenko, Vitali; Agranovich, Alexander; Karvat, Anand; Kwan, Winkle; Saleh, Ziad H; Apte, Aditya A; Deasy, Joseph O

2010-10-01

Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman-Kutcher-Burman NTCP model. Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearman's rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the χ(2) test (p = 0.44). Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort.

Dosimetric and radiobiological comparison of volumetric modulated arc therapy, high-dose rate brachytherapy, and low-dose rate permanent seeds implant for localized prostate cancer.

PubMed

Yang, Ruijie; Zhao, Nan; Liao, Anyan; Wang, Hao; Qu, Ang

2016-01-01

To investigate the dosimetric and radiobiological differences among volumetric modulated arc therapy (VMAT), high-dose rate (HDR) brachytherapy, and low-dose rate (LDR) permanent seeds implant for localized prostate cancer. A total of 10 patients with localized prostate cancer were selected for this study. VMAT, HDR brachytherapy, and LDR permanent seeds implant plans were created for each patient. For VMAT, planning target volume (PTV) was defined as the clinical target volume plus a margin of 5mm. Rectum, bladder, urethra, and femoral heads were considered as organs at risk. A 78Gy in 39 fractions were prescribed for PTV. For HDR and LDR plans, the dose prescription was D90 of 34Gy in 8.5Gy per fraction, and 145Gy to clinical target volume, respectively. The dose and dose volume parameters were evaluated for target, organs at risk, and normal tissue. Physical dose was converted to dose based on 2-Gy fractions (equivalent dose in 2Gy per fraction, EQD2) for comparison of 3 techniques. HDR and LDR significantly reduced the dose to rectum and bladder compared with VMAT. The Dmean (EQD2) of rectum decreased 22.36Gy in HDR and 17.01Gy in LDR from 30.24Gy in VMAT, respectively. The Dmean (EQD2) of bladder decreased 6.91Gy in HDR and 2.53Gy in LDR from 13.46Gy in VMAT. For the femoral heads and normal tissue, the mean doses were also significantly reduced in both HDR and LDR compared with VMAT. For the urethra, the mean dose (EQD2) was 80.26, 70.23, and 104.91Gy in VMAT, HDR, and LDR brachytherapy, respectively. For localized prostate cancer, both HDR and LDR brachytherapy were clearly superior in the sparing of rectum, bladder, femoral heads, and normal tissue compared with VMAT. HDR provided the advantage in sparing of urethra compared with VMAT and LDR. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Dosimetric and radiobiological comparison of volumetric modulated arc therapy, high-dose rate brachytherapy, and low-dose rate permanent seeds implant for localized prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Ruijie, E-mail: ruijyang@yahoo.com; Zhao, Nan; Liao, Anyan

To investigate the dosimetric and radiobiological differences among volumetric modulated arc therapy (VMAT), high-dose rate (HDR) brachytherapy, and low-dose rate (LDR) permanent seeds implant for localized prostate cancer. A total of 10 patients with localized prostate cancer were selected for this study. VMAT, HDR brachytherapy, and LDR permanent seeds implant plans were created for each patient. For VMAT, planning target volume (PTV) was defined as the clinical target volume plus a margin of 5 mm. Rectum, bladder, urethra, and femoral heads were considered as organs at risk. A 78 Gy in 39 fractions were prescribed for PTV. For HDR andmore » LDR plans, the dose prescription was D{sub 90} of 34 Gy in 8.5 Gy per fraction, and 145 Gy to clinical target volume, respectively. The dose and dose volume parameters were evaluated for target, organs at risk, and normal tissue. Physical dose was converted to dose based on 2-Gy fractions (equivalent dose in 2 Gy per fraction, EQD{sub 2}) for comparison of 3 techniques. HDR and LDR significantly reduced the dose to rectum and bladder compared with VMAT. The D{sub mean} (EQD{sub 2}) of rectum decreased 22.36 Gy in HDR and 17.01 Gy in LDR from 30.24 Gy in VMAT, respectively. The D{sub mean} (EQD{sub 2}) of bladder decreased 6.91 Gy in HDR and 2.53 Gy in LDR from 13.46 Gy in VMAT. For the femoral heads and normal tissue, the mean doses were also significantly reduced in both HDR and LDR compared with VMAT. For the urethra, the mean dose (EQD{sub 2}) was 80.26, 70.23, and 104.91 Gy in VMAT, HDR, and LDR brachytherapy, respectively. For localized prostate cancer, both HDR and LDR brachytherapy were clearly superior in the sparing of rectum, bladder, femoral heads, and normal tissue compared with VMAT. HDR provided the advantage in sparing of urethra compared with VMAT and LDR.« less

[Prostatic granulomas revealing a peripheral T-cell lymphoma].

PubMed

Foguem, C; Curlier, E; Rouamba, M-M; Regent, A; Philippe, P

2009-02-01

The presence of granulomas on tissue biopsie has been reported in a wide range of disorders. The clinical presentation and the diagnostic work-up of granulomatosis can be difficult as it is illustrated in the following report. A 59-year-old patient was referred in 2002 for a granulomatous prostatitis. Physical examination was normal. Except for the increase of prostate-specific antigen (which motivated a biopsy), the laboratory results were normal. Thoracic CT-scan disclosed mediastinal lymph nodes. A minor salivary gland biopsy was consistent with the diagnosis of sarcoidosis. In 2004, the patient presented an epidermal necrolysis, and in 2005 the deterioration of general status raised suspicion of a lymphoproliferative disorder. Liver and bone marrow biopsies revealed a granulomatous process. Despite steroid therapy, the patient died. Autopsy discloses a anaplasic T cell lymphoma. This report illustrates the relationship between sarcoidosis and lymphoma as a mode of presentation, a complication, or an accidental but misleading association? The association between anaplastic lymphoma and sarcoidosis is exceptional.

TU-H-CAMPUS-TeP2-05: Selective Protection of Normal Tissue by Cerium Oxide Nanoparticles During Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ouyang, Z; Ngwa, W; Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

2016-06-15

Purpose: Cerium oxide nanoparticles (CONPs) have unique pH dependent properties such that they act as a radical modulator. These properties may be used in radiation therapy (RT) to protect normal tissue. This work investigates the selective radioprotection of CONPs in-vitro and potential for in-situ delivery of CONPs in prostate cancer RT. Methods: i) Normal human umbilical vein endothelial cells (HUVEC) and human prostate cancer cells (PC-3) were treated with 0 or 2 ng/mL CONPs (NP size: 5 nm). 2 Gy of 100 kVp radiation was delivered to the cells 4 hours after the CONP treatment. Cell viability was checked 48more » hours later using MTS assays. ii) A prostate tumor was modeled as a 2-cm diameter sphere. CONPs were proposed to be loaded in a hollow radiotherapy fiducial marker. The concentration profile for the CONPs within the tumor was modeled with a previously validated diffusion equation employed in other studies for nanoparticles 10 nm or less. Results: i) Without radiation, cell viability was above 90% when treated with 2 ng/mL CONPs for both HUVEC and PC-3. After irradiation, a slightly higher viability was observed in HUVEC with CONPs than the ones without CONPs, and this effect was not observed in PC-3. ii) Based on the calculations, 2 ng/mL of CONPs could be delivered to normal cells by diffusion with a 1 µg/mL initial concentration within two weeks. Conclusion: We conclude that CONPs can provide selective radioprotection. The delivery of needed concentrations of CONPs is feasible via in-situ release from radiotherapy biomaterials (e.g. fiducials) loaded with the CONPs.« less

The Role of the Sonic Hedgehog Pathway for Prostate Cancer Progression

DTIC Science & Technology

2006-02-01

were reviewed to determine the nature of the disease and the tumor histology . In addition, immunohistochemistry with keratin antibodies was used to...cell carcinomas. This study also includes specimens for normal stomach tissues (n ¼ 11), gastritis (n ¼ 4) and other stomach tissues (n ¼ 3) (see...nature of the disease and the tumor histology [24]. The randomly sorted samples with masked identity were evaluated by at least two independent

Stokes polarimetry imaging of dog prostate tissue

NASA Astrophysics Data System (ADS)

Kim, Jihoon; Johnston, William K., III; Walsh, Joseph T., Jr.

2010-02-01

Prostate cancer is the second leading cause of death in the United States in 2009. Radical prostatectomy (complete removal of the prostate) is the most common treatment for prostate cancer, however, differentiating prostate tissue from adjacent bladder, nerves, and muscle is difficult. Improved visualization could improve oncologic outcomes and decrease damage to adjacent nerves and muscle important for preservation of potency and continence. A novel Stokes polarimetry imaging (SPI) system was developed and evaluated using a dog prostate specimen in order to examine the feasibility of the system to differentiate prostate from bladder. The degree of linear polarization (DOLP) image maps from linearly polarized light illumination at different visible wavelengths (475, 510, and 650 nm) were constructed. The SPI system used the polarization property of the prostate tissue. The DOLP images allowed advanced differentiation by distinguishing glandular tissue of prostate from the muscular-stromal tissue in the bladder. The DOLP image at 650 nm effectively differentiated prostate and bladder by strong DOLP in bladder. SPI system has the potential to improve surgical outcomes in open or robotic-assisted laparoscopic removal of the prostate. Further in vivo testing is warranted.

Thioredoxin 1 in Prostate Tissue Is Associated with Gleason Score, Erythrocyte Antioxidant Enzyme Activity, and Dietary Antioxidants.

PubMed

Vance, Terrence M; Azabdaftari, Gissou; Pop, Elena A; Lee, Sang Gil; Su, L Joseph; Fontham, Elizabeth T H; Bensen, Jeannette T; Steck, Susan E; Arab, Lenore; Mohler, James L; Chen, Ming-Hui; Koo, Sung I; Chun, Ock K

2015-01-01

Background. Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer-related mortality in men in the US. Growing evidence suggests that oxidative stress is involved in prostate cancer. Methods. In this study, thioredoxin 1 (Trx 1), an enzyme and subcellular indicator of redox status, was measured in prostate biopsy tissue from 55 men from the North Carolina-Louisiana Prostate Cancer Project. A pathologist blindly scored levels of Trx 1. The association between Trx 1 and the Gleason score, erythrocyte antioxidant enzyme activity, and dietary antioxidant intake was determined using Fisher's exact test. Results. Trx 1 levels in benign prostate tissue in men with incident prostate cancer were positively associated with the Gleason score (P = 0.01) and inversely associated with dietary antioxidant intake (P = 0.03). In prostate cancer tissue, Trx 1 levels were associated with erythrocyte glutathione peroxidase activity (P = 0.01). No association was found for other erythrocyte enzymes. Greater Gleason score of malignant tissue corresponds to a greater difference in Trx 1 levels between malignant and benign tissue (P = 0.04). Conclusion. These results suggest that the redox status of prostate tissue is associated with prostate cancer grade and both endogenous and exogenous antioxidants.

Deregulated E2F5/p38/SMAD3 Circuitry Reinforces the Pro-Tumorigenic Switch of TGFβ Signaling in Prostate Cancer.

PubMed

Majumder, Subhadipa; Bhowal, Ankur; Basu, Sanmitra; Mukherjee, Pritha; Chatterji, Urmi; Sengupta, Sanghamitra

2016-11-01

Transforming growth factor-β signaling exerts divergent effects on normal and cancer cells, although mechanism underlying this differential behavior remains unclear. In this study, expression of 94 genes pertaining to the TGF-β signaling pathway was compared between tumor and benign tissue samples from the human prostate gland to identify major discriminators driving prostate carcinogenesis. E2F5 was identified as one of the most deregulated genes in prostate cancer tissues, predominantly in samples with Gleason-score 6. Expression of other deregulated components of TGF-β signaling was examined by qRT-PCR, Western blot, and immune-staining. Function of E2F5 and p38 in prostate cancer was investigated using siRNA-treatment of PC3 cell-line followed by analyses of associated components and cell cycle. Observations revealed that E2F5 overexpression was accompanied by significantly higher phosphorylation of SMAD3 at Ser-208 in the linker region (pSMAD3L) and p38 in tumor tissue. A striking difference in SMAD3 phosphorylation, marked by preponderance of pSMAD3L and pSMAD3C (Ser-423 and 425) in tumor and benign tissues, respectively was noted. Co-localization of E2F5 with pSMAD3L in the nuclei of tumor and PC3 cells indicated a functional interface between the proteins. Downregulation of E2F5 and p38 in PC3 cells resulted in marked reduction of phosphorylation of SMAD3 and perturbation of cell cycle with an arrest of cells in G1 . Our findings unearthed that E2F5/p38 axis played a cardinal role in uncontrolled cellular proliferation in prostate cancer through pSMAD3L activation. It also underscores a strong potential for E2F5 to be incorporated as a tool in early detection of prostate cancer. J. Cell. Physiol. 231: 2482-2492, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

[Therapeutic efficacy of compound Xuanju capsule on autoimmune prostatitis in rats: an experimental study].

PubMed

Li, Tian-Fu; Wu, Qiu-Yue; Li, Wei-Wei; Zhang, Cui; Li, Na; Shang, Xue-Jun; Xia, Xin-Yi; Xu, Hao-Qin; Huang, Yu-Feng

2014-05-01

To evaluate the therapeutic effect of Compound Xuanju Capsule (CXC) on autoimmune prostatitis in rat models. Sixty healthy male Wistar rats were randomly divided into five groups of equal number: blank control, low-concentration purified prostate protein (low-conc PPP), low-conc PPP + CXC treatment, high-concentration PPP (hi-con PPP), and hi-conc PPP + CXC treatment. Autoimmune prostatitis models were established by intragastric administration of PPP solution at 15 mg/ml (low concentration) and 80 mg/ml, respectively. At 30 days after modeling, the rats in the blank control and low-conc and hi-conc PPP model groups were treated with normal saline, and those in the other two groups with CXC at a daily dose of 0.068 g/ml. At 30, 45, and 60 days, all the animals were sacrificed for observation of pathological changes in the prostate tissue and determination of the levels of IL-8, IL-10, and TNF-alpha in the serum. Compared with the PPP models, the hi-conc PPP + CXC group showed significantly reduced levels of IL-8 and TNF-alpha in the serum at 45 days ([148.54 +/- 17.23] and [62.14 +/- 5.59] pg/ml vs [100.77 +/- 11.08] and [32.63 +/- 2.91] pg/ml, P < 0.05) and at 60 days ([143.69 +/- 17.28] and [59.38 +/- 5.50] pg/mlvs [95.77 +/-10.53] and [29.63 +/- 2.66] pg/ml, P < 0.05), and so did the low-cone PPP + CXC group at 45 days ([128.47 +/- 12.21] and [40.43 +/- 3.64] pg/ml vs [111.76 +/- 10.07] and [35.44 +/- 3.17] pg/ml, P < 0.05) and at 60 days ([131.07 +/- 10.93] and [43.34 +/- 3.91] pg/ml vs [97.46 +/- 8.75] and [30.44 +/- 2.75] pg/ml, P < 0.05). The serum level of IL-10 was remarkably elevated in the hi-cone PPP + CXC group as compared with that of the PPP models at 45 and 60 days ([189.14 +/- 16.78] and [184.14 +/- 15.89] pg/ml vs [230.48 +/- 29.96] and [248.48 +/- 31.03] pg/ml, P < 0.05), and so was it in low-cone PPP + CXC group ([223.14 +/- 17.87] and [224.14 +/- 17.93] pg/ml vs [231.42 +/- 23.18] and [249.42 +/- 24.97] pg/ml, P < 0.05). Pathological examination revealed morphological damages to the prostate tissue and infiltration of inflammatory cells in the model rats, but no obvious changes in the normal controls. At 15 days of treatment, the rats in the PPP + CXC group showed enlarged prostate glandular cavity, mild proliferation of epithelial cells, no obvious infiltration of inflammatory cells in the interstitial tissue, and a few visible fibrous tissues under the light microscope. Compound Xuanju Capsule is efficacious on autoimmune prostatis in rats by reducing inflammatory changes in the prostate tissue and improving the expression of inflammatory factors.

Preferential expression of cystein-rich secretory protein-3 (CRISP-3) in chronic pancreatitis.

PubMed

Liao, Q; Kleeff, J; Xiao, Y; Guweidhi, A; Schambony, A; Töpfer-Petersen, E; Zimmermann, A; Büchler, M W; Friess, H

2003-04-01

Chronic pancreatitis (CP) is a progressive inflammatory process resulting in exocrine and endocrine pancreatic insufficiency in advanced stages. Cysteine-rich secretory protein (CRISP-3) has been identified as a defense-associated molecule with predominant expression in the salivary gland, pancreas and prostate. In this study, we investigated CRISP-3 expression in normal pancreatic tissues, chronic pancreatitis tissues, pancreatic cancer tissues and pancreatic cancer cell lines, as well as in other gastrointestinal organs. 15 normal pancreatic tissues, 14 chronic pancreatitis tissues and 14 pancreatic cancer tissues as well as three pancreatic cancer cell lines were analyzed. Moreover, hepatocellular carcinoma and esophageal, stomach and colon cancers were also analyzed together with the corresponding normal controls. CRISP-3 was expressed at moderate to high levels in chronic pancreatitis tissues and at moderate levels in pancreatic cancer tissues but at low levels in normal pancreatic tissues, and was absent in three pancreatic cancer cell lines. CRISP-3 expression was below the level of detection in all cancerous gastrointestinal tissues and in all normal tissues except 2 of 16 colon tissue samples. CRISP-3 mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells and in small proliferating ductal cells in CP tissues and CP-like lesions in pancreatic cancer tissues. In contrast, CRISP-3 expression was weak to absent in the cytoplasm of cancer cells as well as in acinar cells and ductal cells in pancreatic cancer tissues and normal pancreatic tissues. These results reveal that the distribution of CRISP-3 in gastrointestinal tissues is predominantly in the pancreas. High levels of CRISP-3 in acinar cells dedifferentiating into small proliferating ductal cells in CP and CP-like lesions in pancreatic cancer suggests a role of this molecule in the pathophysiology of CP.

Tumor suppressor BRCA1 is expressed in prostate cancer and controls IGF-I receptor (IGF-IR) gene transcription in an androgen receptor-dependent manner

PubMed Central

Schayek, Hagit; Haugk, Kathy; Sun, Shihua; True, Lawrence D.; Plymate, Stephen R.; Werner, Haim

2010-01-01

Purpose The insulin-like growth factor (IGF) system plays an important role in prostate cancer. The BRCA1 gene encodes a transcription factor with tumor suppressor activity. The involvement of BRCA1 in prostate cancer, however, has not yet been elucidated. The purpose of the present study was to examine the functional correlations between BRCA1 and the IGF system in prostate cancer. Experimental Design An immunohistochemical analysis of BRCA1 was performed on Tissue Microarrays comprising 203 primary prostate cancer specimens. In addition, BRCA1 levels were measured in prostate cancer xenografts and in cell lines representing early stages of the disease (P69 cells) and advanced stages (M12 cells). The ability of BRCA1 to regulate IGF-IR expression was studied by coexpression experiments using a BRCA1 expression vector along with an IGF-IR promoter-luciferase reporter. Results We found significantly elevated BRCA1 levels in prostate cancer in comparison to histologically normal prostate tissue (p < 0.001). In addition, an inverse correlation between BRCA1 and IGF-IR levels was observed in the AR-negative P69 and M12 prostate cancer-derived cell lines. Coexpression experiments in M12 cells revealed that BRCA1 was able to suppress IGF-IR promoter activity and endogenous IGF-IR levels. On the other hand, BRCA1 enhanced IGF-IR levels in LnCaP C4-2 cells expressing an endogenous AR. Conclusions We provide evidence that BRCA1 differentially regulates IGF-IR expression in AR positive and negative prostate cancer cells. The mechanism of action of BRCA1 involves modulation of IGF-IR gene transcription. In addition, immunohistochemical data is consistent with a potential survival role of BRCA1 in prostate cancer. PMID:19223505

An efficient method for native protein purification in the selected range from prostate cancer tissue digests

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahmad, Rumana; Nicora, Carrie D.; Shukla, Anil K.

Prostate cancer (CP) cells differ from their normal counterpart in gene expression. Genes encoding secreted or extracellular proteins with increased expression in CP may serve as potential biomarkers. For their detection and quantification, assays based on monoclonal antibodies are best suited for development in a clinical setting. One approach to obtain antibodies is to use recombinant proteins as immunogen. However, the synthesis of recombinant protein for each identified candidate is time-consuming and expensive. It is also not practical to generate high quality antibodies to all identified candidates individually. Furthermore, non-native forms (e.g., recombinant) of proteins may not always lead tomore » useful antibodies. Our approach was to purify a subset of proteins from CP tissue specimens for use as immunogen.« less

Optical coherence tomography of the prostate nerves

NASA Astrophysics Data System (ADS)

Chitchian, Shahab

Preservation of the cavernous nerves during prostate cancer surgery is critical in preserving a man's ability to have spontaneous erections following surgery. These microscopic nerves course along the surface of the prostate within a few millimeters of the prostate capsule, and they vary in size and location from one patient to another, making preservation of the nerves difficult during dissection and removal of a cancerous prostate gland. These observations may explain in part the wide variability in reported sexual potency rates (9--86%) following prostate cancer surgery. Any technology capable of providing improved identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery would be of great assistance in improving sexual function after surgery, and result in direct patient benefit. Optical coherence tomography (OCT) is a noninvasive optical imaging technique capable of performing high-resolution cross-sectional in vivo and in situ imaging of microstructures in biological tissues. OCT imaging of the cavernous nerves in the rat and human prostate has recently been demonstrated. However, improvements in the OCT system and the quality of the images for identification of the cavernous nerves is necessary before clinical use. The following chapters describe complementary approaches to improving identification and imaging of the cavernous nerves during OCT of the prostate gland. After the introduction to OCT imaging of the prostate gland, the optimal wavelength for deep imaging of the prostate is studied in Chapter 2. An oblique-incidence single point measurement technique using a normal-detector scanning system was implemented to determine the absorption and reduced scattering coefficients, mua and m's , of fresh canine prostate tissue, ex vivo, from the diffuse reflectance profile of near-IR light as a function of source-detector distance. The effective attenuation coefficient, mueff, and the Optical Penetration Depth (OPD) were then calculated for near-IR wavelengths of 1064 nm, 1307 nm, and 1555 nm. Chapters 3 and 4 describe locally adaptive denoising algorithms applied to reduce speckle noise in OCT images of the prostate taken by experimental and clinical systems, respectively. The dual-tree complex wavelet transform (CDWT) is a relatively recent enhancement to the discrete wavelet transform (DWT), with important additional properties: It is nearly shift invariant and directionally selective in two and higher dimensions. The CDWT algorithm was implemented for denoising of OCT images. In Chapter 5, 2-D OCT images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. To detect these nerves, three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The Gabor feature was applied with different standard deviations in the x and y directions. In the Daubechies wavelet feature, an 8-tap Daubechies orthonormal wavelet was implemented, and the low pass sub-band was chosen as the filtered image. Finally, Laws feature extraction was applied to the images. The features were segmented using a nearest-neighbor classifier. Morphological post-processing was used to remove small voids. In Chapter 6, a new algorithm based on thresholding and first-order derivative class of differential edge detection was implemented to see deeper in the OCT images. One of the main limitations in OCT imaging of the prostate tissue is the inability to image deep into opaque tissues. Currently, OCT is limited to an image depth of approximately 1 min in opaque tissues. Theoretical comparisons of detection performance for Fourier domain (FD) and time domain (TD) OCT have been previously reported. In Chapter 7, we compare several image quality metrics including signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and equivalent number of looks (ENL) for TD-OCT and FD-OCT images taken of the rat prostate, in vivo. The results show that TD-OCT has inferior CNR, but superior SNR compared to FD-OCT, and that TD-OCT is better for deep imaging of opaque tissues. Finally, Chapter 8 summarizes the study and future directions for OCT imaging of the prostate gland are discussed.

The Anti-Inflammatory Effects of a Yin Zhi Huang Soup in an Experimental Autoimmune Prostatitis Rat Model

PubMed Central

Zhang, Xikui; Zhu, Weikun; Lu, Taikun; Chen, Jinchun; Zou, Qiang; Zheng, Qizhong; Chen, Junying; Jiang, Changming; Jin, Guanyu

2017-01-01

The present study aimed to investigate the therapeutic effects of the Chinese herbal medicine Yin Zhi Huang soup (YZS) in an experimental autoimmune prostatitis (EAP) rat model. In total, 48 rats were randomly divided into the following four groups (n = 12/group): saline group, pathological model group, Qianlietai group, and YZS group. We determined the average wet weight of the prostate tissue, the ratio of the wet weight of the prostate tissue to body weight, tumor necrosis factor-alpha (TNF-α) levels in the blood serum, the expression of inducible nitric oxide synthase (iNOS) in the rats' prostate tissues, and the pathological changes in the prostate tissue using light microscopy. YZS reduced the rats' prostate wet weight, the ratio of the prostate wet weight to body weight, and TNF-α levels in the blood serum and inhibited the expression of iNOS in the rats' prostate tissues (P < 0.05). Following YZS treatment, the pathological changes in the rats' prostates were improved compared with those in the model group (P < 0.05). Furthermore, YZS treatment reduced inflammatory changes in the prostate tissue. It also significantly suppressed proinflammatory cytokines, such as TNF-α, and chemokines, such as iNOS, in the rat model of EAP. PMID:29430255

The Anti-Inflammatory Effects of a Yin Zhi Huang Soup in an Experimental Autoimmune Prostatitis Rat Model.

PubMed

Deng, Longsheng; Zhang, Xikui; Zhu, Weikun; Lu, Taikun; Chen, Jinchun; Zou, Qiang; Zheng, Qizhong; Chen, Junying; Jiang, Changming; Jin, Guanyu

2017-01-01

The present study aimed to investigate the therapeutic effects of the Chinese herbal medicine Yin Zhi Huang soup (YZS) in an experimental autoimmune prostatitis (EAP) rat model. In total, 48 rats were randomly divided into the following four groups ( n = 12/group): saline group, pathological model group, Qianlietai group, and YZS group. We determined the average wet weight of the prostate tissue, the ratio of the wet weight of the prostate tissue to body weight, tumor necrosis factor-alpha (TNF- α ) levels in the blood serum, the expression of inducible nitric oxide synthase (iNOS) in the rats' prostate tissues, and the pathological changes in the prostate tissue using light microscopy. YZS reduced the rats' prostate wet weight, the ratio of the prostate wet weight to body weight, and TNF- α levels in the blood serum and inhibited the expression of iNOS in the rats' prostate tissues ( P < 0.05). Following YZS treatment, the pathological changes in the rats' prostates were improved compared with those in the model group ( P < 0.05). Furthermore, YZS treatment reduced inflammatory changes in the prostate tissue. It also significantly suppressed proinflammatory cytokines, such as TNF- α , and chemokines, such as iNOS, in the rat model of EAP.

Endoscopic Assessment and Prediction of Prostate Urethral Disintegration After Histotripsy Treatment in a Canine Model*

PubMed Central

Schade, George R.; Styn, Nicholas R.; Hall, Timothy L.

2012-01-01

Abstract Background and Purpose Histotripsy is a nonthermal focused ultrasound technology that uses acoustic cavitation to homogenize tissue. Previous research has demonstrated that the prostatic urethra is more resistant to histotripsy effects than prostate parenchyma, a finding that may complicate the creation of transurethral resection of the prostate-like treatment cavities. The purpose of this study was to characterize the endoscopic appearance of the prostatic urethra during and after histotripsy treatment and to identify features that are predictive of urethral disintegration. Materials and Methods Thirty-five histotripsy treatments were delivered in a transverse plane traversing the prostatic urethra in 17 canine subjects (1–3/prostate ≥1 cm apart). Real-time endoscopy was performed in the first four subjects to characterize development of acute urethral treatment effect (UTE). Serial postprocedure endoscopy was performed in all subjects to assess subsequent evolution of UTE. Results Endoscopy during histotripsy was feasible with observation of intraurethral cavitation, allowing characterization of the real-time progression of UTE from normal to frank urethral disintegration. While acute urethral fragmentation occurred in 3/35 (8.6%) treatments, frank urethral disintegration developed in 24/35 (68.5%) within 14 days of treatment. Treating until the appearance of hemostatic pale gray shaggy urothelium was the best predictor of achieving urethral fragmentation within 14 days of treatment with positive and negative predictive values of 0.91 and 0.89, respectively. Conclusion Endoscopic assessment of the urethra may be a useful adjunct to prostatic histotripsy to help guide therapy to ensure urethral disintegration, allowing drainage of the homogenized adenoma and effective tissue debulking. PMID:22050511

Prostate Stem Cell Antigen: A Prospective Therapeutic and Diagnostic Target

PubMed Central

Raff, Adam B.; Gray, Andrew; Kast, W. Martin

2009-01-01

The development of novel clinical tools to combat cancer is an intense field of research and recent efforts have been directed at the identification of proteins that may provide diagnostic, prognostic and/or therapeutic applications due to their restricted expression. To date, a number of protein candidates have emerged as potential clinical tools in the treatment of prostate cancer. Discovered over ten year ago, prostate stem cell antigen (PSCA) is a cell surface antigen that belongs to the Ly-6/Thy-1 family of glycosylphosphatidylinositol-anchored proteins. PSCA is highly overexpressed in human prostate cancer, with limited expression in normal tissues, making it an ideal target for both diagnosis and therapy. Several studies have now clearly correlated the expression of PSCA with relevant clinical benchmarks, such as Gleason score and metastasis, while others have demonstrated the efficacy of PSCA targeting in treatment through various modalities. The purpose of this review is to present the current body of knowledge about PSCA and its potential role in the treatment of human prostate cancer. PMID:18838214

Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation.

PubMed

Schulz, Wolfgang A; Ingenwerth, Marc; Djuidje, Carolle E; Hader, Christiane; Rahnenführer, Jörg; Engers, Rainer

2010-09-22

The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as "cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.

Insulin receptor isoforms A and B as well as insulin receptor substrates-1 and -2 are differentially expressed in prostate cancer.

PubMed

Heni, Martin; Hennenlotter, Jörg; Scharpf, Marcus; Lutz, Stefan Z; Schwentner, Christian; Todenhöfer, Tilman; Schilling, David; Kühs, Ursula; Gerber, Valentina; Machicao, Fausto; Staiger, Harald; Häring, Hans-Ulrich; Stenzl, Arnulf

2012-01-01

In different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation. We studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27(Kip1) was quantified by real-time RT-PCR and immunohistochemistry. Insulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27(Kip1) content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019). We found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.

Does Inflammation Mediate the Obesity and BPH Relationship? An Epidemiologic Analysis of Body Composition and Inflammatory Markers in Blood, Urine, and Prostate Tissue, and the Relationship with Prostate Enlargement and Lower Urinary Tract Symptoms.

PubMed

Fowke, Jay H; Koyama, Tatsuki; Fadare, Oluwole; Clark, Peter E

2016-01-01

BPH is a common disease associated with age and obesity. However, the biological pathways between obesity and BPH are unknown. Our objective was to investigate biomarkers of systemic and prostate tissue inflammation as potential mediators of the obesity and BPH association. Participants included 191 men without prostate cancer at prostate biopsy. Trained staff measured weight, height, waist and hip circumferences, and body composition by bioelectric impedance analysis. Systemic inflammation was estimated by serum IL-6, IL-1β, IL-8, and TNF-α; and by urinary prostaglandin E2 metabolite (PGE-M), F2-isoprostane (F2iP), and F2-isoprostane metabolite (F2iP-M) levels. Prostate tissue was scored for grade, aggressiveness, extent, and location of inflammatory regions, and also stained for CD3 and CD20 positive lymphocytes. Analyses investigated the association between multiple body composition scales, systemic inflammation, and prostate tissue inflammation against BPH outcomes, including prostate size at ultrasound and LUTS severity by the AUA-symptom index (AUA-SI). Prostate size was significantly associated with all obesity measures. For example, prostate volume was 5.5 to 9.0 mls larger comparing men in the 25th vs. 75th percentile of % body fat, fat mass (kg) or lean mass (kg). However, prostate size was not associated with proinflammatory cytokines, PGE-M, F2iP, F2iP-M, prostate tissue inflammation scores or immune cell infiltration. In contrast, the severity of prostate tissue inflammation was significantly associated with LUTS, such that there was a 7 point difference in AUA-SI between men with mild vs. severe inflammation (p = 0.004). Additionally, men with a greater waist-hip ratio (WHR) were significantly more likely to have severe prostate tissue inflammation (p = 0.02), and a high WHR was significantly associated with moderate/severe LUTS (OR = 2.56, p = 0.03) among those participants with prostate tissue inflammation. The WHR, an estimate of centralized obesity, was associated with the severity of inflammatory regions in prostate tissue and with LUTS severity among men with inflammation. Our results suggest centralized obesity advances prostate tissue inflammation to increase LUTS severity. Clinically targeting centralized fat deposition may reduce LUTS severity. Mechanistically, the lack of a clear relationship between systemic inflammatory or oxidative stress markers in blood or urine with prostate size or LUTS suggests pathways other than systemic inflammatory signaling may link body adiposity to BPH outcomes.

Radiobiological Impact of Planning Techniques for Prostate Cancer in Terms of Tumor Control Probability and Normal Tissue Complication Probability

PubMed Central

Rana, S; Cheng, CY

2014-01-01

Background: The radiobiological models describe the effects of the radiation treatment on cancer and healthy cells, and the radiobiological effects are generally characterized by the tumor control probability (TCP) and normal tissue complication probability (NTCP). Aim: The purpose of this study was to assess the radiobiological impact of RapidArc planning techniques for prostate cancer in terms of TCP and normal NTCP. Subjects and Methods: A computed tomography data set of ten cases involving low-risk prostate cancer was selected for this retrospective study. For each case, two RapidArc plans were created in Eclipse treatment planning system. The double arc (DA) plan was created using two full arcs and the single arc (SA) plan was created using one full arc. All treatment plans were calculated with anisotropic analytical algorithm. Radiobiological modeling response evaluation was performed by calculating Niemierko's equivalent uniform dose (EUD)-based Tumor TCP and NTCP values. Results: For prostate tumor, the average EUD in the SA plans was slightly higher than in the DA plans (78.10 Gy vs. 77.77 Gy; P = 0.01), but the average TCP was comparable (98.3% vs. 98.3%; P = 0.01). In comparison to the DA plans, the SA plans produced higher average EUD to bladder (40.71 Gy vs. 40.46 Gy; P = 0.03) and femoral heads (10.39 Gy vs. 9.40 Gy; P = 0.03), whereas both techniques produced NTCP well below 0.1% for bladder (P = 0.14) and femoral heads (P = 0.26). In contrast, the SA plans produced higher average NTCP compared to the DA plans (2.2% vs. 1.9%; P = 0.01). Furthermore, the EUD to rectum was slightly higher in the SA plans (62.88 Gy vs. 62.22 Gy; P = 0.01). Conclusion: The SA and DA techniques produced similar TCP for low-risk prostate cancer. The NTCP for femoral heads and bladder was comparable in the SA and DA plans; however, the SA technique resulted in higher NTCP for rectum in comparison with the DA technique. PMID:24761232

Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

PubMed

Yellepeddi, Venkata K; Radhakrishnan, Jayashree; Radhakrishnan, Rajan

2018-02-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 μg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs. © 2017 Wiley Periodicals, Inc.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

PubMed Central

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

Nuclear morphometry in histological specimens of canine prostate cancer: Correlation with histological subtypes, Gleason score, methods of collection and survival time.

PubMed

Di Donato, Guido; Laufer-Amorim, Renée; Palmieri, Chiara

2017-10-01

Ten normal prostates, 22 benign prostatic hyperplasia (BPH) and 29 prostate cancer (PC) were morphometrically analyzed with regard to mean nuclear area (MNA), mean nuclear perimeter (MNP), mean nuclear diameter (MND), coefficient of variation of the nuclear area (NACV), mean nuclear diameter maximum (MDx), mean nuclear diameter minimum (MDm), mean nuclear form ellipse (MNFe) and form factor (FF). The relationship between nuclear morphometric parameters and histological type, Gleason score, methods of sample collection, presence of metastases and survival time of canine PC were also investigated. Overall, nuclei from neoplastic cells were larger, with greater variation in nuclear size and shape compared to normal and hyperplastic cells. Significant differences were found between more (small acinar/ductal) and less (cribriform, solid) differentiated PCs with regard to FF (p<0.05). MNA, MNP, MND, MDx, and MDm were significantly correlated with the Gleason score of PC (p<0.05). MNA, MNP, MDx and MNFe may also have important prognostic implications in canine prostatic cancer since negatively correlated with the survival time. Biopsy specimens contained nuclei that were smaller and more irregular in comparison to those in prostatectomy and necropsy specimens and therefore factors associated with tissue sampling and processing may influence the overall morphometric evaluation. The results indicate that nuclear morphometric analysis in combination with Gleason score can help in canine prostate cancer grading, thus contributing to the establishment of a more precise prognosis and patient's management. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of 6 and 15 MV on intensity-modulated radiation therapy prostate cancer treatment: plan evaluation, tumour control probability and normal tissue complication probability analysis, and the theoretical risk of secondary induced malignancies

PubMed Central

Hussein, M; Aldridge, S; Guerrero Urbano, T; Nisbet, A

2012-01-01

Objective The aim of this study was to investigate the effect of 6 and 15-MV photon energies on intensity-modulated radiation therapy (IMRT) prostate cancer treatment plan outcome and to compare the theoretical risks of secondary induced malignancies. Methods Separate prostate cancer IMRT plans were prepared for 6 and 15-MV beams. Organ-equivalent doses were obtained through thermoluminescent dosemeter measurements in an anthropomorphic Aldersen radiation therapy human phantom. The neutron dose contribution at 15 MV was measured using polyallyl-diglycol-carbonate neutron track etch detectors. Risk coefficients from the International Commission on Radiological Protection Report 103 were used to compare the risk of fatal secondary induced malignancies in out-of-field organs and tissues for 6 and 15 MV. For the bladder and the rectum, a comparative evaluation of the risk using three separate models was carried out. Dose–volume parameters for the rectum, bladder and prostate planning target volume were evaluated, as well as normal tissue complication probability (NTCP) and tumour control probability calculations. Results There is a small increased theoretical risk of developing a fatal cancer from 6 MV compared with 15 MV, taking into account all the organs. Dose–volume parameters for the rectum and bladder show that 15 MV results in better volume sparing in the regions below 70 Gy, but the volume exposed increases slightly beyond this in comparison with 6 MV, resulting in a higher NTCP for the rectum of 3.6% vs 3.0% (p=0.166). Conclusion The choice to treat using IMRT at 15 MV should not be excluded, but should be based on risk vs benefit while considering the age and life expectancy of the patient together with the relative risk of radiation-induced cancer and NTCPs. PMID:22010028

Circular RNA Myosin Light Chain Kinase (MYLK) Promotes Prostate Cancer Progression through Modulating Mir-29a Expression.

PubMed

Dai, Yuanqing; Li, Dongjie; Chen, Xiong; Tan, Xinji; Gu, Jie; Chen, Mingquan; Zhang, Xiaobo

2018-05-25

BACKGROUND In developed countries, prostate cancer (PCa) is a frequently diagnosed cancer with the second highest fatality rate. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) stably expressed in cells and involved in a series of carcinomas. However, few research studies have reported on the role of circRNAs in PCa. MATERIAL AND METHODS We used qRT-PCR to detect the expression of circMYLK (circRNA ID: hsa_circ_0141940) and miR-29a in PCa tissues and cell lines. MTT, colony formation, and TUNEL assays were performed to analysis the cell viability of PCa cells. Transwell and wound scratch assays were performed to investigate the cell invasion and migration of PCa cells. RESULTS In the present study, we confirmed that circMYLK expression level was significantly higher in PCa samples and PCa cells than in normal tissues and normal prostatic cells. The upregulated circRNA-MYLK promoted PCa cells proliferation, invasion, and migration; however, si-circRNA-MYLK significantly accelerated the PCa cell apoptosis. We also observed that the aforementioned function of circRNA-MYLK on PCa cells was affected through targeting miR-29a. CONCLUSIONS We confirmed circRNA-MYLK was an oncogene in PCa and revealed a novel mechanism underlying circRNA-MYLK in PC progression.

MR elastography of prostate cancer: quantitative comparison with histopathology and repeatability of methods.

PubMed

Sahebjavaher, Ramin S; Nir, Guy; Honarvar, Mohammad; Gagnon, Louis O; Ischia, Joseph; Jones, Edward C; Chang, Silvia D; Fazli, Ladan; Goldenberg, S Larry; Rohling, Robert; Kozlowski, Piotr; Sinkus, Ralph; Salcudean, Septimiu E

2015-01-01

The purpose of this work was to assess trans-perineal prostate magnetic resonance elastography (MRE) for (1) repeatability in phantoms/volunteers and (2) diagnostic power as correlated with histopathology in prostate cancer patients. The three-dimensional (3D) displacement field was obtained using a fractionally encoded gradient echo sequence using a custom-made transducer. The repeatability of the method was assessed based on three repeat studies and by changing the driving frequency by 3% in studies on a phantom and six healthy volunteers. Subsequently, 11 patients were examined with MRE prior to radical prostatectomy. The areas under the receiver operating characteristic curves were calculated using a windowed voxel-to-voxel approach by comparing the 2D registered slides, masked with the Gleason score. For the repeatability study, the average intraclass correlation coefficient for elasticity images was 99% for repeat phantom studies, 98% for ±6 Hz phantom studies, 95% for volunteer repeat studies with 2 min acquisition time, 82% for ±2 Hz volunteer studies with 2 min acquisition time and 73% for repeat volunteer studies with 8 min acquisition time. For the patient study, the average elasticity was 8.2 ± 1.7 kPa in the prostate capsule, 7.5 ± 1.9 kPa in the peripheral zone (PZ), 9.7 ± 3.0 kPa in the central gland (CG) and 9.0 ± 3.4 kPa in the transition zone. In the patient study, cancerous tissue with Gleason score at least 3 + 3 was significantly (p < 0.05) different from normal tissue in 10 out of 11 cases with tumors in the PZ, and 6 out of 9 cases with tumors in the CG. However, the overall case-averaged area under the curve was 0.72 in the PZ and 0.67 in the CG. Cancerous tissue was not always stiffer than normal tissue. The inversion algorithm was sensitive to (i) vibration amplitude and displacement nodes and (ii) misalignment of the 3D wave field due to subject movement. Copyright © 2014 John Wiley & Sons, Ltd.

Prostate-derived Ets factor, an oncogenic driver in breast cancer.

PubMed

Sood, Ashwani K; Geradts, Joseph; Young, Jessica

2017-05-01

Prostate-derived Ets factor (PDEF), a member of the Ets family of transcription factors, differs from other family members in its restricted expression in normal tissues and its unique DNA-binding motif. These interesting attributes coupled with its aberrant expression in cancer have rendered PDEF a focus of increasing interest by tumor biologists. This review provides a current understanding of the characteristics of PDEF expression and its role in breast cancer. The bulk of the evidence is consistent with PDEF overexpression in most breast tumors and an oncogenic role for this transcription factor in breast cancer. In addition, high PDEF expression in estrogen receptor-positive breast tumors showed significant correlation with poor overall survival in several independent cohorts of breast cancer patients. Together, these findings demonstrate PDEF to be an oncogenic driver of breast cancer and a biomarker of poor prognosis in this cancer. Based on this understanding and the limited expression of PDEF in normal human tissues, the development of PDEF-based therapeutics for prevention and treatment of breast cancer is also discussed.

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takam, Rungdham; Bezak, Eva; Yeoh, Eric E.

2010-09-15

Purpose: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences inmore » radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.« less

Time resolved optical biopsy spectroscopy of normal, benign and malignant tissues from NADH and FAD changes

NASA Astrophysics Data System (ADS)

Masilamani, V.; Das, B. B.; Secor, J.; AlSalhi, M.; Amer, S. B.; Farhat, K.; Rabah, D.; Alfano, R. R.

2012-01-01

Histo pathological examination is the gold standard to discriminate between benign and malignant growth of tissue. But this is invasive and stressful. Hence many non invasive imaging techniques, such as CT, MRI, PET, etc are employed, each having certain advantages and disadvantages. In this context optical biopsy is a newly emerging technique, since it employs non-ionizing radiation like light or laser, which could be shined directly or launched through optical fiber to reach any part of the body. This paper reports results of time resolved emission spectra of 24 excised tissue sample (normal control=12; benign=4; malignant=8) of breast and prostate, employing a 390nm, 100 fs, Ti-Sapphire laser pulses. The fluorescence decay times were measured using streak camera and fitted for single and bi- exponential decays with reliability of 97%. Our results show the distinct difference between normal, benign and malignant tissues attributed changes of NADH and FAD levels.

Primary cilia are increased in number and demonstrate structural abnormalities in human cancer.

PubMed

Yasar, Binnaz; Linton, Kim; Slater, Christian; Byers, Richard

2017-07-01

Primary cilia play an important role in the regulation of cell signalling pathways and are thought to have a role in cancer but have seldom been studied in human cancer samples. Primary cilia were visualised by dual immunofluorescence for anti-CROCC (ciliary rootlet coiled-coil) and anti-tubulin in a range of human cancers (including carcinomas of stomach, pancreas, prostate, lung and colon, lobular and ductal breast cancers and follicular lymphoma) and in matched normal tissue (stomach, pancreas, lung, large and small intestines, breast and reactive lymph nodes) samples using a tissue microarray; their frequency, association with proliferation, was measured by Ki-67 staining and their structure was analysed. Compared with normal tissues, primary cilia frequency was significantly elevated in adenocarcinoma of the lung (2.75% vs 1.85%, p=0.016), adenocarcinoma of the colon (3.80% vs 2.43%, respectively, p=0.017), follicular lymphoma (1.18% vs 0.83%, p=0.003) and pancreatic adenocarcinoma (7.00% vs 5.26%, p=0.002); there was no statistically significant difference compared with normal control tissue for gastric and prostatic adenocarcinomas or for lobular and ductal breast cancers. Additionally, structural abnormalities of primary cilia were identified in cancer tissues, including elongation of the axoneme, multiple basal bodies and branching of the axoneme. Ki-67 scores ranged from 0.7% to 78.4% and showed no statistically significant correlation with primary cilia frequency across all tissues (p=0.1501). The results show upregulation of primary cilia and the presence of structural defects in a wide range of human cancer tissue samples demonstrating association of dysregulation of primary cilia with human cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model

PubMed Central

Pérez-Alvarado, Carlos; Gómez, Consuelo; Reyes, Miguel; García, Mario; Pérez, Elizabeth; Pérez de la Mora, Carlos; Sanchez, Virginia

2017-01-01

Objective. To evaluate the anti-inflammatory properties of Dialyzable Leukocyte Extract (DLE) in a murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods. Histopathological characterization, prostatein Enzyme-Linked Immunosorbent Assay, and immunohistochemical analysis for CD45, TNF-α, IFN-γ, IL-6, IL-17, and IL-4 molecules were done in prostatic Wistar rats treated with DLE, placebo, or Dexamethasone. Results. Histopathological analysis of animals induced to prostatitis showed inflammatory infiltrate, mainly constituted by leucocytes and mast cells as well as Benign Prostatic Hyperplasia. Serum prostatein concentrations were 14 times higher than those displayed by healthy animals. After DLE and Dexamethasone treatments, the inflammatory infiltrate decreased; the tissue morphology was similar to that of a normal prostate, and the prostatein decreased to the basal levels of healthy animals. DLE treatment produced a decreased expression of the cell surface marker CD45 and the proinflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-17. On the other hand, the expression of anti-inflammatory cytokine IL-4 increased in both the Dexamethasone and DLE groups. Conclusion. DLE is able to modulate the inflammatory response in Experimental Autoimmune Prostatitis (EAP). PMID:28386549

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model.

PubMed

Pérez-Alvarado, Carlos; Gómez, Consuelo; Reyes, Miguel; García, Mario; Pérez, Elizabeth; Pérez de la Mora, Carlos; Sanchez, Virginia; Pérez Ishiwara, D Guillermo

2017-01-01

Objective. To evaluate the anti-inflammatory properties of Dialyzable Leukocyte Extract (DLE) in a murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods. Histopathological characterization, prostatein Enzyme-Linked Immunosorbent Assay, and immunohistochemical analysis for CD45, TNF- α , IFN- γ , IL-6, IL-17, and IL-4 molecules were done in prostatic Wistar rats treated with DLE, placebo, or Dexamethasone. Results. Histopathological analysis of animals induced to prostatitis showed inflammatory infiltrate, mainly constituted by leucocytes and mast cells as well as Benign Prostatic Hyperplasia. Serum prostatein concentrations were 14 times higher than those displayed by healthy animals. After DLE and Dexamethasone treatments, the inflammatory infiltrate decreased; the tissue morphology was similar to that of a normal prostate, and the prostatein decreased to the basal levels of healthy animals. DLE treatment produced a decreased expression of the cell surface marker CD45 and the proinflammatory cytokines TNF- α , IFN- γ , IL-6, and IL-17. On the other hand, the expression of anti-inflammatory cytokine IL-4 increased in both the Dexamethasone and DLE groups. Conclusion. DLE is able to modulate the inflammatory response in Experimental Autoimmune Prostatitis (EAP).

Trimodal spectra for high discrimination of benign and malignant prostate tissue

NASA Astrophysics Data System (ADS)

Al Salhi, Mohamad; Masilamani, Vadivel; Trinka, Vijmasi; Rabah, Danny; Al Turki, Mohammed R.

2011-02-01

High false positives and over diagnosis is a major problem with management of prostate cancer. A non-invasive or a minimally invasive technique to accurately distinguish malignant prostate cancers from benign tumors will be extremely helpful to overcome this problem. In this paper, we had used three different fluorescence spectroscopy techniques viz., Fluorescence Emission Spectrum (FES), Stokes' Shift Spectrum (SSS) and Reflectance Spectrum (RS) to discriminate benign prostate tumor tissues (N=12) and malignant prostate cancer tissues (N=8). These fluorescence techniques were used to determine the relative concentration of naturally occurring biomolecules such as tryptophan, elastin, NADH and flavin which are found to be out of proportion in cancer tissues. Our studies show that combining all three techniques, benign and malignant prostate tissues could be classified with accuracy greater than 90%. This preliminary report is based on in vitro spectroscopy analysis. However, by employing fluorescence endoscopy techniques, this can be extended to in vivo analysis as well. This technique has the potential to identify malignant prostate tissues without surgery.

Prostatic Tissue Elimination After Prostatic Artery Embolization (PAE): A Report of Three Cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leite, Leandro Cardarelli; Assis, Andre Moreira de; Moreira, Airton Mota

PurposeWe report three cases of spontaneous prostatic tissue elimination through the urethra while voiding following technically successful prostatic artery embolization (PAE) as a treatment for lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH).MethodsAll patients were embolized with 100- to 300-μm microspheres alone or in combination with 300- to 500-μm microspheres.ResultsDuring follow-up prior to eliminating the tissue fragments, the three patients all presented with intermittent periods of LUTS improvement and aggravation. After expelling the prostatic tissue between 1 and 5 months of follow-up, significant improvements in LUTS and urodynamic parameters were observed in all patients.ConclusionsUrethral obstruction after PAEmore » caused by sloughing prostate tissue is a potential complication of the procedure and should be considered in patients with recurrent LUTS in order to avoid inappropriate management.« less

Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer.

PubMed

Sörensen, Jens; Owenius, Rikard; Lax, Michelle; Johansson, Silvia

2013-02-01

[(18)F]Fluciclovine (anti-[(18)F]FACBC) is a synthetic amino acid developed for PET assessment of the anabolic component of tumour metabolism in clinical routine. This phase 1 trial evaluated the safety, tracer stability and uptake kinetics of [(18)F]fluciclovine in patients. Six patients with biopsy-proven prostate cancer were investigated with 3-T MRI and PET/CT. All underwent dynamic [(18)F]fluciclovine PET/CT of the pelvic area for up to 120 min after injection of 418 ± 10 MBq of tracer with simultaneous blood sampling of radioactivity. The kinetics of uptake in tumours and normal tissues were evaluated using standardized uptake values (SUVs) and compartmental modelling. Tumour deposits as defined by MRI were clearly visualized by PET. Urine excretion was minimal and normal tissue background was low. Uptake of [(18)F]fluciclovine in tumour from the blood was rapid and the tumour-to-normal tissue contrast was highest between 1 and 15 min after injection with a 65 % reduction in mean tumour uptake at 90 min after injection. A one-compartment model fitted the tracer kinetics well. Early SUVs correlated well with both the influx rate constant (K (1)) and the volume of distribution of the tracer (V (T)). There were no signs of tracer metabolite formation. The product was well tolerated in all patients without significant adverse events. [(18)F]Fluciclovine shows high uptake in prostate cancer deposits and appears safe for use in humans. The production is robust and the formulation stable in vivo. An early imaging window seems to provide the best visual results. SUV measurements capture most of the kinetic information that can be obtained from more advanced models, potentially simplifying quantification in future studies.

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.

PubMed

Li, Qinlong; Yin, Lijuan; Jones, Lawrence W; Chu, Gina C-Y; Wu, Jason B-Y; Huang, Jen-Ming; Li, Quanlin; You, Sungyong; Kim, Jayoung; Lu, Yi-Tsung; Mrdenovic, Stefan; Wang, Ruoxiang; Freeman, Michael R; Garraway, Isla; Lewis, Michael S; Chung, Leland W K; Zhau, Haiyen E

2016-12-20

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

MR elastography and diffusion-weighted imaging of ex vivo prostate cancer: quantitative comparison to histopathology.

PubMed

Sahebjavaher, Ramin S; Nir, Guy; Gagnon, Louis O; Ischia, Joseph; Jones, Edward C; Chang, Silvia D; Yung, Andrew; Honarvar, Mohammad; Fazli, Ladan; Goldenberg, S Larry; Rohling, Robert; Sinkus, Ralph; Kozlowski, Piotr; Salcudean, Septimiu E

2015-01-01

The purpose of this work was (1) to develop a magnetic resonance elastography (MRE) system for imaging of the ex vivo human prostate and (2) to assess the diagnostic power of mono-frequency and multi-frequency MRE and diffusion weighted imaging (DWI) alone and combined as correlated with histopathology in a patient study. An electromagnetic driver was designed specifically for MRE studies in small-bore MR scanners. Ex vivo prostate specimens (post-fixation) of 14 patients who underwent radical prostatectomy were imaged with MRE at 7 T (nine cases had DWI). In six patients, the MRE examination was performed at three frequencies (600, 800, 1000 Hz) to extract the power-law exponent Gamma. The images were registered to wholemount pathology slides marked with the Gleason score. The areas under the receiver-operator-characteristic curves (AUC) were calculated. The methods were validated in a phantom study and it was demonstrated that (i) the driver does not interfere with the acquisition process and (ii) the driver can generate amplitudes greater than 100 µm for frequencies less than 1 kHz. In the quantitative study, cancerous tissue with Gleason score at least 3 + 3 was distinguished from normal tissue in the peripheral zone (PZ) with an average AUC of 0.75 (Gd ), 0.75 (Gl ), 0.70 (Gamma-Gd ), 0.68 (apparent diffusion coefficient, ADC), and 0.82 (Gd  + Gl  + ADC). The differentiation between PZ and central gland was modest for Gd (p < 0.07), Gl (p < 0.06) but not significant for Gamma (p < 0.2). A correlation of 0.4 kPa/h was found between the fixation time of the prostate specimen and the stiffness of the tissue, which could affect the diagnostic power results. DWI and MRE may provide complementary information; in fact MRE performed better than ADC in distinguishing normal from cancerous tissue in some cases. Multi-frequency (Gamma) analysis did not appear to improve the results. However, in light of the effect of tissue fixation, the clinical implication of our results may be inconclusive and more experiments are needed. Copyright © 2014 John Wiley & Sons, Ltd.

Enoxacin penetration into human prostatic tissue.

PubMed Central

Bergeron, M G; Roy, R; Lessard, C; Foucault, P

1988-01-01

Concurrent enoxacin concentrations in serum and prostatic tissue were determined in 14 patients. The mean ratios of enoxacin concentration in tissue over concentration in serum were 1.4 +/- 0.2 (standard error of the mean). The levels in serum and prostatic tissue were above the MICs for most urinary pathogens. PMID:3196004

Microgravity

NASA Image and Video Library

2000-12-15

Paul Ducheyne, a principal investigator in the microgravity materials science program and head of the University of Pernsylvania's Center for Bioactive Materials and Tissue Engineering, is leading the trio as they use simulated microgravity to determine the optimal characteristics of tiny glass particles for growing bone tissue. The result could make possible a much broader range of synthetic bone-grafting applications. Even in normal gravity, bioactive glass particles enhance bone growth in laboratory tests with flat tissue cultures. Ducheyne and his team believe that using the bioactive microcarriers in a rotating bioreactor in microgravity will produce improved, three-dimensional tissue cultures. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: NASA and University of Pennsylvania Center for Bioactive Materials and Tissue Engineering.

In vivo cryoablation of prostate tissue with temperature monitoring by optoacoustic imaging

NASA Astrophysics Data System (ADS)

Petrova, Elena V.; Motamedi, Massoud; Oraevsky, Alexander A.; Ermilov, Sergey A.

2016-03-01

Cryoablation of prostate cancer is an FDA approved clinical procedure, which involves repetitive rapid cooling of a lesion to lethal temperatures of -40°C and below. The major drawback of the technique is the insufficient control over the fast thermal processes that may result in severe complications (impotence, incontinence, perforation of the rectal wall) and morbidity. The developed optoacoustic imaging technique provides non-invasive real-time temperature mapping of tissue adjacent to prostate and enables more efficient control over the procedure, which is necessary to reduce side effects and accelerate the physician's learning curve. In these studies we successfully demonstrated real-time transrectal optoacoustic imaging during prostate cryoablation in live canine model focused on optoacoustic thermography of the rectal wall within the depth of 1cm. Our method utilized previously discovered universal thermal dependence of the normalized optoacoustic response of blood. Nanosecond-pulse radiation of Ti-Sapphire laser tuned to the isosbestic point of hemoglobin (802+/-3 nm) was delivered via fiberoptic illuminators assembled on both sides of the linear array of the 128-channel transrectal ultrasound probe. Temperature readouts at discrete locations inside and nearby prostate were also performed using standard transperineal needle sensors. The effect of homeostasis on optoacoustic imaging in live tissue was examined during cooling and shown to be significant only within the range of +/-1.5°C in respect to the body temperature. Accuracy of in vivo optoacoustic temperature measurements was determined as +/-2°C for the range of temperature from +35 to -15°C, which is more than sufficient for tracking the essential isotherms in the course of clinical procedures.

Expression and potential role of the peptide orexin-A in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona

The peptides orexin-A and orexin-B and their G protein-coupled OX1 and OX2 receptors are involved in multiple physiological processes in the central nervous system and peripheral organs. Altered expression or signaling dysregulation of orexins and their receptors have been associated with a wide range of human diseases including narcolepsy, obesity, drug addiction, and cancer. Although orexin-A, its precursor molecule prepro-orexin and OX1 receptor have been detected in the human normal and hyperplastic prostate tissues, their expression and function in the prostate cancer (PCa) remains to be addressed. Here, we demonstrate for the first time the immunohistochemical localization of orexin-A inmore » human PCa specimens, and the expression of prepro-orexin and OX1 receptor at both protein and mRNA levels in these tissues. Orexin-A administration to the human androgen-dependent prostate carcinoma cells LNCaP up-regulates OX1 receptor expression resulting in a decrease of cell survival. Noteworthy, nanomolar concentrations of the peptide counteract the testosterone-induced nuclear translocation of the androgen receptor in the cells: the orexin-A action is prevented by the addition of the OX1 receptor antagonist SB-408124 to the test system. These findings indicate that orexin-A/OX1 receptor interaction interferes with the activity of the androgen receptor which regulates PCa onset and progression, thus suggesting that orexin-A and its receptor might represent novel therapeutic targets to challenge this aggressive cancer. - Highlights: • Orexin-A and OX1 receptor are present in human cancer prostate tissues. • Orexin-A up-regulates OX1 receptor expression in LNCaP cells. • Orexin-A inhibits testosterone-induced nuclear translocation of androgen receptor.« less

The epigenetics of prostate cancer diagnosis and prognosis: update on clinical applications.

PubMed

Blute, Michael L; Damaschke, Nathan A; Jarrard, David F

2015-01-01

There is a major deficit in our ability to detect and predict the clinical behavior of prostate cancer (PCa). Epigenetic changes are associated with PCa development and progression. This review will focus on recent results in the clinical application of diagnostic and prognostic epigenetic markers. The development of high throughput technology has seen an enormous increase in the discovery of new markers that encompass epigenetic changes including those in DNA methylation and histone modifications. Application of these findings to urine and other biofluids, but also cancer and noncancerous prostate tissue, has resulted in new biomarkers. There has been a recent commercial development of a DNA methylation-based assay for identifying PCa risk from normal biopsy tissue. Other biomarkers are currently in the validation phase and encompass combinations of multiple genes. Epigenetic changes improve the specificity and sensitivity of PCa diagnosis and have the potential to help determine clinical prognosis. Additional studies will not only provide new and better biomarker candidates, but also have the potential to inform new therapeutic strategies given the reversibility of these processes.

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

PubMed Central

Maroulakou, I G; Anver, M; Garrett, L; Green, J E

1994-01-01

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands. Images PMID:7972041

Prostate biopsy

MedlinePlus

... shows that you have a higher than normal prostate specific antigen (PSA) level Your provider discovers a lump or abnormality in your prostate during a digital rectal exam Normal Results Normal ...

Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia.

PubMed

Nejishima, Hiroaki; Yamamoto, Noriko; Suzuki, Mika; Furuya, Kazuyuki; Nagata, Naoya; Yamada, Shizuo

2012-10-01

Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. Copyright © 2012 Wiley Periodicals, Inc.

Role of oxidative stress in a rat model of radiation-induced erectile dysfunction.

PubMed

Kimura, Masaki; Rabbani, Zahid N; Zodda, Andrew R; Yan, Hui; Jackson, Isabel L; Polascik, Thomas J; Donatucci, Craig F; Moul, Judd W; Vujaskovic, Zeljko; Koontz, Bridget F

2012-06-01

Chronic oxidative stress is one of the major factors playing an important role in radiation-induced normal tissue injury. However, the role of oxidative stress in radiation-induced erectile dysfunction (ED) has not been fully investigated. Aims.  To investigate role of oxidative stress after prostate-confined irradiation in a rat model of radiation-induced ED. Fifty-four young adult male rats (10-12 weeks of age) were divided into age-matched sham radiotherapy (RT) and RT groups. Irradiated animals received prostate-confined radiation in a single 20 Gy fraction. Intracavernous pressure (ICP) measurements with cavernous nerve electrical stimulation were conducted at 2, 4, and 9 weeks following RT. The protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits (Nox4 and gp91(phox)), markers of oxidative DNA damage (8-hydroxy-2'-deoxyguanosine [8-OHdG]), lipid peroxidation (4-hydroxynonenal [4HNE]), and inflammatory response including inducible nitric oxide synthase, macrophage activation (ED-1), and nitrotyrosine, and endogenous antioxidant defense by nuclear factor erythroid 2-related factor (Nrf2) were evaluated in irradiated prostate tissue and corpora cavernosa (CC). In addition, we investigated the relationships between results of ICP/mean arterial pressure (MAP) ratios and expression level of oxidative stress markers. In the RT group, hemodynamic functional studies demonstrated a significant time-dependent decrease in ICP. Increased expression of Nox4, gp91(phox), 8-OHdG, and 4HNE were observed in the prostate and CC after RT. Similarly, expressions of inflammatory markers were significantly increased. There was a trend for increased Nrf2 after 4 weeks. ICP/MAP ratio negatively correlated with higher expression level of oxidative markers. NADPH oxidase activation and chronic oxidative stress were observed in irradiated prostate tissue and CC, which correlated with lower ICP/MAP ratio. Persistent inflammatory responses were also found in both tissues after RT. These findings suggest that oxidative stress plays a crucial role in the development of radiation-induced ED. © 2012 International Society for Sexual Medicine.

Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.

Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity wasmore » assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing gammaH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2mug/mL], Trinovin [10mug/mL], and Prostate Rx [50 mug/mL]). However, both Trinovin (10mug/mL) and Prostate Rx (6mug/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.« less

Chondroitin sulfatases differentially regulate Wnt signaling in prostate stem cells through effects on SHP2, phospho-ERK1/2, and Dickkopf Wnt signaling pathway inhibitor (DKK3)

PubMed Central

Bhattacharyya, Sumit; Feferman, Leo; Tobacman, Joanne K.

2017-01-01

The chondroitin sulfatases N-acetylgalactosamine-4-sulfatase (ARSB) and galactosamine-N-acetyl-6-sulfatase (GALNS) remove either the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and dermatan sulfate, or the 6-sulfate group of chondroitin 6-sulfate, chondroitin 4,6-disulfate (chondroitin sulfate E), or keratan sulfate. In human prostate cancer tissues, the ARSB activity was reduced and the GALNS activity was increased, compared to normal prostate tissue. In human prostate stem cells, when ARSB was reduced by silencing or GALNS was increased by overexpression, activity of SHP2, the ubiquitous non-receptor tyrosine phosphatase, declined, attributable to increased binding of SHP2 with C4S. This led to increases in phospho-ERK1/2, Myc/Max nuclear DNA binding, DNA methyltransferase (DNMT) activity and expression, and methylation of the Dickkopf Wnt signaling pathway inhibitor (DKK)3 promoter and to reduced DKK3 expression. Since DKK3 negatively regulates Wnt/β-catenin signaling, silencing of ARSB or overexpression of GALNS disinhibited (increased) Wnt/β-catenin signaling. These findings indicate that the chondroitin sulfatases can exert profound effects on Wnt-mediated processes, due to epigenetic effects that modulate Wnt signaling. PMID:29245974

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma.

PubMed

Kil, P J M; Goldschmidt, H M J; Wieggers, B J A; Kariakine, O B; Studer, U E; Whelan, P; Hetherington, J; de Reijke, Th M; Hoekstra, J W; Collette, L

2003-01-01

To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to clinical progression. Finally to compare TPS with prostate-specific antigen (PSA) measurements in terms of prognostic impact in patients with metastatic prostatic carcinoma. TPS and PSA measurements were performed before start of and monthly during intermittent MAB in 68 patients participating in EORTC protocol 30954. Both TPS and PSA were measured in serum. Fifty-six patients from eight centers were included in the final analysis because at least three TPS values were available. TPS and PSA values were correlated with clinical course of the disease. Median follow-up was 21.3 months. Three patient groups were defined on clinical grounds: (a) clinically progressive disease (n=18); (b) clinically stable disease (n=33); and (c) patients who did not reach a predefined nadir PSA value following 9 months of treatment (n=5). Pretreatment TPS was significantly higher in the clinically progressive patients than in the other patient groups (p=0.0041). When grouping patients according to their pretreatment TPS values (cut-off value of 100 U/l) the pretreatment TPS value (>100 U/l) proved to be a statistically significant prognostic factor with respect to time to progression: elevated TPS was associated with a 3.8 increased risk for progressive disease (p=0.0055). Pretreatment PSA (>100 ng/ml) was of no prognostic value for time to progression. In five patients increase of TPS coincided with or preceded clinical progression during treatment, whereas PSA remained normal. Additional value of pretreatment TPS measurements in metastatic prostate cancer patients is found in defining the patients with rapid clinical progression. Following MAB an increase in TPS signifies clinical progression even if PSA is found to remain normal.

SU-E-T-13: A Comparative Dosimetric Study On Radio-Dynamic Therapy for Pelvic Cancer Treatment: Strategies for Bone Marrow Dose and Volume Reduction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, C; Renmin Hospital of Wuhan University, Wuhan, Hubei Province; Wang, B

Purpose: Radio-dynamic therapy (RDT) is a potentially effective modality for local and systemic cancer treatment. Using RDT, the administration of a radio-sensitizer enhances the biological effect of high-energy photons. Although the sensitizer uptake ratio of tumor to normal tissue is normally high, one cannot simply neglect its effect on critical structures. In this study, we aim to explore planning strategies to improve bone marrow sparing without compromising the plan quality for RDT treatment of pelvic cancers. Methods: Ten cervical and ten prostate cancer patients who previously received radiotherapy at our institution were selected for this study. For each patient, ninemore » plans were created using the Varian Eclipse treatmentplanning-system (TPS) with 3D-CRT, IMRT, and VMAT delivery techniques containing various gantry angle combinations and optimization parameters (dose constraints to the bone marrow). To evaluate the plans for bone marrow sparing, the dose-volume parameters V5, V10, V15, V20, V30, and V40 for bone marrow were examined. Effective doseenhancement factors for the sensitizer were used to weigh the dose-volume histograms for various tissues from individual fractions. Results: The planning strategies had different impacts on bone marrow sparing for the cervical and prostate cases. For the cervical cases, provided the bone marrow constraints were properly set during optimization, the dose to bone marrow sparing was found to be comparable between different IMRT and VMAT plans regardless of the gantry angle selection. For the prostate cases, however, careful selection of gantry angles could dramatically improve the bone marrow sparing, although the dose distribution in bone marrow was clinically acceptable for all prostate plans that we created. Conclusion: For intensity-modulated RDT planning for cervical cancer, planners should set bone marrow constraints properly to avoid any adverse damage, while for prostate cancer one can carefully select gantry angles to improve bone marrow sparing when necessary.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Underwood, Tracy, E-mail: tunderwood@mgh.harvard.edu; Department of Medical Physics and Bioengineering, University College London, London; Giantsoudi, Drosoula

Purpose: For prostate treatments, robust evidence regarding the superiority of either intensity modulated radiation therapy (IMRT) or proton therapy is currently lacking. In this study we investigated the circumstances under which proton therapy should be expected to outperform IMRT, particularly the proton beam orientations and relative biological effectiveness (RBE) assumptions. Methods and Materials: For 8 patients, 4 treatment planning strategies were considered: (A) IMRT; (B) passively scattered standard bilateral (SB) proton beams; (C) passively scattered anterior oblique (AO) proton beams, and (D) AO intensity modulated proton therapy (IMPT). For modalities (B)-(D) the dose and linear energy transfer (LET) distributions weremore » simulated using the TOPAS Monte Carlo platform and RBE was calculated according to 3 different models. Results: Assuming a fixed RBE of 1.1, our implementation of IMRT outperformed SB proton therapy across most normal tissue metrics. For the scattered AO proton plans, application of the variable RBE models resulted in substantial hotspots in rectal RBE weighted dose. For AO IMPT, it was typically not possible to find a plan that simultaneously met the tumor and rectal constraints for both fixed and variable RBE models. Conclusion: If either a fixed RBE of 1.1 or a variable RBE model could be validated in vivo, then it would always be possible to use AO IMPT to dose-boost the prostate and improve normal tissue sparing relative to IMRT. For a cohort without rectum spacer gels, this study (1) underlines the importance of resolving the question of proton RBE within the framework of an IMRT versus proton debate for the prostate and (2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments.« less

Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer.

PubMed

Shao, Yaping; Ye, Guozhu; Ren, Shancheng; Piao, Hai-Long; Zhao, Xinjie; Lu, Xin; Wang, Fubo; Ma, Wang; Li, Jia; Yin, Peiyuan; Xia, Tian; Xu, Chuanliang; Yu, Jane J; Sun, Yinghao; Xu, Guowang

2018-07-15

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies. © 2018 UICC.

The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases

PubMed Central

Azzouni, Faris; Godoy, Alejandro; Li, Yun; Mohler, James

2012-01-01

Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family. PMID:22235201

Dose perturbation due to the presence of a prostatic urethral stent in patients receiving pelvic radiotherapy: an in vitro study.

PubMed

Gez, E; Cederbaum, M; Yachia, D; Bar-Deroma, R; Kuten, A

1997-01-01

Temporary metallic intraprostatic stent is a new alternative treatment for patients with urinary obstructive syndrome caused by prostate cancer. Definitive radiotherapy is a treatment of choice for localized prostate cancer. This study evaluates in vitro the effect of a urethral intraprostatic metallic stent on the dose absorbed by the surrounding tissue. The study was designed to mimic the conditions under which the prostatic stent is placed in the body during pelvic irradiation. A urethral stent composed of a 50% nickel-50% titanium alloy (Uracoil-InStent) was imbedded in material mimicking normal tissue (bolus) at a simulated body depth of 10 cm. The distribution of the absorbed dose of irradiation was determined by film dosimetry using Kodak X-Omat V film. Irradiation was done in a single field at the isocenter of a 6 MV linear accelerator with a field size of 7 x 7 cm. The degree of film blackening was in direct proportion to the absorbed dose. The measurements showed an increase in dose of up to 20% immediately before the stent and a decrease of up to 18% immediately after the stent. These changes occurred within a range of 1-3 mm from both sides of the stent. In practice, irradiation in prostate cancer is given by two pairs of opposed co-axial fields; a total of four fields (Box Technique). The dose perturbations are partly cancelled in a pair of opposed beams resulting in a net variation of +/- 4%; therefore, the presence of the intraprostatic stent should not influence radiotherapy planning for prostate cancer.

Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray.

PubMed

Higgins, John P T; Kaygusuz, Gulsah; Wang, Lingli; Montgomery, Kelli; Mason, Veronica; Zhu, Shirley X; Marinelli, Robert J; Presti, Joseph C; van de Rijn, Matt; Brooks, James D

2007-05-01

The morphologic distinction between prostate and urothelial carcinoma can be difficult. To identify novel diagnostic markers that may aid in the differential diagnosis of prostate versus urothelial carcinoma, we analyzed expression patterns in prostate and bladder cancer tissues using complementary DNA microarrays. Together with our prior studies on renal neoplasms and normal kidney, these studies suggested that the gene for placental S100 (S100P) is specifically expressed in benign and malignant urothelial cells. Using tissue microarrays, a polyclonal antiserum against S100P protein stained 86% of 295 urothelial carcinomas while only 3% of 260 prostatic adenocarcinomas and 1% of 133 renal cell carcinomas stained. A commercially available monoclonal antibody against S100P stained 78% of 300 urothelial carcinomas while only 2% of 256 prostatic adenocarcinomas and none of 137 renal cell carcinomas stained. A second gene, GATA3, also showed high level expression in urothelial tumors by cDNA array. A commercially available monoclonal antibody against GATA3 stained 67% of 308 urothelial carcinomas, but none of the prostate or renal carcinomas. For comparison, staining was also performed for p63 and cytokeratin 5/6. p63 stained 87% of urothelial carcinomas whereas CK5/6 stained 54%. Importantly, when S100P and p63 were combined 95% of urothelial carcinomas were labeled by one or both markers. We conclude that the detection of S100P and GATA3 protein expression may help distinguish urothelial carcinomas from other genitourinary neoplasms that enter into the differential diagnosis.

Correlation of p63 immunohistochemistry with histology and contrast enhanced MRI in characteristic lesions induced by minimally invasive thermal treatments in a dog prostate

NASA Astrophysics Data System (ADS)

Pascal, A.; Butts-Pauly, K.; Plata, J.; Sommer, G.; Daniel, B.; Bouley, D. M.

2017-03-01

Thermal ablation techniques are important tools to treat low grade tumors in the prostate gland. The use of Magnetic Resonance Imaging (MRI) has been an excellent tool to visualize and assess the thermally ablated areas in real time. In this study slides from dog prostates previously treated with cryoablation or High Intensity Focal Ultrasound (HIFU) were immunohistochemically stained with the biomarker p63, in order to determine if this marker would be helpful for differentiatiating between viable, sub lethally damaged and normal glands. Digitized slides were analyzed using Sedeen Viewer software, and compared with corresponding representative H&E slides and MR images. p63 staining in the cryoablated acute duration prostates was negative in the coagulation necrosis zone (region of interest subjected to the coldest temperatures). In acute duration HIFU treated prostates, the central heat-fixed zone (region of interest subjected to the hottest temperatures) still displayed + p63 staining. Cryoablated or HIFU subacute duration treated prostates were very hemorrhagic, but presented the same stain pattern in the treated areas as the acute duration prostates, and in chronic duration prostates, whether treated with cryo or HIFU, glands displayed robust p63 staining most prevalent in the outer edges of the lesion where there was extensive glandular regeneration. In conclusion, this study demonstrates the value of p63 IHC and its usefulness in detecting viable prostate basal cells in normal dog prostates following either cryoablation of HIFU. Our results suggest that the portions of the lesion with complete loss of p63 staining correspond well to the non-enhancing region in cryoablated prostates, as viewed with MRI. However, p63 staining in the heat-fixed zone in acute harvested HIFU treated prostates remains positive, suggesting either inadequate heat to destroy basal cells, or heat-fixation of the p63 antigen and false positive staining. Therefore p63 staining does not appear to be beneficial in determining cell viability in HIFU-treated tissues, and would not aid in predicting if unwanted tumor cells in a similarly treated area could regenerate.

Microgravity

NASA Image and Video Library

1998-01-01

The heart of the bioreactor is the rotating wall vessel, shown without its support equipment. Volume is about 125 mL. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

NASA Bioreactor

NASA Technical Reports Server (NTRS)

1998-01-01

The heart of the bioreactor is the rotating wall vessel, shown without its support equipment. Volume is about 125 mL. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis.

PubMed

Hanada, Keigo; Furuya, Kazuyuki; Yamamoto, Noriko; Nejishima, Hiroaki; Ichikawa, Kiyonoshin; Nakamura, Tsutomu; Miyakawa, Motonori; Amano, Seiji; Sumita, Yuji; Oguro, Nao

2003-11-01

A novel nonsteroidal androgen receptor (AR) binder, S-40503, was successfully generated in order to develop selective androgen receptor modulators (SARMs). We evaluated the binding specificity for nuclear receptors (NRs) and osteoanabolic activities of S-40503 in comparison with a natural nonaromatizable steroid, 5alpha-dihydrotestosterone (DHT). The compound preferentially bound to AR with nanomolar affinity among NRs. When S-40503 was administrated into orchiectomized (ORX) rats for 4 weeks, bone mineral density (BMD) of femur and muscle weight of levator ani were increased as markedly as DHT, but prostate weight was not elevated over the normal at any doses tested. In contrast, DHT administration caused about 1.5-fold increase in prostate weight. The reduced virilizing activity was clearly evident from the result that 4-week treatment of normal rats with S-40503 showed no enlargement of prostate. To confirm the bone anabolic effect, S-40503 was given to ovariectomized (OVX) rats for 2 months. The compound significantly increased the BMD and biomechanical strength of femoral cortical bone, whereas estrogen, anti-bone resorptive hormone, did not. The increase in periosteal mineral apposition rate (MAR) of the femur revealed direct bone formation activity of S-40503. It was unlikely that the osteoanabolic effect of the compound was attribute to the enhancement of muscle mass, because immobilized ORX rats treated with S-40503 showed a marked increase in BMD of tibial cortical bone without any actions on the surrounding muscle tissue. Collectively, our novel compound served as a prototype for SARMs, which had unique tissue selectivity with high potency for bone formation and lower impact upon sex accessory tissues.

Lack of Evidence for Green Tea Polyphenols as DNA Methylation Inhibitors in Murine Prostate

PubMed Central

Morey Kinney, Shannon R.; Zhang, Wa; Pascual, Marien; Greally, John M.; Gillard, Bryan M.; Karasik, Ellen; Foster, Barbara A.; Karpf, Adam R.

2009-01-01

Green tea polyphenols (GTPs) have been reported to inhibit DNA methylation in cultured cells. Here we tested whether oral consumption of GTPs affects normal or cancer specific DNA methylation in vivo, using mice. Wildtype (WT) and Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice were administered 0.3% GTPs in drinking water beginning at 4 weeks of age. To monitor DNA methylation, we measured 5-methyl-deoxycytidine (5mdC) levels, methylation of the B1 repetitive element, and methylation of the Mage-a8 gene. Each of these parameters were unchanged in prostate, gut, and liver from WT mice at both 12 and 24 weeks of age, with the single exception of a decrease of 5mdC in the liver at 12 weeks. In GTP-treated TRAMP mice, 5mdC levels and the methylation status of four loci hypermethylated during tumor progression were unaltered in TRAMP prostates at 12 or 24 weeks. Quite surprisingly, GTP treatment did not inhibit tumor progression in TRAMP mice, although known pharmacodynamic markers of GTPs were altered in both WT and TRAMP prostates. We also administered 0.1%, 0.3%, or 0.6% GTPs to TRAMP mice for 12 weeks and measured 5mdC levels and methylation of B1 and Mage-a8 in prostate, gut, and liver tissues. No dose-dependent alterations in DNA methylation status were observed. Genome-wide DNA methylation profiling using the HELP assay also revealed no significant hypomethylating effect of GTP. These data indicate that oral administration of GTPs does not affect normal or cancer-specific DNA methylation in the murine prostate. PMID:19934341

Non-Invasive Prostate Cancer Characterization with Diffusion-Weighted MRI: Insight from In silico Studies of a Transgenic Mouse Model

PubMed Central

Hill, Deborah K.; Heindl, Andreas; Zormpas-Petridis, Konstantinos; Collins, David J.; Euceda, Leslie R.; Rodrigues, Daniel N.; Moestue, Siver A.; Jamin, Yann; Koh, Dow-Mu; Yuan, Yinyin; Bathen, Tone F.; Leach, Martin O.; Blackledge, Matthew D.

2017-01-01

Diffusion-weighted magnetic resonance imaging (DWI) enables non-invasive, quantitative staging of prostate cancer via measurement of the apparent diffusion coefficient (ADC) of water within tissues. In cancer, more advanced disease is often characterized by higher cellular density (cellularity), which is generally accepted to correspond to a lower measured ADC. A quantitative relationship between tissue structure and in vivo measurements of ADC has yet to be determined for prostate cancer. In this study, we establish a theoretical framework for relating ADC measurements with tissue cellularity and the proportion of space occupied by prostate lumina, both of which are estimated through automatic image processing of whole-slide digital histology samples taken from a cohort of six healthy mice and nine transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. We demonstrate that a significant inverse relationship exists between ADC and tissue cellularity that is well characterized by our model, and that a decrease of the luminal space within the prostate is associated with a decrease in ADC and more aggressive tumor subtype. The parameters estimated from our model in this mouse cohort predict the diffusion coefficient of water within the prostate-tissue to be 2.18 × 10−3 mm2/s (95% CI: 1.90, 2.55). This value is significantly lower than the diffusion coefficient of free water at body temperature suggesting that the presence of organelles and macromolecules within tissues can drastically hinder the random motion of water molecules within prostate tissue. We validate the assumptions made by our model using novel in silico analysis of whole-slide histology to provide the simulated ADC (sADC); this is demonstrated to have a significant positive correlation with in vivo measured ADC (r2 = 0.55) in our mouse population. The estimation of the structural properties of prostate tissue is vital for predicting and staging cancer aggressiveness, but prostate tissue biopsies are painful, invasive, and are prone to complications such as sepsis. The developments made in this study provide the possibility of estimating the structural properties of prostate tissue via non-invasive virtual biopsies from MRI, minimizing the need for multiple tissue biopsies and allowing sequential measurements to be made for prostate cancer monitoring. PMID:29250485

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2002-10-01

Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors vertical line 1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1-2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in human prostate carcinogenesis and represent potential biomarkers for the assessment of dietary, chemopreventive and therapeutic agents.

[Ultrasound physiotherapy treatment of prostatitis].

PubMed

Talberg, P I; Andryukhin, M I; Mazina, S E; Nikolaev, A L

2016-12-01

Develop a method of treatment of prostatitis based on the use of a standard antibiotic, immunomodulatory therapy, and transrectal ultrasound physiotherapy. The dynamics of the accumulation of the antibiotic was investigated in male rats. Sonication was performed immediately before the administration of the antibiotic and its accumulation in the process at 10, 20, 40, 60, 80, 100 min after dosing. The clinical study included 138 patients with chronic prostatitis. Patients of the experimental group, in addition to standard therapy, 10 sessions of transrectal ultrasound physical therapy was performed. The efficacy of treatment was assessed after 14 and 28 days after initiation. and its discussion. Experiments on laboratory animals have shown that the highest concentration and the residence time of antibiotic in the prostate tissue is noted ultrasonic treatment in the period of maximum blood concentration of the test drug. The data obtained allow to determine that the ultrasonic treatment must be performed considering the pharmacokinetics of the antibiotic. In conducting clinical trials on day 14 of treatment and clinical manifestations of prostatitis bacterial microflora in prostatic secretions were no patients in both groups. In 15% of patients of the experimental group the number of leukocytes decreased to the normal range. After 28 days the amount of leukocytes was normal in 51% of patients in the control and 85% in the experimental group. In animal experiments defined the optimal time interval separating the moment of injection of the antibiotic from the beginning of sonication. Clinical studies have shown that the transrectal ultrasound exposure during the period of maximum concentration of the antibiotic in the blood, improves patient outcomes by 33.8%.

EFEMP1 as a novel DNA methylation marker for prostate cancer: array-based DNA methylation and expression profiling.

PubMed

Kim, Yong-June; Yoon, Hyung-Yoon; Kim, Seon-Kyu; Kim, Young-Won; Kim, Eun-Jung; Kim, Isaac Yi; Kim, Wun-Jae

2011-07-01

Abnormal DNA methylation is associated with many human cancers. The aim of the present study was to identify novel methylation markers in prostate cancer (PCa) by microarray analysis and to test whether these markers could discriminate normal and PCa cells. Microarray-based DNA methylation and gene expression profiling was carried out using a panel of PCa cell lines and a control normal prostate cell line. The methylation status of candidate genes in prostate cell lines was confirmed by real-time reverse transcriptase-PCR, bisulfite sequencing analysis, and treatment with a demethylation agent. DNA methylation and gene expression analysis in 203 human prostate specimens, including 106 PCa and 97 benign prostate hyperplasia (BPH), were carried out. Further validation using microarray gene expression data from the Gene Expression Omnibus (GEO) was carried out. Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was identified as a lead candidate methylation marker for PCa. The gene expression level of EFEMP1 was significantly higher in tissue samples from patients with BPH than in those with PCa (P < 0.001). The sensitivity and specificity of EFEMP1 methylation status in discriminating between PCa and BPH reached 95.3% (101 of 106) and 86.6% (84 of 97), respectively. From the GEO data set, we confirmed that the expression level of EFEMP1 was significantly different between PCa and BPH. Genome-wide characterization of DNA methylation profiles enabled the identification of EFEMP1 aberrant methylation patterns in PCa. EFEMP1 might be a useful indicator for the detection of PCa.

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

PubMed Central

Flores, Orielyz; Santra, Santimukul; Kaittanis, Charalambos; Bassiouni, Rania; Khaled, Amr S; Khaled, Annette R.; Grimm, Jan; Perez, J Manuel

2017-01-01

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size. PMID:28744329

The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

PubMed

Whitaker, Hayley C; Kote-Jarai, Zsofia; Ross-Adams, Helen; Warren, Anne Y; Burge, Johanna; George, Anne; Bancroft, Elizabeth; Jhavar, Sameer; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Saunders, Edward; Page, Elizabeth; Mitra, Anita; Mitchell, Gillian; Lindeman, Geoffrey J; Evans, D Gareth; Blanco, Ignacio; Mercer, Catherine; Rubinstein, Wendy S; Clowes, Virginia; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Donaldson, Alan; Izatt, Louise; Dorkins, Huw; Male, Alison; Tucker, Kathy; Stapleton, Alan; Lam, Jimmy; Kirk, Judy; Lilja, Hans; Easton, Douglas; Cooper, Colin; Eeles, Rosalind; Neal, David E

2010-10-13

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

The rs10993994 Risk Allele for Prostate Cancer Results in Clinically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine

PubMed Central

Whitaker, Hayley C.; Warren, Anne Y.; Burge, Johanna; George, Anne; Bancroft, Elizabeth; Jhavar, Sameer; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Saunders, Edward; Page, Elizabeth; Mitra, Anita; Mitchell, Gillian; Lindeman, Geoffrey J.; Evans, D. Gareth; Blanco, Ignacio; Mercer, Catherine; Rubinstein, Wendy S.; Clowes, Virginia; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Donaldson, Alan; Izatt, Louise; Dorkins, Huw; Male, Alison; Tucker, Kathy; Stapleton, Alan; Lam, Jimmy; Kirk, Judy; Lilja, Hans; Easton, Douglas; Cooper, Colin; Eeles, Rosalind; Neal, David E.

2010-01-01

Background Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. Methodology/Principal Findings MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. Conclusions These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring. PMID:20967219

Organoid culture systems for prostate epithelial tissue and prostate cancer tissue

PubMed Central

Drost, Jarno; Karthaus, Wouter R.; Gao, Dong; Driehuis, Else; Sawyers, Charles L.; Chen, Yu; Clevers, Hans

2016-01-01

Summary This protocol describes a recently developed strategy to generate 3D prostate organoid cultures from healthy mouse and human prostate (either bulk or FAC-sorted single luminal and basal cells), metastatic prostate cancer lesions and circulating tumour cells. Organoids derived from healthy material contain the differentiated luminal and basal cell types, whereas organoids derived from prostate cancer tissue mimic the histology of the tumour. The stepwise establishment of these cultures and the fully defined serum-free conditioned medium that is required to sustain organoid growth are outlined. Organoids established using this protocol can be used to study many different aspects of prostate biology, including homeostasis, tumorigenesis and drug discovery. PMID:26797458

Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer.

PubMed

Rudnicka, Caroline; Mochizuki, Satsuki; Okada, Yasunori; McLaughlin, Claire; Leedman, Peter J; Stuart, Lisa; Epis, Michael; Hoyne, Gerard; Boulos, Sherif; Johnson, Liam; Schlaich, Markus; Matthews, Vance

2016-10-01

Prostate cancer is one of the most prevalent cancers in men. It is critical to identify and characterize oncogenes that drive the pathogenesis of human prostate cancer. The current study builds upon previous research showing that a disintegrin and metallproteinase (ADAM)28 is involved in the pathogenesis of numerous cancers. Our novel study used overexpression, pharmacological, and molecular approaches to investigate the biological function of ADAM28 in human prostate cancer cells, with a focus on cell proliferation and migration. The results of this study provide important insights into the role of metalloproteinases in human prostate cancer.The expression of ADAM28 protein levels was assessed within human prostate tumors and normal adjacent tissue by immunohistochemistry. Immunocytochemistry and western blotting were used to assess ADAM28 protein expression in human prostate cancer cell lines. Functional assays were conducted to assess proliferation and migration in human prostate cancer cells in which ADAM28 protein expression or activity had been altered by overexpression, pharmacological inhibition, or by siRNA gene knockdown.The membrane bound ADAM28 was increased in human tumor biopsies and prostate cancer cell lines. Pharmacological inhibition of ADAM28 activity and/or knockdown of ADAM28 significantly reduced proliferation and migration of human prostate cancer cells, while overexpression of ADAM28 significantly increased proliferation and migration.ADAM28 is overexpressed in primary human prostate tumor biopsies, and it promotes human prostate cancer cell proliferation and migration. This study supports the notion that inhibition of ADAM28 may be a potential novel therapeutic strategy for human prostate cancer.

The Prostate Cancer Biorepository Network (PCBN)

DTIC Science & Technology

2016-10-01

site includes blood (serum, plasma, and buffy coat), prostatectomy tissues (frozen), biopsies and metastatic tissue from rapid autopsies (paraffin...embedded material and tissue microarrays (TMAs)), prostate cancer patient derived xenografts (PDX) and derived specimens (DNA and RNA) from prostate...Genitourinary Cancer Biorepository set up a rapid autopsy program to provide access to metastatic tissue and create patient derived xenograft (PDX

Method of constructing a microwave antenna

NASA Technical Reports Server (NTRS)

Ngo, Phong (Inventor); Arndt, G. Dickey (Inventor); Carl, James (Inventor)

2003-01-01

A method, simulation, and apparatus are provided that are highly suitable for treatment of benign prostatic hyperplasia (BPH). A catheter is disclosed that includes a small diameter disk loaded monopole antenna surrounded by fusion material having a high heat of fusion and a melting point preferably at or near body temperature. Microwaves from the antenna heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. The fusion material keeps the urethra cool by means of the heat of fusion of the fusion material. This prevents damage to the urethra while the prostatic tissue is necrosed. A computer simulation is provided that can be used to predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of the catheter and method of applying microwave energy a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Method of Constructing a Microwave Antenna

NASA Technical Reports Server (NTRS)

Arndt, G. Dickey (Inventor); Carl, James (Inventor); Ngo, Phong (Inventor)

2003-01-01

A method, simulation, and apparatus are provided that are highly suitable for treatment of benign prostatic hyperplasia (BPH). A catheter is disclosed that includes a small diameter disk loaded monopole antenna surrounded by fusion material having a high heat of fusion and a melting point preferably at or near body temperature. Microwaves from the antenna heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. The fusion material keeps the urethra cool by means of the heat of fusion of the fusion material. This prevents damage to the urethra while the prostatic tissue is necrosed. A computer simulation is provided that can be used to predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of the catheter and method of applying microwave energy a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Method for selective thermal ablation

NASA Technical Reports Server (NTRS)

Ngo, Phong (Inventor); Arndt, G. Dickey (Inventor); Raffoul, George W. (Inventor); Carl, James (Inventor)

2003-01-01

A method, simulation, and apparatus are provided that are highly suitable for treatment of benign prostatic hyperplasia (BPH). A catheter is disclosed that includes a small diameter disk loaded monopole antenna surrounded by fusion material having a high heat of fusion and a melting point preferably at or near body temperature. Microwaves from the antenna heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. The fusion material keeps the urethra cool by means of the heat of fusion of the fusion material. This prevents damage to the urethra while the prostatic tissue is necrosed. A computer simulation is provided that can be used to predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of the catheter and method of applying microwave energy a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Method for Selective Thermal Ablation

NASA Technical Reports Server (NTRS)

Arndt, G. Dickey (Inventor); Carl, James (Inventor); Ngo, Phong (Inventor); Raffoul, George W. (Inventor)

2003-01-01

A method, simulation, and apparatus are provided that are highly suitable for treatment of benign prostatic hyperplasia (BPH). A catheter is disclosed that includes a small diameter disk loaded monopole antenna surrounded by fusion material having a high heat of fusion and a melting point preferably at or near body temperature. Microwaves from the antenna heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. The fusion material keeps the urethra cool by means of the heat of fusion of the fusion material. This prevents damage to the urethra while the prostatic tissue is necrosed. A computer simulation is provided that can be used to predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of the catheter and method of applying microwave energy a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Transcatheter Microwave Antenna

NASA Technical Reports Server (NTRS)

Arndt, Dickey G. (Inventor); Carl, James R. (Inventor); Ngo, Phong (Inventor); Raffoul, George W. (Inventor)

2001-01-01

A method, simulation, and apparatus are provided that are highly suitable for treatment of benign prostatic hyperplasia (BPH). A catheter is disclosed that includes a small diameter disk loaded monopole antenna surrounded by fusion material having a high heat of fusion and a melting point preferably at or near body temperature. Microwaves from the antenna heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. The fusion material keeps the urethra cool by means of the heat of fusion of the fusion material. This prevents damage to the urethra while the prostatic tissue is necrosed. A computer simulation is provided that can be used to predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of the catheter and method of applying microwave energy a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Improvement in Therapeutic Efficacy and Reduction in Cellular Toxicity: Introduction of a Novel Anti-PSMA-Conjugated Hybrid Antiandrogen Nanoparticle.

PubMed

Thangavel, Chellappagounder; Perepelyuk, Maryna; Boopathi, Ettickan; Liu, Yi; Polischak, Steven; Deshpande, Deepak A; Rafiq, Khadija; Dicker, Adam P; Knudsen, Karen E; Shoyele, Sunday A; Den, Robert B

2018-05-07

Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)-conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide. Selectivity and enhanced efficacy was achieved through coating the particle with PSMA. The PSMA-conjugated nanoparticle was internalized selectively in AR expressing prostate cancer cells. It did not elicit an inflammatory effect. The efficacy of enzalutamide was not compromised through insertion into the nanoparticle; in fact, lower systemic drug concentrations of enzalutamide resulted in comparable clinical activity. Normal muscle cells were not impacted by the PSMA-conjugated containing antiandrogen. This approach represents a novel strategy to increase the specificity and effectiveness of antiandrogen treatment for men with castrate resistant prostate cancer. The ability to deliver higher drug concentrations in prostate cancer cells may translate into improved clinical end points including overall survival.

Thermoacoustic imaging of prostate cancer: comparison to histology

NASA Astrophysics Data System (ADS)

Patch, S. K.; Griep, S. K.; Jacobsohn, K.; See, W. A.; Hull, D.

2014-03-01

Ex vivo imaging of fresh prostate specimens was performed to test the hypothesis that the thermoacoustic (TA) contrast mechanism generated with very high frequency electromagnetic (EM) irradiation is sensitive to prostate cancer. Ex vivo imaging was performed immediately after radical prostatectomy, performed as part of normal care. Irradiation pulsewidth was 700 ns and duty cycle was extremely low. Typical specific absorption rate (SAR) throughout the prostate was 70-90 kW/kg during pulsing, but time-averaged SAR was below 2 W/kg. TA pressure pulses generated by rapid heating due to EM energy deposition were detected using single element transducers. 15g/L glycine powder mixed into DI water served as acoustic couplant, which was chilled to prevent autolysis. Spatial encoding was performed by scanning in tomographic "step-and-shoot" mode, with 3 mm translation between slices and 1.8-degree rotation between tomographic views. Histology slides for 3 cases scanned with 2.25 MHz transducers were marked for comparison to TA reconstructions. These three cases showed little, moderate, and severe involvement in the histology levels surrounding the verumontanum. TA signal strength decreased with percent cancerous involvement. When VHF is used for tissue heating, the TA contrast mechanism is driven by ionic content and we observed suppressed TA signal from diseased prostate tissue in the peripheral zone. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity.

Prostate-specific membrane antigen as a target for cancer imaging and therapy

PubMed Central

KIESS, A. P.; BANERJEE, S. R.; MEASE, R. C.; ROWE, S. P.; RAO, A.; FOSS, C. A.; CHEN, Y.; YANG, X.; CHO, S. Y.; NIMMAGADDA, S.; POMPER, M. G.

2016-01-01

The prostate-specific membrane antigen (PSMA) is a molecular target whose use has resulted in some of the most productive work toward imaging and treating prostate cancer over the past two decades. A wide variety of imaging agents extending from intact antibodies to low-molecular-weight compounds permeate the literature. In parallel there is a rapidly expanding pool of antibody-drug conjugates, radiopharmaceutical therapeutics, small-molecule drug conjugates, theranostics and nanomedicines targeting PSMA. Such productivity is motivated by the abundant expression of PSMA on the surface of prostate cancer cells and within the neovasculature of other solid tumors, with limited expression in most normal tissues. Animating the field is a variety of small-molecule scaffolds upon which the radionuclides, drugs, MR-detectable species and nanoparticles can be placed with relative ease. Among those, the urea-based agents have been most extensively leveraged, with expanding clinical use for detection and more recently for radiopharmaceutical therapy of prostate cancer, with surprisingly little toxicity. PSMA imaging of other cancers is also appearing in the clinical literature, and may overtake FDG for certain indications. Targeting PSMA may provide a viable alternative or first-line approach to managing prostate and other cancers. PMID:26213140

Ultrahigh b-values MRI in normal human prostate: Initial research on reproducibility and age-related differences.

PubMed

Shi, Changzheng; Zhang, Dong; Xiao, Zeyu; Wang, Li; Ma, Rong; Chen, Hanwei; Luo, Liangping

2017-09-01

To investigate the reproducibility of diffusion-weighted imaging (DWI) with ultrahigh b-values, and analyze the age-related differences in normal prostates. In all, 67 healthy participants were divided into three age groups (group A, 15-30 years; group B, 31-50 years; group C, ≥51 years), and underwent DWI scanning twice with 15 b-factors from 0 to 3000 at 3.0T. Triexponential fits were applied to calculate the molecular diffusion coefficient (D), the pseudo-diffusion coefficient (D*), the ultrahigh apparent diffusion coefficient (ADC uh ), and perfusion fraction (f). The interobserver and short-term interscan reproducibility were evaluated, and the change in these parameters with age were assessed. The D, ADC uh , and f values presented good to excellent reproducibility. With increasing age, a trend of increasing D values was observed, with significant difference in both peripheral zone (PZ, P = 0.01) and central gland (CG, P = 0.01) of normal prostate tissue. The f value increased in the CG beginning at 50 years of age while the ADC uh value decreased in the PZ after 50 years of age; all of them showed significant differences between groups A and C and groups B and C (P = 0.01/0.01). The D, ADC uh , and f values have good to excellent reproducibility in the normal prostate, and these values change with age. The ultrahigh b-values magnetic resonance imaging (MRI) can provide additional information (ADC uh ), which is different from the IVIM (intravoxel incoherent motion)-derived parameters. 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:801-812. © 2017 International Society for Magnetic Resonance in Medicine.

The expression of Egfl7 in human normal tissues and epithelial tumors.

PubMed

Fan, Chun; Yang, Lian-Yue; Wu, Fan; Tao, Yi-Ming; Liu, Lin-Sen; Zhang, Jin-Fan; He, Ya-Ning; Tang, Li-Li; Chen, Guo-Dong; Guo, Lei

2013-04-23

To investigate the expression of Egfl7 in normal adult human tissues and human epithelial tumors.
 RT-PCR and Western blot were employed to detect Egfl7 expression in normal adult human tissues and 10 human epithelial tumors including hepatocellular carcinoma (HCC), lung cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, malignant glioma, ovarian cancer and renal cancer. Immunohistochemistry and cytoimmunofluorescence were subsequently used to determine the localization of Egfl7 in human epithelial tumor tissues and cell lines. ELISA was also carried out to examine the serum Egfl7 levels in cancer patients. In addition, correlations between Egfl7 expression and clinicopathological features as well as prognosis of HCC and breast cancer were also analyzed on the basis of immunohistochemistry results.
 Egfl7 was differentially expressed in 19 adult human normal tissues and was overexpressed in all 10 human epithelial tumor tissues. The serum Egfl7 level was also significantly elevated in cancer patients. The increased Egfl7 expression in HCC correlated with vein invasion, absence of capsule formation, multiple tumor nodes and poor prognosis. Similarly, upregulation of Egfl7 in breast cancer correlated strongly with TNM stage, lymphatic metastasis, estrogen receptor positivity, Her2 positivity and poor prognosis. 
 Egfl7 is significantly upregulated in human epithelial tumor tissues, suggesting Egfl7 to be a potential biomarker for human epithelial tumors, especially HCC and breast cancer.

Microwave Medical Treatment Apparatus and Method

NASA Technical Reports Server (NTRS)

Arndt, G. Dickey (Inventor); Ngo, Phong H. (Inventor); Carl, James R. (Inventor); George, W. Rflfoul (Inventor)

2005-01-01

Methods, simulations, and apparatus are provided that may be utilized for medical treatments which are especially suitable for treatment of benign prostatic hyperplasia (BPH). In a preferred embodiment, a plurality of separate microwave antennas are utilized to heat prostatic tissue to promote necrosing of the prostatic tissue that relieves the pressure of the prostatic tissue against the urethra as the body reabsorbs the necrosed or dead tissue. By utilizing constructive and destructive interference of the microwave transmission, the energy can be deposited on the tissues to be necrosed while protecting other tissues such as the urethra. Saline injections to alter the conductivity of the tissues may also be used to further focus the energy deposits. A computer simulation is Provided that can be used to Predict the resulting temperature profile produced in the prostatic tissue. By changing the various control features of one or more catheters and the methods of applying microwave energy, a temperature profile can be predicted and produced that is similar to the temperature profile desired for the particular patient.

Clinical Usefulness of the Histoculture Drug Response Assay for Prostate Cancer and Benign Prostate Hypertrophy (BPH).

PubMed

Hoffman, Robert M

2018-01-01

The histoculture drug response assay (HDRA) has been adapted to determine androgen sensitivity in Gelfoam histoculture of human benign prostatic tissue as well as prostate cancer. Gelfoam histoculture was used to measure androgen-independent and androgen-dependent growth of benign and malignant prostate tissue. The androgen-sensitivity index was significantly higher in 23 paired specimens of prostate cancer compared to benign prostate hypertrophy (BPH). Genistein decreased the androgen-sensitivity index of BPH and prostate cancer in Gelfoam ® histoculture in a dose-dependent manner.

Synthesis and evaluation of [64Cu]PSMA-617 targeted for prostate-specific membrane antigen in prostate cancer.

PubMed

Cui, Can; Hanyu, Masayuki; Hatori, Akiko; Zhang, Yiding; Xie, Lin; Ohya, Tomoya; Fukada, Masami; Suzuki, Hisashi; Nagatsu, Kotaro; Jiang, Cuiping; Luo, Rui; Shao, Guoqiang; Zhang, Mingrong; Wang, Feng

2017-01-01

We radiolabeled a ligand, PSMA-617, of prostate-specific membrane antigen (PSMA) with copper-64 ( 64 Cu), to evaluate the metabolism, biodistribution, and potential of [ 64 Cu]PSMA-617 for PET imaging of prostate cancer. [ 64 Cu]PSMA-617 was synthesized by heating PSMA-617 with [ 64 Cu]CuCl 2 in buffer solution at 90°C for 5 min. In vitro uptake was determined in two cell lines of prostate cancer. In vivo regional distributions were determined in normal and tumor-bearing mice. High radiolabeling efficiency of 64 Cu for PSMA-617 yielded [ 64 Cu]PSMA-617 with >99% radiochemical purity. In vitro cellular uptake experiments demonstrated the specificity of [ 64 Cu]PSMA-617 for PSMA-positive LNCaP cells. Biodistribution observations of normal mice revealed high uptake of radioactivity in the kidney and liver. PET with [ 64 Cu]PSMA-617 visualized tumor areas implanted by PSMA-positive LNCaP cells in the mice. Two hours after the injection of [ 64 Cu]PSMA-617 into mice, a radiolabeled metabolite was observed in the blood, liver, urine, and LNCaP tumor tissues. [ 64 Cu]PSMA-617 was easily synthesized, and exhibited a favorable biodistribution in PSMA-positive tumors. Although this radioligand shows slow clearance for kidney and high liver uptake, change of its chelator moiety and easy radiolabeling may enable development of new 64 Cu or 67 Cu-labeled PSMA ligands for imaging and radiotherapy.

Synthesis and evaluation of [64Cu]PSMA-617 targeted for prostate-specific membrane antigen in prostate cancer

PubMed Central

Cui, Can; Hanyu, Masayuki; Hatori, Akiko; Zhang, Yiding; Xie, Lin; Ohya, Tomoya; Fukada, Masami; Suzuki, Hisashi; Nagatsu, Kotaro; Jiang, Cuiping; Luo, Rui; Shao, Guoqiang; Zhang, Mingrong; Wang, Feng

2017-01-01

We radiolabeled a ligand, PSMA-617, of prostate-specific membrane antigen (PSMA) with copper-64 (64Cu), to evaluate the metabolism, biodistribution, and potential of [64Cu]PSMA-617 for PET imaging of prostate cancer. [64Cu]PSMA-617 was synthesized by heating PSMA-617 with [64Cu]CuCl2 in buffer solution at 90°C for 5 min. In vitro uptake was determined in two cell lines of prostate cancer. In vivo regional distributions were determined in normal and tumor-bearing mice. High radiolabeling efficiency of 64Cu for PSMA-617 yielded [64Cu]PSMA-617 with >99% radiochemical purity. In vitro cellular uptake experiments demonstrated the specificity of [64Cu]PSMA-617 for PSMA-positive LNCaP cells. Biodistribution observations of normal mice revealed high uptake of radioactivity in the kidney and liver. PET with [64Cu]PSMA-617 visualized tumor areas implanted by PSMA-positive LNCaP cells in the mice. Two hours after the injection of [64Cu]PSMA-617 into mice, a radiolabeled metabolite was observed in the blood, liver, urine, and LNCaP tumor tissues. [64Cu]PSMA-617 was easily synthesized, and exhibited a favorable biodistribution in PSMA-positive tumors. Although this radioligand shows slow clearance for kidney and high liver uptake, change of its chelator moiety and easy radiolabeling may enable development of new 64Cu or 67Cu-labeled PSMA ligands for imaging and radiotherapy. PMID:28533936

Highly specific expression of luciferase gene in lungs of naive nude mice directed by prostate-specific antigen promoter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Hongwei; Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA 22908; Li Jinzhong

PSA promoter has been demonstrated the utility for tissue-specific toxic gene therapy in prostate cancer models. Characterization of foreign gene overexpression in normal animals elicited by PSA promoter should help evaluate therapy safety. Here we constructed an adenovirus vector (AdPSA-Luc), containing firefly luciferase gene under the control of the 5837 bp long prostate-specific antigen promoter. A charge coupled device video camera was used to non-invasively image expression of firefly luciferase in nude mice on days 3, 7, 11 after injection of 2 x 10{sup 9} PFU of AdPSA-Luc virus via tail vein. The result showed highly specific expression of themore » luciferase gene in lungs of mice from day 7. The finding indicates the potential limitations of the suicide gene therapy of prostate cancer based on selectivity of PSA promoter. By contrary, it has encouraging implications for further development of vectors via PSA promoter to enable gene therapy for pulmonary diseases.« less

Radiographic and anatomic basis for prostate contouring errors and methods to improve prostate contouring accuracy.

PubMed

McLaughlin, Patrick W; Evans, Cheryl; Feng, Mary; Narayana, Vrinda

2010-02-01

Use of highly conformal radiation for prostate cancer can lead to both overtreatment of surrounding normal tissues and undertreatment of the prostate itself. In this retrospective study we analyzed the radiographic and anatomic basis of common errors in computed tomography (CT) contouring and suggest methods to correct them. Three hundred patients with prostate cancer underwent CT and magnetic resonance imaging (MRI). The prostate was delineated independently on the data sets. CT and MRI contours were compared by use of deformable registration. Errors in target delineation were analyzed and methods to avoid such errors detailed. Contouring errors were identified at the prostatic apex, mid gland, and base on CT. At the apex, the genitourinary diaphragm, rectum, and anterior fascia contribute to overestimation. At the mid prostate, the anterior and lateral fasciae contribute to overestimation. At the base, the bladder and anterior fascia contribute to anterior overestimation. Transition zone hypertrophy and bladder neck variability contribute to errors of overestimation and underestimation at the superior base, whereas variable prostate-to-seminal vesicle relationships with prostate hypertrophy contribute to contouring errors at the posterior base. Most CT contouring errors can be detected by (1) inspection of a lateral view of prostate contours to detect projection from the expected globular form and (2) recognition of anatomic structures (genitourinary diaphragm) on the CT scans that are clearly visible on MRI. This study shows that many CT prostate contouring errors can be improved without direct incorporation of MRI data. Copyright 2010 Elsevier Inc. All rights reserved.

Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

PubMed

Yu, Yue; Lee, Jennifer Suehyun; Xie, Ning; Li, Estelle; Hurtado-Coll, Antonio; Fazli, Ladan; Cox, Michael; Plymate, Stephen; Gleave, Martin; Dong, Xuesen

2014-01-01

Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood. Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels. Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion. Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

Potentiation of Inflammatory CXCL8 Signalling Sustains Cell Survival in PTEN-deficient Prostate Carcinoma

PubMed Central

Maxwell, Pamela J.; Coulter, Jonathan; Walker, Steven M.; McKechnie, Melanie; Neisen, Jessica; McCabe, Nuala; Kennedy, Richard D.; Salto-Tellez, Manuel; Albanese, Chris; Waugh, David J.J.

2014-01-01

Background: Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised. Objective: To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa. Design, setting, and participants: Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten+/−) mice harbouring inactivation of one PTEN allele. Interventions: Small interfering RNA (siRNA)–or small hairpin RNA (shRNA)–directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions. Outcome measurements and statistical analysis: Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays. Results and limitations: Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten+/− murine prostate tissue relative to normal epithelium in wild-type PTEN (PtenWT) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study. Conclusions: PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium. PMID:22939387

Realizing the Translational Potential of Telomere Length Variation as a Tissue-Based Prognostic Marker for Prostate Cancer

DTIC Science & Technology

2014-10-01

Telomere Length Variation as a Tissue- Based Prognostic Marker for Prostate Cancer PRINCIPAL INVESTIGATOR: Elizabeth A. Platz CONTRACTING...Translational Potential of Telomere Length Variation as a Tissue- Based Prognostic Marker for Prostate Cancer 5b. GRANT NUMBER W81XWH-12-1-0545 5c...combination of telomere length variability in prostate cancer cells and short telomere length in cancer-associated stromal cells is an independent

Randomized Clinical Trial of Brewed Green and Black Tea in Men with Prostate Cancer Prior to Prostatectomy

PubMed Central

Henning, Susanne M.; Wang, Piwen; Said, Jonathan W.; Huang, Min; Grogan, Tristan; Elashoff, David; Carpenter, Catherine L.; Heber, David; Aronson, William J.

2014-01-01

Background Preclinical and epidemiologic studies suggest chemopreventive effects of green tea (GT) and black tea (BT) in prostate cancer. In the current study we determined the effect of GT and BT consumption on biomarkers related to prostate cancer development and progression. Methods In this exploratory, open label, phase II trial 113 men diagnosed with prostate cancer were randomized to consume six cups daily of brewed GT, BT or water (control) prior to radical prostatectomy (RP). The primary endpoint was prostate tumor markers of cancer development and progression determined by tissue immunostaining of proliferation (Ki67), apoptosis (Bcl-2, Bax, Tunel), inflammation [nuclear and cytoplasmic nuclear factor kappa B (NFκB)] and oxidation [8-hydroxydeoxy- guanosine (8OHdG)]. Secondary endpoints of urinary oxidation, tea polyphenol uptake in prostate tissue, and serum prostate specific antigen (PSA) were evaluated by high performance liquid chromatography and ELISA analysis. Results Ninety three patients completed the intervention. There was no significant difference in markers of proliferation, apoptosis and oxidation in RP tissue comparing GT and BT to water control. Nuclear staining of NFkB was significantly decreased in RP tissue of men consuming GT (p=0.013) but not BT (p=0.931) compared to water control. Tea polyphenols were detected in prostate tissue from 32 of 34 men consuming GT but not in the other groups. Evidence of a systemic antioxidant effect was observed (reduced urinary 8OHdG) only with GT consumption (p=0.03). GT, but not BT or water, also led to a small but statistically significant decrease in serum prostate-specific antigen (PSA) levels (p=0.04). Conclusion Given the GT-induced changes in NFkB and systemic oxidation, and uptake of GT polyphenols in prostate tissue, future longer-term studies are warranted to further examine the role of GT for prostate cancer prevention and treatment, and possibly for other prostate conditions such as prostatitis. PMID:25545744

Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells12

PubMed Central

Wittig-Blaich, Stephanie M; Kacprzyk, Lukasz A; Eismann, Thorsten; Bewerunge-Hudler, Melanie; Kruse, Petra; Winkler, Eva; Strauss, Wolfgang S L; Hibst, Raimund; Steiner, Rudolf; Schrader, Mark; Mertens, Daniel; Sültmann, Holger; Wittig, Rainer

2011-01-01

The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases. PMID:21750652

Influence of the neural microenvironment on prostate cancer.

PubMed

Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J; Ayala, Gustavo

2018-02-01

Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Analysis of iron, zinc, selenium and cadmium in paraffin-embedded prostate tissue specimens using inductively coupled plasma mass-spectrometry

USGS Publications Warehouse

Sarafanov, A.G.; Todorov, T.I.; Kajdacsy-Balla, A.; Gray, Michael A.; MacIas, V.; Centeno, J.A.

2008-01-01

Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent a valuable and abundant resource of pathologic material for various biomedical studies. In the present study, we report the application of high-resolution inductively coupled mass-spectrometry (ICP-MS) for quantification of Fe, Zn, Se and Cd in FFPE prostate tissue. These elements have a possible role in the development of prostate diseases: while Zn and Se are needed for a healthy prostate, Cd shows multiple toxic and carcinogenic effects. Excessive accumulation of Fe induces the production of highly reactive hydroxyl radical species, which may play a role in cancer etiopathogenesis. To assess whether the levels of these metals in the FFPE prostate tissue represent their original content, we compared their levels with those in the fresh tissue (on dry weight basis) in samples obtained from 15 patients. We found that in FFPE tissue, the recoveries of Se, Fe, Cd and Zn were progressively decreased, 97??11% (r=0.88), 82??22% (r=0.86), 59??23% (r=0.69) and 24??11% (r=0.38), respectively. Thus, the use of correction factors, determined as k=0.16 for Se, k=0.20 for Fe, k=0.27 for Cd and k=0.67 for Zn, is required to estimate the retrospective levels of these elements in the parental non-processed fresh (wet) prostate tissue. The technique used in this study enables the analysis of archival FFPE prostate tissue for the concentrations of Fe, Zn, Se and Cd to study association between the levels of these metals and prostate disease. ?? 2008.

Bare Bones of Bioactive Glass

NASA Technical Reports Server (NTRS)

2000-01-01

Paul Ducheyne, a principal investigator in the microgravity materials science program and head of the University of Pernsylvania's Center for Bioactive Materials and Tissue Engineering, is leading the trio as they use simulated microgravity to determine the optimal characteristics of tiny glass particles for growing bone tissue. The result could make possible a much broader range of synthetic bone-grafting applications. Even in normal gravity, bioactive glass particles enhance bone growth in laboratory tests with flat tissue cultures. Ducheyne and his team believe that using the bioactive microcarriers in a rotating bioreactor in microgravity will produce improved, three-dimensional tissue cultures. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. Credit: NASA and University of Pennsylvania Center for Bioactive Materials and Tissue Engineering.

Norfloxacin penetration into human renal and prostatic tissues.

PubMed Central

Bergeron, M G; Thabet, M; Roy, R; Lessard, C; Foucault, P

1985-01-01

Concurrent norfloxacin concentrations in serum, kidney, and prostatic tissue were determined in 14 patients. Mean ratios of norfloxacin concentration in tissue over concentration in serum were 6.6 +/- 2.8 for the kidney and 1.7 +/- 0.2 for the prostate samples. The levels were above the MICs of most urinary pathogens. PMID:3834837

Study of two different radioactive sources for prostate brachytherapy treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pereira Neves, Lucio; Perini, Ana Paula; Souza Santos, William de

In this study we evaluated two radioactive sources for brachytherapy treatments. Our main goal was to quantify the absorbed doses on organs and tissues of an adult male patient, submitted to a brachytherapy treatment with two radioactive sources. We evaluated a {sup 192}Ir and a {sup 125}I radioactive sources. The {sup 192}Ir radioactive source is a cylinder with 0.09 cm in diameter and 0.415 cm long. The {sup 125}I radioactive source is also a cylinder, with 0.08 cm in diameter and 0.45 cm long. To evaluate the absorbed dose distribution on the prostate, and other organs and tissues of anmore » adult man, a male virtual anthropomorphic phantom MASH, coupled in the radiation transport code MCNPX 2.7.0, was employed.We simulated 75, 90 and 102 radioactive sources of {sup 125}I and one of {sup 192}Ir, inside the prostate, as normally used in these treatments, and each treatment was simulated separately. As this phantom was developed in a supine position, the displacement of the internal organs of the chest, compression of the lungs and reduction of the sagittal diameter were all taken into account. For the {sup 192}Ir, the higher doses values were obtained for the prostate and surrounding organs, as the colon, gonads and bladder. Considering the {sup 125}I sources, with photons with lower energies, the doses to organs that are far from the prostate were lower. All values for the dose rates are in agreement with those recommended for brachytherapy treatments. Besides that, the new seeds evaluated in this work present usefulness as a new tool in prostate brachytherapy treatments, and the methodology employed in this work may be applied for other radiation sources, or treatments. (authors)« less

Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.

PubMed

Sah, Bert-Ram; Burger, Irene A; Schibli, Roger; Friebe, Matthias; Dinkelborg, Ludger; Graham, Keith; Borkowski, Sandra; Bacher-Stier, Claudia; Valencia, Ray; Srinivasan, Ananth; Hany, Thomas F; Mu, Linjing; Wild, Peter J; Schaefer, Niklaus G

2015-03-01

The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv). BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Development of Assays for Detecting Significant Prostate Cancer Based on Molecular Alterations Associated with Cancer in Non-Neoplastic Prostate Tissue

DTIC Science & Technology

2015-10-01

with Cancer in Non-Neoplastic Prostate Tissue PRINCIPAL INVESTIGATOR: Farhad Kosari, Ph.D. CONTRACTING ORGANIZATION: Mayo Clinic Rochester, MN...E-Mail: kosari.farhad@mayo.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Mayo Clinic Rochester, MN 55905-0002 8...with the Tissue Request Acquisition Group (TRAG) at the Mayo Clinic , a process was implemented for the collection of resected prostates from

Microgravity

NASA Image and Video Library

1998-01-01

Astronaut John Blaha replaces an exhausted media bag and filled waste bag with fresh bags to continue a bioreactor experiment aboard space station Mir in 1996. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. This image is from a video downlink. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC).

A stochastic model for the normal tissue complication probability (NTCP) and applicationss.

PubMed

Stocks, Theresa; Hillen, Thomas; Gong, Jiafen; Burger, Martin

2017-12-11

The normal tissue complication probability (NTCP) is a measure for the estimated side effects of a given radiation treatment schedule. Here we use a stochastic logistic birth-death process to define an organ-specific and patient-specific NTCP. We emphasize an asymptotic simplification which relates the NTCP to the solution of a logistic differential equation. This framework is based on simple modelling assumptions and it prepares a framework for the use of the NTCP model in clinical practice. As example, we consider side effects of prostate cancer brachytherapy such as increase in urinal frequency, urinal retention and acute rectal dysfunction. © The authors 2016. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

NASA Bioreactor

NASA Technical Reports Server (NTRS)

1998-01-01

Astronaut John Blaha replaces an exhausted media bag and filled waste bag with fresh bags to continue a bioreactor experiment aboard space station Mir in 1996. NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators. This image is from a video downlink. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC).

EMBOLIZATION OF DOG PROSTATES WITH YTTRIUM-90 MICROSPHERES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greene, W.M.

1963-10-01

Experiments exploring means for the protection of adjacent normal tissue while delivering a destructive dose of radiation to malignant tissue were conducted. By injection of radioactive ceramic spheres or particles, too large to pass through capillaries or arteriovenous shunts, relatively high doses of radiation can be distributed homogeneously to a circumscribed area. Attempts were made to determine the uniformity of distribution and the radiation effect of varying doses of spheres injected into the arterial supply of the dog prostate. Nonradioactive and radioactive ceramic microspheres of 60 mu dia were used since this size exceeds the diameter of capillaries and arteriovenousmore » shunts. Yttrium-90 microspheres of varying radioactivity were used. Doses injected into right and left hypogastric arteries varied from 0.69 to 28.4 mc/side (92-1260 mc/ g prostate). Homogeneous distribution of radioactivity within the prostate was demonstrated by autoradiography. Distribution to some other organs (rectum, penis, and bladder) occurred because arterial supply to these structures was not isolated and occluded. The amount of radioactivity found in the lungs suggested more venous drainage in some cases than seemed apparent, and because of the infarctions of pelvic organs may have leaked radioactive spheres into the venous circuit. In 6 of the 8 dogs which died prematurely (2 to 7 days after surgery) obvious infarction of the prostate and in some other pelvic structures had occurred. That the radioactivity contributed to the infarction is suggested by the results in the dogs which received large doses of radioactivity (18.9 and 28.4 mc per side) in minimal amounts of spheres (100to 150 mg per side). The intensely concentrated radioactivity within the arteriolar lumens may have caused vasculitis and subsequent thrombosis. Although homogeneous destruction of the prostate gland occurred, the effect of a given dose ranged unpredictably through three groups: no apparent effect at all, destruction of the prostate, and early death with infarction of the prostate and other pelvic organs. It was concluded that with the present technique the range between the dose of radioactivity which caused no obvious response and the dose which is related to acute death is too narrow to allow reasonably predictable results, but that further refinement of technique might increase control over tissue destruction.« less

Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat

PubMed Central

Cowin, Prue A.; Foster, Paul; Pedersen, John; Hedwards, Shelley; McPherson, Stephen J.; Risbridger, Gail P.

2008-01-01

Background Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology. Objectives In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring. Methods Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age. Results In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men. Conclusions These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis. PMID:18629315

Feasibility of shutter-speed DCE-MRI for improved prostate cancer detection.

PubMed

Li, Xin; Priest, Ryan A; Woodward, William J; Tagge, Ian J; Siddiqui, Faisal; Huang, Wei; Rooney, William D; Beer, Tomasz M; Garzotto, Mark G; Springer, Charles S

2013-01-01

The feasibility of shutter-speed model dynamic-contrast-enhanced MRI pharmacokinetic analyses for prostate cancer detection was investigated in a prebiopsy patient cohort. Differences of results from the fast-exchange-regime-allowed (FXR-a) shutter-speed model version and the fast-exchange-limit-constrained (FXL-c) standard model are demonstrated. Although the spatial information is more limited, postdynamic-contrast-enhanced MRI biopsy specimens were also examined. The MRI results were correlated with the biopsy pathology findings. Of all the model parameters, region-of-interest-averaged K(trans) difference [ΔK(trans) ≡ K(trans)(FXR-a) - K(trans)(FXL-c)] or two-dimensional K(trans)(FXR-a) vs. k(ep)(FXR-a) values were found to provide the most useful biomarkers for malignant/benign prostate tissue discrimination (at 100% sensitivity for a population of 13, the specificity is 88%) and disease burden determination. (The best specificity for the fast-exchange-limit-constrained analysis is 63%, with the two-dimensional plot.) K(trans) and k(ep) are each measures of passive transcapillary contrast reagent transfer rate constants. Parameter value increases with shutter-speed model (relative to standard model) analysis are larger in malignant foci than in normal-appearing glandular tissue. Pathology analyses verify the shutter-speed model (FXR-a) promise for prostate cancer detection. Parametric mapping may further improve pharmacokinetic biomarker performance. Copyright © 2012 Wiley Periodicals, Inc.

SQUID magnetometry from nanometer to centimeter length scales

NASA Astrophysics Data System (ADS)

Hatridge, Michael Jonathan

Information stored in magnetic fields plays an important role in everyday life. This information exists over a remarkably wide range of sizes, so that magnetometry at a variety of length scales can extract useful information. Examples at centimeter to millimeter length scales include measurement of spatial and temporal character of fields generated in the human brain and heart, and active manipulation of spins in the human body for non-invasive magnetic resonance imaging (MRI). At micron length scales, magnetometry can be used to measure magnetic objects such as flux qubits; at nanometer length scales it can be used to study individual magnetic domains, and even individual spins. The development of Superconducting QUantum Interference Device (SQUID) based magnetometer for two such applications, in vivo prepolarized, ultra-low field MRI of humans and dispersive readout of SQUIDs for micro- and nanoscale magnetometry, are the focus of this thesis. Conventional MRI has developed into a powerful clinical tool for imaging the human body. This technique is based on nuclear magnetic resonance of protons with the addition application of three-dimensional magnetic field gradients to encode spatial information. Most clinical MRI systems involve magnetic fields generated by superconducting magnets, and the current trend is to higher magnetic fields than the widely used 1.5-T systems. Nonetheless, there is ongoing interest in the development of less expensive imagers operating at lower fields. The prepolarized, SQUID detected ultra-low field MRI (ULF MRI) developed by the Clarke group allows imaging in very weak fields (typically 132 muT, corresponding to a resonant frequency of 5.6 kHz). At these low field strengths, there is enhanced contrast in the longitudinal relaxation time of various tissue types, enabling imaging of objects which are not visible to conventional MRI, for instance prostate cancer. We are currently investigating the contrast between normal and cancerous prostate tissue in ex vivo prostate specimens in collaboration with the UCSF Genitourinary Oncology/Prostate SPORE Tissue Core. In characterizing pairs of nominally normal and cancerous tissue, we measure a marked difference in the longitudinal relaxation times, with an average value of cancerous tissue 0.66 times shorter than normal prostate tissue. However, in vivo imaging is required to definitively demonstrate the feasibility of ULF MR imaging of prostate cancer. To that end, we have worked to improve the performance of the system to facilitate human imaging. This is accomplished by increasing the prepolarizing field amplitude, and minimizing magnetic noise in the SQUID detector. We have achieved polarizing fields as high as 150 mT and SQUID effective field noise below 1 fT Hz-1/2, enabling us to demonstrate proof-of-principle in vivo images of the human forearm with 2 x 2 x 10 mm3 resolution in 6 minutes. On a much smaller spatial scale, there is currently fundamental and technological interest in measuring and manipulating nanoscale magnets, particularly in the quantum coherent regime. The observation of the dynamics of such systems requires a magnetometer with not only exceptional sensitivity but also high gain, wide bandwidth and low backaction. We demonstrate a dispersive magnetometer consisting of a two-junction SQUID in parallel with an integrated, lumped-element capacitor. Input flux signals are encoded as a phase modulation of the microwave drive tone applied to the magnetometer, resulting in a single quadrature voltage signal. For strong drive power, the nonlinearity of the resonator results in quantum limited, phase sensitive parametric amplification of this signal. We have achieved a bandwidth of 20 MHz---approximately two orders of magnitude higher than dispersive devices of comparable sensitivity---with an effective flux noise of 0.29 muphi0 Hz-12 . This performance is in excellent agreement with our theoretical model.

Tookad-mediated photodynamic effects on the prostate and its adjacent tissues: in vivo study in canine models

NASA Astrophysics Data System (ADS)

Huang, Zheng; Chen, Qun; Luck, David; Beckers, Jill; Blanc, Dominique; Hetzel, Fred W.

2005-04-01

Photodynamic therapy (PDT) mediated with a vascular acting photosensitizer Tookad (pd-bacteriopheophorbide), was investigated as an alternative treatment modality for prostate cancer. Tookad photodynamic effects on the prostate and its adjacent tissues were evaluated in canine models. Interstitial prostate PDT was performed by irradiating individual lobes with a diode laser (763 nm) and 1-cm cylindrical diffuser fibers at various light doses to activate the IV administered photosensitizer Tookad (1 - 2 mg/kg). The sensitivity of the adjacent tissues to Tookad-PDT was determined by superficially irradiating the surfaces of the bladder, colon, abdominal muscle and pelvic plexus with a microlens fiber at various drug/light doses. PDT effect on the prostatic urethra was evaluated by transurethral irradiation. The prostate and adjacent tissues were harvested one-week after the treatment and subjected to histopathologic examination. At one-week post interstitial prostate PDT, the animals recovered well with little or no urethral complications. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. The bladder, colon, abdominal muscle and pelvic plexus, appeared to also be sensitive to Tookad-PDT at light dose levels greater than 40 Jcm2. Urethral mucosa appeared less sensitive to Tookad-PDT. In conclusion, Tookad-mediated PDT demonstrates very strong vascular effects and can provide an effective alternative for the treatment of localized prostate cancer. Protection of the adjacent tissues should be taken into consideration in the total prostate ablation process due to their sensitivity to the Tookad-mediated PDT.

A novel minimally invasive dual-modality fiber optic probe for prostate cancer detection

NASA Astrophysics Data System (ADS)

Sharma, Vikrant

Prostate cancer is the most common form of cancer in males, and is the second leading cause of cancer related deaths in United States. In prostate cancer diagnostics and therapy, there is a critical need for a minimally invasive tool for in vivo evaluation of prostate tissue. Such a tool finds its niche in improving TRUS (trans-rectal ultrasound) guided biopsy procedure, surgical margin assessment during radical prostatectomy, and active surveillance of patients with a certain risk levels. This work is focused on development of a fiber-based dual-modality optical device (dMOD), to differentiate prostate cancer from benign tissue, in vivo. dMOD utilizes two independent optical techniques, LRS (light reflectance spectroscopy) and AFLS (auto-fluorescence lifetime spectroscopy). LRS quantifies scattering coefficient of the tissue, as well as concentrations of major tissue chromophores like hemoglobin derivatives, β-carotene and melanin. AFLS was designed to target lifetime signatures of multiple endogenous fluorophores like flavins, porphyrins and lipo-pigments. Each of these methods was independently developed, and the two modalities were integrated using a thin (1-mm outer diameter) fiber-optic probe. Resulting dMOD probe was implemented and evaluated on animal models of prostate cancer, as well as on human prostate tissue. Application of dMOD to human breast cancer (invasive ductal carcinoma) identification was also evaluated. The results obtained reveal that both LRS and AFLS are excellent techniques to discriminate prostate cancer tissue from surrounding benign tissue in animal models. Each technique independently is capable of providing near absolute (100%) accuracy for cancer detection, indicating that either of them could be used independently without the need of implementing them together. Also, in case of human breast cancer, LRS and AFLS provided comparable accuracies to dMOD, LRS accuracy (96%) being the highest for the studied population. However, the dual-modality integration proved to be ideal for human prostate cancer detection, as dMOD provided much better accuracy i.e., 82.7% for cancer detection in intra-capsular prostatic tissues (ICT), and 92.4% for cancer detection in extra-capsular prostatic tissues (ECT), when compared with either LRS (74.7% ICT, 86.6% ECT) or AFLS(67.1% ICT, 82.1% ECT) alone. A classification algorithm was also developed to identify different grades of prostate cancers based on Gleason scores (GS). When stratified by grade, each high grade prostate cancer (GS 7, 8 and 9) was successfully identified using dMOD with excellent accuracy in ICT (88%, 90%, 85%), as well as ECT (91%, 92%, 94%).

Serum Autoantibodies in Chronic Prostate Inflammation in Prostate Cancer Patients.

PubMed

Schlick, Bettina; Massoner, Petra; Lueking, Angelika; Charoentong, Pornpimol; Blattner, Mirjam; Schaefer, Georg; Marquart, Klaus; Theek, Carmen; Amersdorfer, Peter; Zielinski, Dirk; Kirchner, Matthias; Trajanoski, Zlatko; Rubin, Mark A; Müllner, Stefan; Schulz-Knappe, Peter; Klocker, Helmut

2016-01-01

Chronic inflammation is frequently observed on histological analysis of malignant and non-malignant prostate specimens. It is a suspected supporting factor for prostate diseases and their progression and a main cause of false positive PSA tests in cancer screening. We hypothesized that inflammation induces autoantibodies, which may be useful biomarkers. We aimed to identify and validate prostate inflammation associated serum autoantibodies in prostate cancer patients and evaluate the expression of corresponding autoantigens. Radical prostatectomy specimens of prostate cancer patients (N = 70) were classified into high and low inflammation groups according to the amount of tissue infiltrating lymphocytes. The corresponding pre-surgery blood serum samples were scrutinized for autoantibodies using a low-density protein array. Selected autoantigens were identified in prostate tissue and their expression pattern analyzed by immunohistochemistry and qPCR. The identified autoantibody profile was cross-checked in an independent sample set (N = 63) using the Luminex-bead protein array technology. Protein array screening identified 165 autoantibodies differentially abundant in the serum of high compared to low inflammation patients. The expression pattern of three corresponding antigens were established in benign and cancer tissue by immunohistochemistry and qPCR: SPAST (Spastin), STX18 (Syntaxin 18) and SPOP (speckle-type POZ protein). Of these, SPAST was significantly increased in prostate tissue with high inflammation. All three autoantigens were differentially expressed in primary and/or castration resistant prostate tumors when analyzed in an inflammation-independent tissue microarray. Cross-validation of the inflammation autoantibody profile on an independent sample set using a Luminex-bead protein array, retrieved 51 of the significantly discriminating autoantibodies. Three autoantibodies were significantly upregulated in both screens, MUT, RAB11B and CSRP2 (p>0.05), two, SPOP and ZNF671, close to statistical significance (p = 0.051 and 0.076). We provide evidence of an inflammation-specific autoantibody profile and confirm the expression of corresponding autoantigens in prostate tissue. This supports evaluation of autoantibodies as non-invasive markers for prostate inflammation.

Serum Autoantibodies in Chronic Prostate Inflammation in Prostate Cancer Patients

PubMed Central

Schlick, Bettina; Massoner, Petra; Lueking, Angelika; Charoentong, Pornpimol; Blattner, Mirjam; Schaefer, Georg; Marquart, Klaus; Theek, Carmen; Amersdorfer, Peter; Zielinski, Dirk; Kirchner, Matthias; Trajanoski, Zlatko; Rubin, Mark A.; Müllner, Stefan; Schulz-Knappe, Peter; Klocker, Helmut

2016-01-01

Background Chronic inflammation is frequently observed on histological analysis of malignant and non-malignant prostate specimens. It is a suspected supporting factor for prostate diseases and their progression and a main cause of false positive PSA tests in cancer screening. We hypothesized that inflammation induces autoantibodies, which may be useful biomarkers. We aimed to identify and validate prostate inflammation associated serum autoantibodies in prostate cancer patients and evaluate the expression of corresponding autoantigens. Methods Radical prostatectomy specimens of prostate cancer patients (N = 70) were classified into high and low inflammation groups according to the amount of tissue infiltrating lymphocytes. The corresponding pre-surgery blood serum samples were scrutinized for autoantibodies using a low-density protein array. Selected autoantigens were identified in prostate tissue and their expression pattern analyzed by immunohistochemistry and qPCR. The identified autoantibody profile was cross-checked in an independent sample set (N = 63) using the Luminex-bead protein array technology. Results Protein array screening identified 165 autoantibodies differentially abundant in the serum of high compared to low inflammation patients. The expression pattern of three corresponding antigens were established in benign and cancer tissue by immunohistochemistry and qPCR: SPAST (Spastin), STX18 (Syntaxin 18) and SPOP (speckle-type POZ protein). Of these, SPAST was significantly increased in prostate tissue with high inflammation. All three autoantigens were differentially expressed in primary and/or castration resistant prostate tumors when analyzed in an inflammation-independent tissue microarray. Cross-validation of the inflammation autoantibody profile on an independent sample set using a Luminex-bead protein array, retrieved 51 of the significantly discriminating autoantibodies. Three autoantibodies were significantly upregulated in both screens, MUT, RAB11B and CSRP2 (p>0.05), two, SPOP and ZNF671, close to statistical significance (p = 0.051 and 0.076). Conclusions We provide evidence of an inflammation-specific autoantibody profile and confirm the expression of corresponding autoantigens in prostate tissue. This supports evaluation of autoantibodies as non-invasive markers for prostate inflammation. PMID:26863016

Inhibition effects of chlorogenic acid on benign prostatic hyperplasia in mice.

PubMed

Huang, Ya; Chen, Huaguo; Zhou, Xin; Wu, Xingdong; Hu, Enming; Jiang, Zhengmeng

2017-08-15

This study aimed to evaluate the inhibitory effects and explore mechanisms of chlorogenic acid against testosterone-induced benign prostatic hyperplasia (BPH) in mice. Benign prostatic hyperplasia model was induced in experimental groups by daily subcutaneous injections of testosterone propionate (7.5mg/kg/d) consecutively for 14 d. A total of 60 mice were randomly divided into six groups: (Group 1) normal control group, (Group 2) benign prostatic hyperplasia model control group, (Group 3) benign prostatic hyperplasia mice treated with finasteride at a dose of 1mg/kg, (Group 4) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 0.8mg/kg (low dose group), (Group 5) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 1.6mg/kg (medium dose group) and (Group 6) benign prostatic hyperplasia mice treated with chlorogenic acid at dose levels of 3.2mg/kg (high dose group). Animals were sacrificed on the scheduled termination, pick out the eyeball to get blood, then prostates were weighed and prostatic index were determined. Then the serum acid phosphatase (ACP), prostatic acid phosphatase (PACP) and typeⅡ5-alpha-reductase (SRD5A2) levels were measured and observed morphological changes of the prostate. Comparing with benign prostatic hyperplasia model group, the high and medium dose of chlorogenic acid could significantly reduce prostate index and levels of acid phosphatase, prostatic acid phosphatase and typeⅡ5-alpha-reductase (P<0.05 or P<0.01). These findings were supported by histopathological observations of prostate tissues. Histopathological examination also indicated that chlorogenic acid treatment at the high and medium doses inhibited testosterone-induced prostatic hyperplasia. The results indicated that chlorogenic acid exhibited restraining effect on benign prostatic hyperplasia model animals, and its mechanism might be related to inhibit typeⅡ5-alpha reductase activity. Copyright © 2017. Published by Elsevier B.V.

Metabolite Analysis and Histology on the Exact Same Tissue: Comprehensive Metabolomic Profiling and Metabolic Classification of Prostate Cancer

NASA Astrophysics Data System (ADS)

Huan, Tao; Troyer, Dean A.; Li, Liang

2016-08-01

We report a method of metabolomic profiling of intact tissue based on molecular preservation by extraction and fixation (mPREF) and high-performance chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS). mPREF extracts metabolites by aqueous methanol from tissue biopsies without altering tissue architecture and thus conventional histology can be performed on the same tissue. In a proof-of-principle study, we applied dansylation LC-MS to profile the amine/phenol submetabolome of prostate needle biopsies from 25 patient samples derived from 16 subjects. 2900 metabolites were consistently detected in more than 50% of the samples. This unprecedented coverage allowed us to identify significant metabolites for differentiating tumor and normal tissues. The panel of significant metabolites was refined using 36 additional samples from 18 subjects. Receiver Operating Characteristic (ROC) analysis showed area-under-the-curve (AUC) of 0.896 with sensitivity of 84.6% and specificity of 83.3% using 7 metabolites. A blind study of 24 additional validation samples gave a specificity of 90.9% at the same sensitivity of 84.6%. The mPREF extraction can be readily implemented into the existing clinical workflow. Our method of combining mPREF with CIL LC-MS offers a powerful and convenient means of performing histopathology and discovering or detecting metabolite biomarkers in the same tissue biopsy.

Differential expression of VEGF ligands and receptors in prostate cancer.

PubMed

Woollard, David J; Opeskin, Kenneth; Coso, Sanja; Wu, Di; Baldwin, Megan E; Williams, Elizabeth D

2013-05-01

Prostate cancer disseminates to regional lymph nodes, however the molecular mechanisms responsible for lymph node metastasis are poorly understood. The vascular endothelial growth factor (VEGF) ligand and receptor family have been implicated in the growth and spread of prostate cancer via activation of the blood vasculature and lymphatic systems. The purpose of this study was to comprehensively examine the expression pattern of VEGF ligands and receptors in the glandular epithelium, stroma, lymphatic vasculature and blood vessels in prostate cancer. The localization of VEGF-A, VEGF-C, VEGF-D, VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 was examined in cancerous and adjacent benign prostate tissue from 52 subjects representing various grades of prostate cancer. Except for VEGFR-2, extensive staining was observed for all ligands and receptors in the prostate specimens. In epithelial cells, VEGF-A and VEGFR-1 expression was higher in tumor tissue compared to benign tissue. VEGF-D and VEGFR-3 expression was significantly higher in benign tissue compared to tumor in the stroma and the endothelium of lymphatic and blood vessels. In addition, the frequency of lymphatic vessels, but not blood vessels, was lower in tumor tissue compared with benign tissue. These results suggest that activation of VEGFR-1 by VEGF-A within the carcinoma, and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important signaling mechanisms involved in the progression and subsequent metastatic spread of prostate cancer. Thus inhibition of these pathways may contribute to therapeutic strategies for the management of prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

Telocytes play a key role in prostate tissue organisation during the gland morphogenesis.

PubMed

Sanches, Bruno D A; Maldarine, Juliana S; Zani, Bruno C; Tamarindo, Guilherme H; Biancardi, Manoel F; Santos, Fernanda C A; Rahal, Paula; Góes, Rejane M; Felisbino, Sérgio L; Vilamaior, Patricia S L; Taboga, Sebastião R

2017-12-01

Telocytes are CD34-positive interstitial cells, known to exert several functions, one of which is a role in tissue organisation, previously demonstrated by telocytes in the myocardium. The existence of telocytes in the prostate has recently been reported, however, there is a lack of information regarding the function of these cells in prostate tissue, and information regarding the possible role of these cells in prostatic development. This study used immunofluorescence techniques in prostate tissue and prostatic telocytes in culture to determine the relationship between telocytes and prostate morphogenesis. Furthermore, immunofluorescent labelling of telocytes was performed on prostate tissue at different stages of early postnatal development. Initially, CD34-positive cells are found at the periphery of the developing alveoli, later in the same region, c-kit-positive cells and cells positive for both factors are verified and CD34-positive cells were predominantly observed in the interalveolar stroma and the region surrounding the periductal smooth muscle. Fluorescence assays also demonstrated that telocytes secrete TGF-β1 and are ER-Beta (ERβ) positive. The results suggest that telocytes play a changing role during development, initially supporting the differentiation of periductal and perialveolar smooth muscle, and later, producing dense networks that separate alveoli groups and form a barrier between the interalveolar region and periurethral smooth muscle. We conclude that telocytes play a relevant role in prostate tissue organisation during postnatal development. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chronic prostatic infection and inflammation by Propionibacterium acnes in a rat prostate infection model.

PubMed

Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

2012-01-01

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.

Chronic Prostatic Infection and Inflammation by Propionibacterium acnes in a Rat Prostate Infection Model

PubMed Central

Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

2012-01-01

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection. PMID:23240022

Prostate Cancer Pathology Resource Network

DTIC Science & Technology

2012-07-01

microarrays (TMAs), serum, plasma , buffy coat, prostatic fluid, and derived specimens (DNA and RNA); these specimens are linked to clinical and...research community. The specimens in the PCBN include tissues from prostatectomies, serum, plasma , buffy coat, prostatic fluid, derived specimens such...prostatectomy, seminal vesicles), body fluids (serum, plasma , buffy coat, prostatic fluid; most can be matched to tumor and benign tissue), and

[Role of angiotensin II receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer].

PubMed

Chibichyan, M B; Kogan, M I; Chernogubova, E A; Pavlenko, I A; Matishov, D G

2016-12-01

To identify markers for predicting aggressive forms of prostate cancer. The study retrospectively evaluated expression of angiotensin II type 2 receptors (AT2-R) in prostate needle biopsy tissue from patients with and without biochemical recurrence after combined hormone and radiation therapy. The study findings showed that low expression of AT2-R in prostate tissue was associated with a high risk of biochemical recurrence. The data on the nature of AT2-R expression in prostate tissue of prostate cancer patients may be considered as a tool for predicting biochemical recurrence after combined hormone and radiation therapy. The test has a sensitivity of 87.5% and specificity of 85.71%.

Multiphoton gradient index endoscopy for evaluation of diseased human prostatic tissue ex vivo

NASA Astrophysics Data System (ADS)

Huland, David M.; Jain, Manu; Ouzounov, Dimitre G.; Robinson, Brian D.; Harya, Diana S.; Shevchuk, Maria M.; Singhal, Paras; Xu, Chris; Tewari, Ashutosh K.

2014-11-01

Multiphoton microscopy can instantly visualize cellular details in unstained tissues. Multiphoton probes with clinical potential have been developed. This study evaluates the suitability of multiphoton gradient index (GRIN) endoscopy as a diagnostic tool for prostatic tissue. A portable and compact multiphoton endoscope based on a 1-mm diameter, 8-cm length GRIN lens system probe was used. Fresh ex vivo samples were obtained from 14 radical prostatectomy patients and benign and malignant areas were imaged and correlated with subsequent H&E sections. Multiphoton GRIN endoscopy images of unfixed and unprocessed prostate tissue at a subcellular resolution are presented. We note several differences and identifying features of benign versus low-grade versus high-grade tumors and are able to identify periprostatic tissues such as adipocytes, periprostatic nerves, and blood vessels. Multiphoton GRIN endoscopy can be used to identify both benign and malignant lesions in ex vivo human prostate tissue and may be a valuable diagnostic tool for real-time visualization of suspicious areas of the prostate.

Disruption of Prostate Microvasculature by Combining Microbubble-Enhanced Ultrasound and Prothrombin

PubMed Central

Liu, Yongliang; Qiao, Lu; Gao, Wenhong; Zhang, Weiguo; Liu, Zheng

2016-01-01

Previous studies have shown a unique method to disrupt tumor vasculature using pulsed, high-pressure amplitude therapeutic ultrasound combined with microbubbles. In this study, we attempted to destroy the prostate vasculature of canine prostates using microbubble-enhanced ultrasound (MEUS) and prothrombin. The prostates of 43 male mongrel canines were surgically exposed. Twenty-two prostates were treated using MEUS (n = 11) or MEUS and prothrombin (PMEUS, n = 11). The other 21 prostates, which were treated using microbubbles (n = 7), ultrasound (n = 7) or prothrombin (n = 7) only, served as the controls. Prothrombin was intravenously infused at 20 IU/kg. MEUS was induced using a therapeutic ultrasound device at a peak negative pressure of 4.47 MPa and a microbubble injection. Contrast-enhanced ultrasound was performed to assess the blood perfusion of the prostates. Then, the prostate tissue was harvested immediately after treatment and at 48 hours later for pathological examination. The contrast-enhanced ultrasound peak value of the prostate decreased significantly from 36.2 ± 5.6 to 27.1 ± 6.3 after treatment in the PMEUS group, but it remained unchanged in the other groups. Histological examination found severe microvascular rupture, hemorrhage and thrombosis in both MEUS- and PMEUS-treated prostates immediately after treatment, while disruption in the PMEUS group was more severe than in the MEUS group. Forty-eight hours after treatment, massive necrosis and infiltration of white blood cells occurred in the PMEUS group. This study demonstrated that PMEUS disrupted the normal microvasculature of canine prostates and induced massive necrosis. PMEUS could potentially become a new noninvasive method used for the treatment of benign prostatic hyperplasia. PMID:27643992

Effects of Estrogen Receptor β Stimulation in a Rat Model of Non-Bacterial Prostatic Inflammation

PubMed Central

Mizoguchi, Shinsuke; Mori, Kenichi; Wang, Zhou; Liu, Teresa; Funahashi, Yasuhito; Sato, Fuminori; DeFranco, Donald B.; Yoshimura, Naoki; Mimata, Hiromitsu

2017-01-01

BACKGROUND There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor β (ERβ) could have an immunoprotective role in prostatic tissue. Therefore, we investigated the effect of ERβ-activation on not only prostatic inflammation, but also bladder overactive conditions in a rat model with nonbacterial prostatic inflammation. METHODS Male Sprague-Dawley rats (8 weeks, n = 15) were divided into three groups: sham-saline group (n = 5), formalin-vehicle group (n = 5), and formalin-treatment group (n = 5). The sham-saline group had sham operation and 50 μl normal saline injected into each ventral lobe of the prostate. The formalin-vehicle group had 50 μl 5% formalin injection into bilateral ventral lobes of the prostate. The formalin-treatment group was treated with 3α-Adiol (a selective ERβ agonist precursor) at a dose of 3 mg/kg daily from 2 days before induction of prostatic inflammation, whereas formalin-vehicle rats received vehicle (olive oil). In each group, conscious cystometry was performed on day 28 after intraprostatic formalin injection or sham treatment. After cystometry, the bladder and prostate were harvested for evaluation of mRNA expression and histological analysis. RESULTS In cystometric investigation, the mean number of non-voiding contractions was significantly greater and voiding intervals were significantly shorter in formalin-vehicle rats than those in sham-saline rats (P < 0.05). In RT-qPCR analysis, mRNA expression of NGF, P2X2, and TRPA1 receptors was significantly increased in the bladder mucosa, and mRNA expression of TNF-α, iNOS and COX2 in the ventral lobes of prostate was significantly increased in formalin-vehicle rats compared with sham-saline rats (P < 0.05). In addition, relative mRNA expression ratio of ERβ to ERα (ERβ/ERα) in the ventral lobes of prostate was significantly decreased in formalin-vehicle rats compared with sham-saline rats (P < 0.05). These changes were ameliorated by 3α-Adiol administration in formalin-treatment rats. CONCLUSIONS These results indicate that ERβ activation by 3α-Adiol administration, which normalized the ERβ/ERα expression ratio in the prostate, can improve not only prostatic inflammation, but also bladder overactivity. Therefore, ERβ agonists might be useful for treating irritative bladder symptoms in patients with symptomatic BPH associated with prostatic inflammation. PMID:28181685

Optimal Parameters to Determine the Apparent Diffusion Coefficient in Diffusion Weighted Imaging via Simulation

NASA Astrophysics Data System (ADS)

Perera, Dimuthu

Diffusion weighted (DW) Imaging is a non-invasive MR technique that provides information about the tissue microstructure using the diffusion of water molecules. The diffusion is generally characterized by the apparent diffusion coefficient (ADC) parametric map. The purpose of this study is to investigate in silico how the calculation of ADC is affected by image SNR, b-values, and the true tissue ADC. Also, to provide optimal parameter combination depending on the percentage accuracy and precision for prostate peripheral region cancer application. Moreover, to suggest parameter choices for any type of tissue, while providing the expected accuracy and precision. In this research DW images were generated assuming a mono-exponential signal model at two different b-values and for known true ADC values. Rician noise of different levels was added to the DWI images to adjust the image SNR. Using the two DWI images, ADC was calculated using a mono-exponential model for each set of b-values, SNR, and true ADC. 40,000 ADC data were collected for each parameter setting to determine the mean and the standard-deviation of the calculated ADC, as well as the percentage accuracy and precision with respect to the true ADC. The accuracy was calculated using the difference between known and calculated ADC. The precision was calculated using the standard-deviation of calculated ADC. The optimal parameters for a specific study was determined when both the percentage accuracy and precision were minimized. In our study, we simulated two true ADCs (ADC 0.00102 for tumor and 0.00180 mm2/s for normal prostate peripheral region tissue). Image SNR was varied from 2 to 100 and b-values were varied from 0 to 2000s/mm2. The results show that the percentage accuracy and percentage precision were minimized with image SNR. To increase SNR, 10 signal-averagings (NEX) were used considering the limitation in total scan time. The optimal NEX combination for tumor and normal tissue for prostate peripheral region was 1: 9. Also, the minimum percentage accuracy and percentage precision were obtained when low b-value is 0 and high b-value is 800 mm2/s for normal tissue and 1400 mm2/s for tumor tissue. Results also showed that for tissues with 1 x 10-3 < ADC < 2.1 x 10-3 mm 2/s the parameter combination at SNR = 20, b-value pair 0, 800 mm 2/s with NEX = 1:9 can calculate ADC with a percentage accuracy of less than 2% and percentage precision of 6-8%. Also, for tissues with 0.6 x 10-3 < ADC < 1.25 x 10-3 mm2 /s the parameter combination at SNR = 20, b-value pair 0, 1400 mm 2/s with NEX =1:9 can calculate ADC with a percentage accuracy of less than 2% and percentage precision of 6-8%.

Overexpression of LLT1 (OCIL, CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A (CD161) interaction.

PubMed

Mathew, Stephen O; Chaudhary, Pankaj; Powers, Sheila B; Vishwanatha, Jamboor K; Mathew, Porunelloor A

2016-10-18

Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. Previously, we identified Lectin-like transcript-1 (LLT1/OCIL/CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation. In this study, we have found that LLT1 was overexpressed on prostate cancer cell lines (DU145, LNCaP, 22Rv1 and PC3) and in primary prostate cancer tissues both at the mRNA and protein level. We further showed that LLT1 is retained intracellularly in normal prostate cells with minimal cell surface expression. Blocking LLT1 interaction with NKRP1A by anti-LLT1 mAb on prostate cancer cells increased the NK-mediated cytotoxicity of prostate cancer cells. The results indicate that prostate cancer cells may evade immune attack by NK cells by expressing LLT1 to inhibit NK cell-mediated cytolytic activity through LLT1-NKRP1A interaction. Blocking LLT1-NKRP1A interaction will make prostate cancer cells susceptible to killing by NK cells and therefore may be a new therapeutic option for treatment of prostate cancer.

Hyper-expression of PAX2 in human metastatic prostate tumors and its role as a cancer promoter in an in vitro invasion model.

PubMed

Ueda, Takashi; Ito, Saya; Shiraishi, Takumi; Kulkarni, Prakash; Ueno, Akihisa; Nakagawa, Hideo; Kimura, Yasunori; Hongo, Fumiya; Kamoi, Kazumi; Kawauchi, Akihiro; Miki, Tsuneharu

2013-09-01

Metastasis is a consequence of many biological events, during which cancer stem cells are shifted into a malignant state. Among these events, invasion of prostate cancer cells into host tissues is possible to be assessed by means of an in vitro invasion model, and is thought to be coupled to altered expression of membrane proteins. Dysregulated functions of the factors regulating organogenesis during embryogenesis are known to facilitate metastasis of many types of cancers. PAX2 (paired box 2) is a member of the PAX transcription factor family, which regulates prostatic ductal growth and branching in organogenesis of mammalian prostates. However, the role of PAX2 in prostate cancer development remains to be determined. PAX2 expression in human prostate cancers and normal prostate epithelium were examined by quantitative RT-PCR and immunohistochemistry. Matrigel invasion assay and a gene array analysis were performed using prostate cancer cell lines transfected with either control or PAX2 siRNA. In human prostate cancers, PAX2 was hyper-expressed in metastatic cancers, but was expressed at lower levels in non-metastatic cancers. Consistent with this, PAX2 knockdown repressed cell growth and invasion in a Matrigel invasion assay. Gene ontology analysis revealed that many cell membrane proteins were downregulated after PAX2 knockdown. Our data suggested that PAX2 hyper-expression promotes the development of the metastatic state in prostate cancer cells, presumably through upregulating the expression of cell membrane proteins. Copyright © 2013 Wiley Periodicals, Inc.

Combined 18F-Fluciclovine PET/MRI Shows Potential for Detection and Characterization of High-Risk Prostate Cancer.

PubMed

Elschot, Mattijs; Selnæs, Kirsten M; Sandsmark, Elise; Krüger-Stokke, Brage; Størkersen, Øystein; Giskeødegård, Guro F; Tessem, May-Britt; Moestue, Siver A; Bertilsson, Helena; Bathen, Tone F

2018-05-01

The objective of this study was to investigate whether quantitative imaging features derived from combined 18 F-fluciclovine PET/multiparametric MRI show potential for detection and characterization of primary prostate cancer. Methods: Twenty-eight patients diagnosed with high-risk prostate cancer underwent simultaneous 18 F-fluciclovine PET/MRI before radical prostatectomy. Volumes of interest (VOIs) for prostate tumors, benign prostatic hyperplasia (BPH) nodules, prostatitis, and healthy tissue were delineated on T2-weighted images, using histology as a reference. Tumor VOIs were marked as high-grade (≥Gleason grade group 3) or not. MRI and PET features were extracted on the voxel and VOI levels. Partial least-squared discriminant analysis (PLS-DA) with double leave-one-patient-out cross-validation was performed to distinguish tumors from benign tissue (BPH, prostatitis, or healthy tissue) and high-grade tumors from other tissue (low-grade tumors or benign tissue). The performance levels of PET, MRI, and combined PET/MRI features were compared using the area under the receiver-operating-characteristic curve (AUC). Results: Voxel and VOI features were extracted from 40 tumor VOIs (26 high-grade), 36 BPH VOIs, 6 prostatitis VOIs, and 37 healthy-tissue VOIs. PET/MRI performed better than MRI and PET alone for distinguishing tumors from benign tissue (AUCs of 87%, 81%, and 83%, respectively, at the voxel level and 96%, 93%, and 93%, respectively, at the VOI level) and high-grade tumors from other tissue (AUCs of 85%, 79%, and 81%, respectively, at the voxel level and 93%, 93%, and 91%, respectively, at the VOI level). T2-weighted MRI, diffusion-weighted MRI, and PET features were the most important for classification. Conclusion: Combined 18 F-fluciclovine PET/multiparametric MRI shows potential for improving detection and characterization of high-risk prostate cancer, in comparison to MRI and PET alone. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Preliminary results on diode-laser assisted vaporization of prostate tissue

NASA Astrophysics Data System (ADS)

Sroka, Ronald; Seitz, Michael; Reich, Oliver; Bachmann, Alexander; Steinbrecher, Verena; Ackermann, Alexander; Stief, Christian

2007-07-01

Introduction and objectives: The aim was to identify the capability and the laser parameter of under water tissue vaporisation by means of a diode laser (1470 nm). Afterwards the feasibility and postoperative clinical outcome of vaporization of the prostate was investigated. Method: After acquiring suitable laser parameters in in-vitro experiments using a perfused tissue model patients (n=10) suffering from bladder outlet obstruction due to benign prostatic hyperplasia (BPH) were treated by diode laser. Their clinical outcome, in terms of acceptance and post-operatively voiding were evaluated. The diode laser emitted light of the wavelength of 1470 nm at 50 W (Biolitec GmbH) and delivered to the tissue by means of a side-fire fibre introduced through a 24F continuous-flow cystoscope. Normal saline was used for irrigation with an additive of 1% ethanol. The prostatic lobes (volume range 35-80ml) were vaporized within the prostatic capsular using sweeping and push and pull technique. The mean time of laser application was 2400 sec (1220-4000 sec) resulting in applied energies of 121 kJ in the mean (range: 61-200kJ). Results: During laser treatment none of the 10 patients showed any significant blood loss or any fluid absorption (no ethanol uptake). Foley catheters were removed between 18 and 168 hours postoperatively (mean: 49.8h+/-46h). After removal of the catheter the mean peak urine flow rate increased from 8.9ml/s +/- 2.9ml/s pre-operatively in comparison to 15.7ml/s +/- 5 ml/s (p=0.049) post-operatively. 8/10 patients were satisfied with their voiding outcome. None of the patients showed appearance of urgency, dysuria, hematuria, or incontinence but two patients required re-catheterization. After a follow-up of 1month, 8/10 patients showed evidence of good results and are satisfied with the outcome. Two patients required consecutive TUR-P. After a follow-up of 6-month the 8 patients are still satisfied. Conclusions: This very early and limited experience using a 50W-Diode laser emitting at 1470 nm indicates a safe and effective treatment modality for quickly relieving bladder outlet obstruction due to BPH. Larger randomized clinical trials to compare this technique with standard transurethral resection of the prostate and increased follow-up data are needed to determine its long-term efficacy and durability.

Investigation of factors affecting hypothermic pelvic tissue cooling using bio-heat simulation based on MRI-segmented anatomic models.

PubMed

Lin, Yuting; Lin, Wei-Ching; Fwu, Peter T; Shih, Tzu-Ching; Yeh, Lee-Ren; Su, Min-Ying; Chen, Jeon-Hor

2015-10-01

This study applied a simulation method to map the temperature distribution based on magnetic resonance imaging (MRI) of individual patients, and investigated the influence of different pelvic tissue types as well as the choice of thermal property parameters on the efficiency of endorectal cooling balloon (ECB). MR images of four subjects with different prostate sizes and pelvic tissue compositions, including fatty tissue and venous plexus, were analyzed. The MR images acquired using endorectal coil provided a realistic geometry of deformed prostate that resembled the anatomy in the presence of ECB. A single slice with the largest two-dimensional (2D) cross-sectional area of the prostate gland was selected for analysis. The rectal wall, prostate gland, peri-rectal fatty tissue, peri-prostatic fatty tissue, peri-prostatic venous plexus, and urinary bladder were manually segmented. Pennes' bioheat thermal model was used to simulate the temperature distribution dynamics, by using an in-house finite element mesh based solver written in MATLAB. The results showed that prostate size and periprostatic venous plexus were two major factors affecting ECB cooling efficiency. For cases with negligible amount of venous plexus and small prostate, the average temperature in the prostate and neurovascular bundles could be cooled down to 25 °C within 30 min. For cases with abundant venous plexus and large prostate, the temperature could not reach 25 °C at the end of 3 h cooling. Large prostate made the cooling difficult to propagate through. The impact of fatty tissue on cooling effect was small. The filling of bladder with warm urine during the ECB cooling procedure did not affect the temperature in the prostate or NVB. In addition to the 2D simulation, in one case a 3D pelvic model was constructed for volumetric simulation. It was found that the 2D slice with the largest cross-sectional area of prostate had the most abundant venous plexus, and was the most difficult slice to cool, thus it may provide a conservative prediction of the cooling effect. This feasibility study demonstrated that the simulation tool could potentially be used for adjusting the setting of ECB for individual patients during hypothermic radical prostatectomy. Further studies using MR thermometry are required to validate the in silico results obtained using simulation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Investigation of factors affecting hypothermic pelvic tissue cooling using bio-heat simulation based on MRI-segmented anatomic models

PubMed Central

Lin, Yuting; Lin, Wei-Ching; Fwu, Peter T.; Shih, Tzu-Ching; Yeh, Lee-Ren; Su, Min-Ying; Chen, Jeon-Hor

2015-01-01

This study applied a simulation method to map the temperature distribution based on magnetic resonance imaging (MRI) of individual patients, and investigated the influence of different pelvic tissue types as well as the choice of thermal property parameters on the efficiency of endorectal cooling balloon (ECB). MR images of four subjects with different prostate sizes and pelvic tissue compositions, including fatty tissue and venous plexus, were analyzed. The MR images acquired using endorectal coil provided a realistic geometry of deformed prostate that resembled the anatomy in the presence of ECB. A single slice with the largest two-dimensional (2D) cross-sectional area of the prostate gland was selected for analysis. The rectal wall, prostate gland, peri-rectal fatty tissue, peri-prostatic fatty tissue, peri-prostatic venous plexus, and urinary bladder were manually segmented. Pennes’ bioheat thermal model was used to simulate the temperature distribution dynamics, by using an in-house finite element mesh based solver written in Matlab. The results showed that prostate size and periprostatic venous plexus were two major factors affecting ECB cooling efficiency. For cases with negligible amount of venous plexus and small prostate, the averaged temperature in the prostate and neurovascular bundles could be cooled down to 25°C within 30 minutes. For cases with abundant venous plexus and large prostate, the temperature could not reach 25°C at the end of 3 hours cooling. Large prostate made the cooling difficult to propagate through. The impact of fatty tissue on cooling effect was small. The filling of bladder with warm urine during the ECB cooling procedure did not affect the temperature in the prostate or NVB. In addition to the 2D simulation, in one case a 3D pelvic model was constructed for volumetric simulation. It was found that the 2D slice with the largest cross-sectional area of prostate had the most abundant venous plexus, and was the most difficult slice to cool, thus it may provide a conservative prediction of the cooling effect. This feasibility study demonstrated that the simulation tool could potentially be used for adjusting the setting of ECB for individual patients during hypothermic radical prostatectomy. Further studies using MR thermometry are required to validate the in silico results obtained using simulation. PMID:26198131

Association of anti-sperm antibodies with chronic prostatitis: A systematic review and meta-analysis.

PubMed

Jiang, Yumei; Cui, Dong; Du, Yuefeng; Lu, Jun; Yang, Lin; Li, Jinmei; Zhang, Jing; Bai, Xiaojing

2016-11-01

Chronic prostatitis is a risk factor for impaired male fertility potential, and anti-sperm antibodies (ASAs) cause the autoimmune disease immune infertility, which has a negative effect on semen parameters. Current studies have investigated the ASA-positive relationship between chronic prostatitis versus normal controls, but have shown inconsistent results. Hence, we systematic searched the PubMed, EMBASE, Science Direct/Elsevier, Medline, and the Cochrane Library up to October 2015 for case-control studies that involved the ASA-positive relationship between chronic prostatitis patients versus normal controls. The meta-analysis was performed with Review Manager and Stata software. After literature search, six studies were identified, including 721 cases of chronic prostatitis and 160 normal controls. Our results illustrated a significant correlation of the ASA-positive relationship between chronic prostatitis patients versus normal controls. The combined odds ratio of the ASA-positive rate in chronic prostatitis patients and normal controls was 3.26 (1.86-5.71). There was also a significant correlation of the ASA-positive relationship between National Institutes of Health (NIH) III versus normal controls, and the combined OR was 2.46 (1.10-5.51). However, there was no significant correlation of the ASA-positive relationship between National Institutes of Health (NIH) II versus normal controls. The present study illustrates that the positive rate of ASAs in chronic prostatitis patients was significantly higher than in the control group, suggesting that chronic prostatitis has a negative effect on male reproductive function. However, studies with larger samples are needed to better illuminate the correlation between ASAs and chronic prostatitis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Influence of the neural microenvironment on prostate cancer

PubMed Central

Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J.

2017-01-01

Background Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. Method We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Result Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells. Conclusion Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. PMID:29131367

Her-2-neu expression and progression toward androgen independence in human prostate cancer.

PubMed

Signoretti, S; Montironi, R; Manola, J; Altimari, A; Tam, C; Bubley, G; Balk, S; Thomas, G; Kaplan, I; Hlatky, L; Hahnfeldt, P; Kantoff, P; Loda, M

2000-12-06

Human prostate cancers are initially androgen dependent but ultimately become androgen independent. Overexpression of the Her-2-neu receptor tyrosine kinase has been associated with the progression to androgen independence in prostate cancer cells. We examined the expression of Her-2-neu in normal and cancerous prostate tissues to assess its role in the progression to androgen independence. Prostate cancer tissue sections were obtained from 67 patients treated by surgery alone (UNT tumors), 34 patients treated with total androgen ablation therapy before surgery (TAA tumors), and 18 patients in whom total androgen ablation therapy failed and who developed bone metastases (androgen-independent [AI] disease). The sections were immunostained for Her-2-neu, androgen receptor (AR), prostate-specific antigen (PSA), and Ki-67 (a marker of cell proliferation) protein expression. Messenger RNA (mRNA) levels and gene amplification of Her-2-neu were examined by RNA in situ hybridization and fluorescent in situ hybridization(FISH), respectively, in a subset of 27 tumors (nine UNT, 11 TAA, and seven AI). All statistical tests were two-sided. Her-2-neu protein expression was statistically significantly higher in TAA tumors than in UNT tumors with the use of two different scoring methods (P =.008 and P =.002). The proportion of Her-2-neu-positive tumors increased from the UNT group (17 of 67) to the TAA group (20 of 34) to the AI group (14 of 18) (P<.001). When compared with UNT tumors, tumor cell proliferation was higher in AI tumors (P =.014) and lower in TAA tumors (P<.001). All tumors expressed AR and PSA proteins. Although Her-2-neu mRNA expression was high in TAA and AI tumors, no Her-2-neu gene amplification was detected by FISH in any of the tumor types. Her-2-neu expression appears to increase with progression to androgen independence. Thus, therapeutic targeting of this tyrosine kinase in prostate cancer may be warranted.

SU-E-T-571: Prostate IMRT QA: Prediction of the Range of Rectal NTCP Using a 2D Field Approach Based on Variations of the Rectal Wall Motion and Thickness.

PubMed

Grigorov, G; Chow, J; Foster, K

2012-06-01

The aims of this study is to (1) introduce a 2D field of possible rectal normal tissue complication probability (NTCP) in prostate intensity modulated radiotherapy (IMRT) plan, so that based on a given prescribed dose the rectal NTCP is merely a function of the rectal wall thickness and rectal motion; and (2) separate the 2D field of rectal NTCP into area of low risk and area of high risk for rectal toxicity < Grade II, based on the threshold rectal NTCP. The 2D field of NTCP model was developed using ten randomly selected prostate IMRT plans. The clinical rectal geometry was initially represented by the cylindrical contour in the treatment planning system. Different combinations of rectal motions, rectal wall thicknesses, planning target volume margins and prescribed doses were used to determine the NTCP in prostate IMRT plans. It was found that the functions bordering the 2D field for the given AP, LR and SI direction can be described as exponential, quadratic and linear equations, respectively. A ratio of the area of 2D field containing data of the low risk NTCP to the entire area of the field was introduced and calculated. Although our method is based on the Kutcher's dose response model and published tissue parameters, other mathematical models can be used in our approach. The 2D field of rectal NTCP is useful to estimate the rectal NTCP range in the prostate pre-treatment and treatment QA. Our method can determine the patient's threshold immobilization for a given rectal wall thickness so that prescribed dose can be delivered to the prostate to avoid rectal complication. Our method is also applicable to multi-phase prostate IMRT, and can be adapted to any treatment planning systems. © 2012 American Association of Physicists in Medicine.

In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

PubMed

Lee, Deanna; Das Gupta, Jaydip; Gaughan, Christina; Steffen, Imke; Tang, Ning; Luk, Ka-Cheung; Qiu, Xiaoxing; Urisman, Anatoly; Fischer, Nicole; Molinaro, Ross; Broz, Miranda; Schochetman, Gerald; Klein, Eric A; Ganem, Don; Derisi, Joseph L; Simmons, Graham; Hackett, John; Silverman, Robert H; Chiu, Charles Y

2012-01-01

XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection.

Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

DTIC Science & Technology

2015-10-01

prostate cancer bone metastasis through the phagocytosis of apoptotic tumor cells (efferocytosis). Specific Aims: 1. To identify the phagocytic ...2: To identify the phagocytic /efferocytic macrophage population in the tumor microenvironment of prostate bone metastases and determine its ability...preparation for Cancer Research. We obtained an array of prostate cancer tissue including bone metastasis (N=72) and stained the tissue for the phagocytic

Genetic and Molecular Mechanisms in Assessing Response in Patients With Prostate Cancer Receiving Enzalutamide Therapy

ClinicalTrials.gov

2018-01-22

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma in the Soft Tissue; Metastatic Prostatic Adenocarcinoma; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Recurrent Prostate Carcinoma; Stage III Prostate Adenocarcinoma; Stage IV Prostate Adenocarcinoma

TMPRSS2-ERG gene fusion status in minute (minimal) prostatic adenocarcinoma.

PubMed

Albadine, Roula; Latour, Mathieu; Toubaji, Antoun; Haffner, Michael; Isaacs, William B; A Platz, Elizabeth; Meeker, Alan K; Demarzo, Angelo M; Epstein, Jonathan I; Netto, George J

2009-11-01

Minute prostatic adenocarcinomas are considered to be of insufficient virulence. Given recent suggestions of TMPRSS2-ERG gene fusion association with aggressive prostatic adenocarcinoma, we evaluated the incidence of TMPRSS2-ERG fusion in minute prostatic adenocarcinomas. A total of 45 consecutive prostatectomies with minute adenocarcinoma were used for tissue microarray construction. A total of 63 consecutive non-minimal, Gleason Score 6 tumors, from a separate PSA Era prostatectomy tissue microarray, were used for comparison. FISH was carried out using ERG break-apart probes. Tumors were assessed for fusion by deletion (Edel) or split (Esplit), duplicated fusions and low-level copy number gain in normal ERG gene locus. Minute adenocarcinomas: Fusion was evaluable in 32/45 tumors (71%). Fifteen out of 32 (47%) tumors were positive for fusion. Six (19%) were of the Edel class and 7 (22%) were classified as combined Edel+Esplit. Non-minute adenocarcinomas (pT2): Fusion was identified in 20/30 tumors (67%). Four (13%) were of Edel class and 5 (17%) were combined Edel+Esplit. Duplicated fusions were encountered in 5 (16%) tumors. Non-minute adenocarcinomas (pT3): Fusion was identified in 19/33 (58%). Fusion was due to a deletion in 6 (18%) tumors. Seven tumors (21%) were classified as combined Edel+Esplit. One tumor showed Esplit alone. Duplicated fusions were encountered in 3 (9%) cases. The incidence of duplicated fusions was higher in non-minute adenocarcinomas (13 vs 0%; P=0.03). A trend for higher incidence of low-level copy number gain in normal ERG gene locus without fusion was noted in non-minute adenocarcinomas (10 vs 0%; P=0.07). We found a TMPRSS2-ERG fusion rate of 47% in minute adenocarcinomas. The latter is not significantly different from that of grade matched non-minute adenocarcinomas. The incidence of duplicated fusion was higher in non-minute adenocarcinomas. Our finding of comparable rate of TMPRSS2-ERG fusion in minute adenocarcinomas may argue against its value as a marker of aggressive prostate carcinoma phenotype.

Role of monocyte-lineage cells in prostate cancer cell invasion and tissue factor expression.

PubMed

Lindholm, Paul F; Lu, Yi; Adley, Brian P; Vladislav, Tudor; Jovanovic, Borko; Sivapurapu, Neela; Yang, Ximing J; Kajdacsy-Balla, André

2010-11-01

Tissue factor (TF) is a cell surface glycoprotein intricately related to blood coagulation and inflammation. This study was performed to investigate the role of monocyte-lineage cells in prostate cancer cell TF expression and cell invasion. Prostate cancer cell invasion was tested with and without added peripheral blood monocytes or human monocyte-lineage cell lines. TF neutralizing antibodies were used to determine the TF requirement for prostate cancer cell invasion activity. Immunohistochemistry was performed to identify prostate tissue CD68 positive monocyte-derived cells and prostate epithelial TF expression. Co-culture of PC-3, DU145, and LNCaP cells with isolated human monocytes significantly stimulated prostate cancer cell invasion activity. TF expression was greater in highly invasive prostate cancer cells and was induced in PC-3, DU145, and LNCaP cells by co-culture with U-937 cells, but not with THP-1 cells. TF neutralizing antibodies inhibited PC-3 cell invasion in co-cultures with monocyte-lineage U-937 or THP-1 cells. Prostate cancer tissues contained more CD68 positive cells in the stroma and epithelium (145 ± 53/mm(2)) than benign prostate (108 ± 31/mm(2)). Samples from advanced stage prostate cancer tended to contain more CD68 positive cells when compared with lower stage lesions. Prostatic adenocarcinoma demonstrated significantly increased TF expression compared with benign prostatic epithelium. This study shows that co-culture with monocyte-lineage cells induced prostate cancer cell invasion activity. PC-3 invasion and TF expression was induced in co-culture with U-937 cells and partially inhibited with TF neutralizing antibodies.

Development of Assays for Detecting Significant Prostate Cancer Based on Molecular Alterations Associated with Cancer in Non-Neoplastic Prostate Tissue

DTIC Science & Technology

2016-12-01

Award Number: W81XWH-11-1-0744 TITLE: Development of Assays for Detecting Significant Prostate Cancer Based on Molecular Alterations Associated...Significant Prostate Cancer Based on Molecular Alterations Associated with Cancer in Non- Neoplastic Prostate Tissue 5b. GRANT NUMBER 10623678 5c...Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The goal of this project was to develop molecular models to

Ultrasound elastography of the prostate: state of the art.

PubMed

Correas, J-M; Tissier, A-M; Khairoune, A; Khoury, G; Eiss, D; Hélénon, O

2013-05-01

Prostate cancer is the cancer exhibiting the highest incidence rate and it appears as the second cause of cancer death in men, after lung cancer. Prostate cancer is difficult to detect, and the treatment efficacy remains limited despite the increase use of biological tests (prostate-specific antigen [PSA] dosage), the development of new imaging modalities, and the use of invasive procedures such as biopsy. Ultrasound elastography is a novel imaging technique capable of mapping tissue stiffness of the prostate. It is known that prostatic cancer tissue is often harder than healthy tissue (information used by digital rectal examination [DRE]). Two elastography techniques have been developed based on different principles: first, quasi-static (or strain) technique, and second, shear wave technique. The tissue stiffness information provided by US elastography should improve the detection of prostate cancer and provide guidance for biopsy. Prostate elastography provides high sensitivity for detecting prostate cancer and shows high negative predictive values, ensuring that few cancers will be missed. US elastography should become an additional method of imaging the prostate, complementing the conventional transrectal ultrasound and MRI. This technique requires significant training (especially for quasi-static elastography) to become familiar with acquisition process, acquisition technique, characteristics and limitations, and to achieve correct diagnoses. Copyright © 2013 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

MR PROSTATE SEGMENTATION VIA DISTRIBUTED DISCRIMINATIVE DICTIONARY (DDD) LEARNING.

PubMed

Guo, Yanrong; Zhan, Yiqiang; Gao, Yaozong; Jiang, Jianguo; Shen, Dinggang

2013-01-01

Segmenting prostate from MR images is important yet challenging. Due to non-Gaussian distribution of prostate appearances in MR images, the popular active appearance model (AAM) has its limited performance. Although the newly developed sparse dictionary learning method[1, 2] can model the image appearance in a non-parametric fashion, the learned dictionaries still lack the discriminative power between prostate and non-prostate tissues, which is critical for accurate prostate segmentation. In this paper, we propose to integrate deformable model with a novel learning scheme, namely the Distributed Discriminative Dictionary ( DDD ) learning, which can capture image appearance in a non-parametric and discriminative fashion. In particular, three strategies are designed to boost the tissue discriminative power of DDD. First , minimum Redundancy Maximum Relevance (mRMR) feature selection is performed to constrain the dictionary learning in a discriminative feature space. Second , linear discriminant analysis (LDA) is employed to assemble residuals from different dictionaries for optimal separation between prostate and non-prostate tissues. Third , instead of learning the global dictionaries, we learn a set of local dictionaries for the local regions (each with small appearance variations) along prostate boundary, thus achieving better tissue differentiation locally. In the application stage, DDDs will provide the appearance cues to robustly drive the deformable model onto the prostate boundary. Experiments on 50 MR prostate images show that our method can yield a Dice Ratio of 88% compared to the manual segmentations, and have 7% improvement over the conventional AAM.

Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

PubMed

Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

2012-04-01

G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

Human Prostate Sphere-Forming Cells Represent a Subset of Basal Epithelial Cells Capable of Glandular Regeneration in Vivo

PubMed Central

Garraway, Isla P; Sun, Wenyi; Tran, Chau P; Perner, Sven; Zhang, Bao; Goldstein, Andrew S; Hahm, Scott A; Haider, Maahum; Head, Christian S; Reiter, Robert E; Rubin, Mark A; Witte, Owen N

2010-01-01

BACKGROUND Prostate stem/progenitor cells function in glandular development and maintenance. They may be targets for tumor initiation, so characterization of these cells may have therapeutic implications. Cells from dissociated tissues that form spheres in vitro often represent stem/progenitor cells. A subset of human prostate cells that form prostaspheres were evaluated for self-renewal and tissue regeneration capability in the present study. METHODS Prostaspheres were generated from 59 prostatectomy specimens. Lineage marker expression and TMPRSS-ERG status was determined via immunohistochemistry and fluorescence in situ hybridization (FISH). Subpopulations of prostate epithelial cells were isolated by cell sorting and interrogated for sphere-forming activity. Tissue regeneration potential was assessed by combining sphere-forming cells with rat urogenital sinus mesenchyme (rUGSM) subcutaneously in immunocompromised mice. RESULTS Prostate tissue specimens were heterogeneous, containing both benign and malignant (Gleason 3–5) glands. TMPRSS-ERG fusion was found in approximately 70% of cancers examined. Prostaspheres developed from single cells at a variable rate (0.5–4%) and could be serially passaged. A basal phenotype (CD44+CD49f+CK5+p63+CK8−AR−PSA−) was observed among sphere-forming cells. Subpopulations of prostate cells expressing tumor-associated calcium signal transducer 2 (Trop2), CD44, and CD49f preferentially formed spheres. In vivo implantation of sphere-forming cells and rUGSM regenerated tubular structures containing discreet basal and luminal layers. The TMPRSS-ERG fusion was absent in prostaspheres derived from fusion-positive tumor tissue, suggesting a survival/growth advantage of benign prostate epithelial cells. CONCLUSION Human prostate sphere-forming cells self-renew, have tissue regeneration capability, and represent a subpopulation of basal cells. Prostate 70: 491–501, 2010. © 2009 Wiley-Liss, Inc. PMID:19938015

Differentiation of prostatitis and prostate cancer using the Prostate Imaging-Reporting and Data System (PI-RADS).

PubMed

Meier-Schroers, Michael; Kukuk, Guido; Wolter, Karsten; Decker, Georges; Fischer, Stefan; Marx, Christian; Traeber, Frank; Sprinkart, Alois Martin; Block, Wolfgang; Schild, Hans Heinz; Willinek, Winfried

2016-07-01

To determine if prostate cancer (PCa) and prostatitis can be differentiated by using PI-RADS. 3T MR images of 68 patients with 85 cancer suspicious lesions were analyzed. The findings were correlated with histopathology. T2w imaging (T2WI), diffusion weighted imaging (DWI), dynamic contrast enhancement (DCE), and MR-Spectroscopy (MRS) were acquired. Every lesion was given a single PI-RADS score for each parameter, as well as a sum score and a PI-RADS v2 score. Furthermore, T2-morphology, ADC-value, perfusion type, citrate/choline-level, and localization were evaluated. 44 of 85 lesions showed PCa (51.8%), 21 chronic prostatitis (24.7%), and 20 other benign tissue such as hyperplasia or fibromuscular tissue (23.5%). The single PI-RADS score for T2WI, DWI, DCE, as well as the aggregated score including and not including MRS, and the PI-RADS v2-score were all significantly higher for PCa than for prostatitis or other tissue (p<0.001). The single PI-RADS score for MRS and the PI-RADS sum score including MRS were significantly higher for prostatitis than for other tissue (p=0.029 and p=0.020), whereas the other parameters were not different. Prostatitis usually presented borderline pathological PI-RADS scores, showed restricted diffusion with ADC≥900mm(2)/s in 100% of cases, was more often indistinctly hypointense on T2WI (66.7%), and localized in the transitional zone (57.1%). An ADC≥900mm(2)/s achieved the highest predictive value for prostatitis (AUC=0.859). Prostatitis can be differentiated from PCa using PI-RADS, since all available parameters are more distinct in cases of cancer. However, there is significant overlap between prostatitis and other benign findings, thus PI-RADS is only suitable to a limited extent for the primary assessment of prostatitis. Restricted diffusion with ADC≥900mm(2)/s is believed to be a good indicator for prostatitis. MRS can help to distinguish between prostatitis and other tissue. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Various clinical application of phase contrast X-ray

NASA Astrophysics Data System (ADS)

Oh, Chilhwan; Park, Sangyong; Ha, Seunghan; Park, Gyuman; Lee, Gunwoo; Lee, Onseok; Je, Jungho

2008-02-01

In biomedical application study using phase contrast X-ray, both sample thickness or density and absorption difference are very important factors in aspects of contrast enhancement. We present experimental evidence that synchrotron hard X-ray are suitable for radiological imaging of biological samples down to the cellular level. We investigated the potential of refractive index radiology using un-monochromatized synchrotron hard X-rays for the imaging of cell and tissue in various diseases. Material had been adopted various medical field, such as apoE knockout mouse in cardiologic field, specimen from renal and prostatic carcinoma patient in urology, basal cell epithelioma in dermatology, brain tissue from autosy sample of pakinson's disease, artificially induced artilrtis tissue from rabbits and extracted tooth from patients of crack tooth syndrome. Formalin and paraffin fixed tissue blocks were cut in 3 mm thickness for the X-ray radiographic imaging. From adjacent areas, 4 μm thickness sections were also prepared for hematoxylin-eosin staining. Radiographic images of dissected tissues were obtained using the hard X-rays from the 7B2 beamline of the Pohang Light Source (PLS). The technique used for the study was the phase contrast images were compared with the optical microscopic images of corresponding histological slides. Radiographic images of various diseased tissues showed clear histological details of organelles in normal tissues. Most of cancerous lesions were well differentiated from adjacent normal tissues and detailed histological features of each tumor were clearly identified. Also normal microstructures were identifiable by the phase contrast imaging. Tissue in cancer or other disease showed clearly different findings from those of surrounding normal tissue. For the first time we successfully demonstrated that synchrotron hard X-rays can be used for radiological imaging of relatively thick tissue samples with great histological details.

hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer

PubMed Central

Franklin, Renty B; Feng, Pei; Milon, B; Desouki, Mohamed M; Singh, Keshav K; Kajdacsy-Balla, André; Bagasra, Omar; Costello, Leslie C

2005-01-01

Background The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. Results hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands). In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. hZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation in adenocarcinomatous glands is likely due to in situ gene silencing. These observations, coupled with the numerous and consistent reports of loss of zinc accumulation in malignant cells in prostate cancer, lead to the plausible proposal that down regulation of hZIP1 is a critical early event in the development prostate cancer. PMID:16153295

Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer.

PubMed

Parwani, Anil V; Marlow, Cameron; Demarzo, Angelo M; Mikolajczyk, Stephen D; Rittenhouse, Harry G; Veltri, Robert W; Chan, Theresa Y

2006-10-01

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.

Increased Expression of Herpes Virus-Encoded hsv1-miR-H18 and hsv2-miR-H9-5p in Cancer-Containing Prostate Tissue Compared to That in Benign Prostate Hyperplasia Tissue

PubMed Central

Shinn, Helen Ki; Yan, Chunri; Kim, Tae-Hwan; Kim, Sang Tae; Kim, Won Tae; Lee, Ok-Jun; Moon, Sung-Kwon; Kim, Nam-Hyung; Kim, Jayoung; Cha, Eun-Jong

2016-01-01

Purpose: Previously, we reported the presence of virus-encoded microRNAs (miRNAs) in the urine of prostate cancer (CaP) patients. In this study, we investigated the expression of two herpes virus-encoded miRNAs in prostate tissue. Methods: A total of 175 tissue samples from noncancerous benign prostatic hyperplasia (BPH), 248 tissue samples from patients with CaP and BPH, and 50 samples from noncancerous surrounding tissues from these same patients were analyzed for the expression of two herpes virus-encoded miRNAs by real-time polymerase chain reaction (PCR) and immunocytochemistry using nanoparticles as molecular beacons. Results: Real-time reverse transcription-PCR results revealed significantly higher expression of hsv1-miR-H18 and hsv2-miRH9- 5p in surrounding noncancerous and CaP tissues than that in BPH tissue (each comparison, P<0.001). Of note, these miRNA were expressed equivalently in the CaP tissues and surrounding noncancerous tissues. Moreover, immunocytochemistry clearly demonstrated a significant enrichment of both hsv1-miR-H18 and hsv2-miR-H9 beacon-labeled cells in CaP and surrounding noncancerous tissue compared to that in BPH tissue (each comparison, P<0.05 for hsv1-miR-H18 and hsv2- miR-H9). Conclusions: These results suggest that increased expression of hsv1-miR-H18 and hsv2-miR-H95p might be associated with tumorigenesis in the prostate. Further studies will be required to elucidate the role of these miRNAs with respect to CaP and herpes viral infections. PMID:27377944

Increased Expression of Herpes Virus-Encoded hsv1-miR-H18 and hsv2-miR-H9-5p in Cancer-Containing Prostate Tissue Compared to That in Benign Prostate Hyperplasia Tissue.

PubMed

Yun, Seok Joong; Jeong, Pildu; Kang, Ho Won; Shinn, Helen Ki; Kim, Ye-Hwan; Yan, Chunri; Choi, Young-Ki; Kim, Dongho; Ryu, Dong Hee; Ha, Yun-Sok; Kim, Tae-Hwan; Kwon, Tae Gyun; Kim, Jung Min; Suh, Sang Heon; Kim, Seon-Kyu; Kim, Seon-Young; Kim, Sang Tae; Kim, Won Tae; Lee, Ok-Jun; Moon, Sung-Kwon; Kim, Nam-Hyung; Kim, Isaac Yi; Kim, Jayoung; Cha, Hee-Jae; Choi, Yung-Hyun; Cha, Eun-Jong; Kim, Wun-Jae

2016-06-01

Previously, we reported the presence of virus-encoded microRNAs (miRNAs) in the urine of prostate cancer (CaP) patients. In this study, we investigated the expression of two herpes virus-encoded miRNAs in prostate tissue. A total of 175 tissue samples from noncancerous benign prostatic hyperplasia (BPH), 248 tissue samples from patients with CaP and BPH, and 50 samples from noncancerous surrounding tissues from these same patients were analyzed for the expression of two herpes virus-encoded miRNAs by real-time polymerase chain reaction (PCR) and immunocytochemistry using nanoparticles as molecular beacons. Real-time reverse transcription-PCR results revealed significantly higher expression of hsv1-miR-H18 and hsv2-miRH9- 5p in surrounding noncancerous and CaP tissues than that in BPH tissue (each comparison, P<0.001). Of note, these miRNA were expressed equivalently in the CaP tissues and surrounding noncancerous tissues. Moreover, immunocytochemistry clearly demonstrated a significant enrichment of both hsv1-miR-H18 and hsv2-miR-H9 beacon-labeled cells in CaP and surrounding noncancerous tissue compared to that in BPH tissue (each comparison, P<0.05 for hsv1-miR-H18 and hsv2- miR-H9). These results suggest that increased expression of hsv1-miR-H18 and hsv2-miR-H95p might be associated with tumorigenesis in the prostate. Further studies will be required to elucidate the role of these miRNAs with respect to CaP and herpes viral infections.

Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies.

PubMed

Raspotnig, Margrethe; Haugen, Mette; Thorsteinsdottir, Maria; Stefansson, Ingunn; Salvesen, Helga B; Storstein, Anette; Vedeler, Christian A

2017-11-01

Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues.

NASA Bioreactor tissue culture

NASA Technical Reports Server (NTRS)

1998-01-01

Dr. Lisa E. Freed of the Massachusetts Institute of Technology and her colleagues have reported that initially disc-like specimens tend to become spherical in space, demonstrating that tissues can grow and differentiate into distinct structures in microgravity. The Mir Increment 3 (Sept. 16, 1996 - Jan. 22, 1997) samples were smaller, more spherical, and mechanically weaker than Earth-grown control samples. These results demonstrate the feasibility of microgravity tissue engineering and may have implications for long human space voyages and for treating musculoskeletal disorders on earth. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Estrogenic Environmental Chemicals and Drugs: Mechanisms for Effects on the Developing Male Urogenital System

PubMed Central

Taylor, Julia A.; Richter, Catherine A.; Ruhlen, Rachel L.; vom Saal, Frederick S.

2011-01-01

Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID:21827855

Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

PubMed

Guimond, Marie-Odile; Battista, Marie-Claude; Nikjouitavabi, Fatemeh; Carmel, Maude; Barres, Véronique; Doueik, Alexandre A; Fazli, Ladan; Gleave, Martin; Sabbagh, Robert; Gallo-Payet, Nicole

2013-07-01

Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance. Copyright © 2013 Wiley Periodicals, Inc.

Identification of viral infections in the prostate and evaluation of their association with cancer

PubMed Central

2010-01-01

Background Several viruses with known oncogenic potential infect prostate tissue, among these are the polyomaviruses BKV, JCV, and SV40; human papillomaviruses (HPVs), and human cytomegalovirus (HCMV) infections. Recently, the Xenotropic Murine Leukemia Virus-related gammaretrovirus (XMRV) was identified in prostate tissue with a high prevalence observed in prostate cancer (PC) patients homozygous for the glutamine variant of the RNASEL protein (462Q/Q). Association studies with the R462Q allele and non-XMRV viruses have not been reported. We assessed associations between prostate cancer, prostate viral infections, and the RNASEL 462Q allele in Mexican cancer patients and controls. Methods 130 subjects (55 prostate cancer cases and 75 controls) were enrolled in the study. DNA and RNA isolated from prostate tissues were screened for the presence of viral genomes. Genotyping of the RNASEL R462Q variant was performed by Taqman method. Results R/R, R/Q, and Q/Q frequencies for R462Q were 0.62, 0.38, and 0.0 for PC cases and 0.69, 0.24, and 0.07 for controls, respectively. HPV sequences were detected in 11 (20.0%) cases and 4 (5.3%) controls. XMRV and HCMV infections were detected in one and six control samples, respectively. The risk of PC was significantly increased (Odds Ratio = 3.98; 95% CI: 1.17-13.56, p = 0.027) by infection of the prostatic tissue with HPV. BKV, JCV, and SV40 sequences were not detected in any of the tissue samples examined. Conclusions We report a positive association between PC and HPV infection. The 462Q/Q RNASEL genotype was not represented in our PC cases; thus, its interaction with prostate viral infections and cancer could not be evaluated. PMID:20576103

Early diagnostic role of PSA combined miR-155 detection in prostate cancer.

PubMed

Guo, T; Wang, X-X; Fu, H; Tang, Y-C; Meng, B-Q; Chen, C-H

2018-03-01

As a kind of malignant tumor in the male genitourinary system, prostate cancer exhibits significantly increased occurrence. Prostate-specific antigen (PSA) expression can be seen in the prostate cancer, prostatitis, and other diseases, therefore, lack of diagnostic specificity. The miR-155 expression is abnormally increased in the tumors. Therefore, this study aims to explore the clinical significance of PSA combined miR-155 detection in the early diagnosis of prostate cancer. A total of 86 patients diagnosed with prostate cancer were enrolled in this study. PSA and miR-155 gene expression in tumor tissue were detected by using Real-time PCR. The serum levels of PSA were measured by using enzyme-linked immunosorbent assay (ELISA). The correlation of PSA and miR-155 expression with age, body mass index (BMI), tumor volume, tumor-node-metastasis (TNM) stage, lymph node metastasis (LNM), and other clinicopathological features were analyzed, respectively. Serum PSA expression and PSA gene in tumor tissue were significantly higher compared to that in adjacent tissues (p<0.05). PSA gene and protein increased significantly with the clinical stage of TNM and decreased following the increase of grade (p<0.05). The miR-155 level was significantly elevated in the tumor tissue compared with para-carcinoma tissue (p<0.05). PSA and miR-155 expressions were positively correlated with TNM stage, tumor volume, and LNM, and negatively correlated with grade (p<0.05). PSA and miR-155 were closely related to the clinicopathological features of prostate cancer. Combined detection is helpful for the early diagnosis of prostate cancer.

Holmium:YAG (lambda=2120nm) vs. Thulium fiber (lambda=1908nm) laser for high-power vaporization of canine prostate tissue

NASA Astrophysics Data System (ADS)

Casperson, Andrew L.; Barton, Robert A.; Scott, Nicholas J.; Fried, Nathaniel M.

2008-02-01

Direct studies comparing different lasers for treatment of BPH are lacking. This preliminary study compares continuous-wave (CW) vs. pulsed prostate tissue vaporization for the Thulium fiber laser and Holmium:YAG laser, both operating near the 1940 nm water absorption peak in tissue. A 50-W Thulium fiber laser (λ= 1908 nm) delivered CW laser radiation through a 600-μm silica fiber in non-contact mode with a 5-mm-diameter spot at the tissue surface. A Holmium:YAG laser (λ= 2120 nm) operated with an energy of 2 J, pulse rate of 25 Hz, and average power of 50 W, and delivered pulsed laser radiation through a 600-μm silica fiber with a 5-mm-diameter laser spot to achieve similar irradiances at the tissue surface. Tissue vaporization was performed in air with the prostate kept hydrated in saline. Tissue vaporization efficiency of both lasers was compared (n = 10 canine prostates for each laser group). Mean vaporization efficiency measured 5.30 +/- 0.48 kJ/g vs. 4.13 +/- 0.46 kJ/g for Thulium fiber and Holmium lasers (P < 0.05). Tissue vaporization rates measured 0.57 +/- 0.05 g/min vs. 0.73 +/- 0.07 g/min (P < 0.05). The Holmium:YAG laser vaporizes prostate tissue at a higher rate than the Thulium fiber laser, for the same average power delivered to the tissue. Both the Thulium fiber laser and Holmium:YAG lasers are capable of vaporizing prostate tissue at a rate > 1 g/min if operated at the high powers (100-W) typically used in the clinic.

Ultra-high performance liquid chromatographic determination of levofloxacin in human plasma and prostate tissue with use of experimental design optimization procedures.

PubMed

Szerkus, O; Jacyna, J; Wiczling, P; Gibas, A; Sieczkowski, M; Siluk, D; Matuszewski, M; Kaliszan, R; Markuszewski, M J

2016-09-01

Fluoroquinolones are considered as gold standard for the prevention of bacterial infections after transrectal ultrasound guided prostate biopsy. However, recent studies reported that fluoroquinolone- resistant bacterial strains are responsible for gradually increasing number of infections after transrectal prostate biopsy. In daily clinical practice, antibacterial efficacy is evaluated only in vitro, by measuring the reaction of bacteria with an antimicrobial agent in culture media (i.e. calculation of minimal inhibitory concentration). Such approach, however, has no relation to the treated tissue characteristics and might be highly misleading. Thus, the objective of this study was to develop, with the use of Design of Experiments approach, a reliable, specific and sensitive ultra-high performance liquid chromatography- diode array detection method for the quantitative analysis of levofloxacin in plasma and prostate tissue samples obtained from patients undergoing prostate biopsy. Moreover, correlation study between concentrations observed in plasma samples vs prostatic tissue samples was performed, resulting in better understanding, evaluation and optimization of the fluoroquinolone-based antimicrobial prophylaxis during transrectal ultrasound guided prostate biopsy. Box-Behnken design was employed to optimize chromatographic conditions of the isocratic elution program in order to obtain desirable retention time, peak symmetry and resolution of levofloxacine and ciprofloxacine (internal standard) peaks. Fractional Factorial design 2(4-1) with four center points was used for screening of significant factors affecting levofloxacin extraction from the prostatic tissue. Due to the limited number of tissue samples the prostatic sample preparation procedure was further optimized using Central Composite design. Design of Experiments approach was also utilized for evaluation of parameter robustness. The method was found linear over the range of 0.030-10μg/mL for human plasma and 0.300-30μg/g for human prostate tissue samples. The intra-day and inter-day variability for levofloxacine from both plasma and prostate samples were less than 10%, with accuracies between 93 and 108% of the nominal values. The limit of detection and the limit of quantification for human plasma were 0.01μg/mL and 0.03μg/mL, respectively. For the prostate tissue, the limit of detection and the limit of quantification were 0.1μg/g and 0.3μg/g, respectively. The average recoveries of levofloxacin were in the range from 99 to 106%. Also, the method fulfills requirements of robustness what was determined and proved by Design of Experiments. The developed method was successfully applied to examine prostate tissue and plasma samples from 140 hospitalized patients enrolled into the clinical study, 12h after oral administration of LVF at a dose of 500mg. The mean (±SD) LVF concentration in prostate was 6.22±3.52μg/g and in plasma 2.54±1.14μg/mL. Due to simplicity of the method and relative small amount of sample needed for the assay, the method can be applied in clinical practice for monitoring of LVF concentrations in plasma and prostate gland. Copyright © 2016 Elsevier B.V. All rights reserved.

Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy.

PubMed

Koontz, Bridget F; Das, Shiva; Temple, Kathy; Bynum, Sigrun; Catalano, Suzanne; Koontz, Jason I; Montana, Gustavo S; Oleson, James R

2009-01-01

Adjuvant radiotherapy for locally advanced prostate cancer improves biochemical and clinical disease-free survival. While comparisons in intact prostate cancer show a benefit for intensity modulated radiation therapy (IMRT) over 3D conformal planning, this has not been studied for post-prostatectomy radiotherapy (RT). This study compares normal tissue and target dosimetry and radiobiological modeling of IMRT vs. 3D conformal planning in the postoperative setting. 3D conformal plans were designed for 15 patients who had been treated with IMRT planning for salvage post-prostatectomy RT. The same computed tomography (CT) and target/normal structure contours, as well as prescription dose, was used for both IMRT and 3D plans. Normal tissue complication probabilities (NTCPs) were calculated based on the dose given to the bladder and rectum by both plans. Dose-volume histogram and NTCP data were compared by paired t-test. Bladder and rectal sparing were improved with IMRT planning compared to 3D conformal planning. The volume of the bladder receiving at least 75% (V75) and 50% (V50) of the dose was significantly reduced by 28% and 17%, respectively (p = 0.002 and 0.037). Rectal dose was similarly reduced, V75 by 33% and V50 by 17% (p = 0.001 and 0.004). While there was no difference in the volume of rectum receiving at least 65 Gy (V65), IMRT planning significant reduced the volume receiving 40 Gy or more (V40, p = 0.009). Bladder V40 and V65 were not significantly different between planning modalities. Despite these dosimetric differences, there was no significant difference in the NTCP for either bladder or rectal injury. IMRT planning reduces the volume of bladder and rectum receiving high doses during post-prostatectomy RT. Because of relatively low doses given to the bladder and rectum, there was no statistically significant improvement in NTCP between the 3D conformal and IMRT plans.

Analysis of Thermally Denatured Depth in Laser Vaporization for Benign Prostatic Hyperplasia using a Simulation of Light Propagation and Heat Transfer (secondary publication)

PubMed Central

Takada, Junya; Honda, Norihiro; Hazama, Hisanao; Ioritani, Naomasa

2016-01-01

Background and Aims: Laser vaporization of the prostate is expected as a less invasive treatment for benign prostatic hyperplasia (BPH), via the photothermal effect. In order to develop safer and more effective laser vaporization of the prostate, it is essential to set optimal irradiation parameters based on quantitative evaluation of temperature distribution and thermally denatured depth in prostate tissue. Method: A simulation model was therefore devised with light propagation and heat transfer calculation, and the vaporized and thermally denatured depths were estimated by the simulation model. Results: The results of the simulation were compared with those of an ex vivo experiment and clinical trial. Based on the accumulated data, the vaporized depth strongly depended on the distance between the optical fiber and the prostate tissue, and it was suggested that contact laser irradiation could vaporize the prostate tissue most effectively. Additionally, it was suggested by analyzing thermally denatured depth comprehensively that laser irradiation at the distance of 3 mm between the optical fiber and the prostate tissue was useful for hemostasis. Conclusions: This study enabled quantitative and reproducible analysis of laser vaporization for BPH and will play a role in clarification of the safety and efficacy of this treatment. PMID:28765672

Prostate histotripsy for BPH: initial canine results

NASA Astrophysics Data System (ADS)

Roberts, William W.; Hall, Timothy L.; Hempel, Christopher R.; Cain, Charles A.

2009-02-01

Histotripsy is an extracorporeal ablative technology that utilizes microsecond pulses of intense ultrasound (< 1% duty cycle) to produce nonthermal, mechanical fractionation of targeted tissue. We have previously demonstrated the feasibility of histotripsy prostate ablation. In this study we sought to assess the chronic tissue response, tolerability and safety of histotripsy in a chronic in vivo canine model. Five acute and thirteen chronic canine subjects were anesthetized and treated with histotripsy targeting the prostate. Pulses consisted of 3 cycle bursts of 750 kHz ultrasound at a repetition rate of 300 Hz delivered transabdominally from a highly focused 15 cm aperture array. Transrectal ultrasound imaging provided accurate targeting and real-time monitoring of histotripsy treatment. Prostates were harvested at 0, 7, 28, or 56 days after treatment. Consistent mechanical tissue fractionation and debulking of prostate tissue was seen acutely and at delayed time points without collateral injury. Urothelialization of the treatment cavity was apparent 28 days after treatment. Canine subjects tolerated histotripsy with minimal hematuria or discomfort. Only mild transient lab abnormalities were noted. Histotripsy is a promising non-invasive therapy for prostate tissue fractionation and debulking that appears safe and well tolerated without systemic side effects in the canine model.

Evaluation of fluid absorption during holmium laser enucleation of prostate by breath ethanol technique.

PubMed

Shah, Hemendra N; Kausik, Vikram; Hegde, Sunil; Shah, Jignesh N; Bansal, Manish B

2006-02-01

In a prospective manner we studied various factors affecting fluid absorption during HoLEP. We also simultaneously evaluated changes in serum electrolytes and hemoglobin decrease during HoLEP. This prospective study comprised of 53 patients who underwent HoLEP at our institute. Irrigation fluid was normal saline tagged with ethanol (1% w/v). Intraoperatively a standard breath analyzer was used to monitor expired breath ethanol levels during the procedure at 10-minute intervals. Patients who absorbed irrigating fluid as indicated by positive intraoperative breath tests were considered absorbers. Serum electrolyte and hemoglobin estimations were done before and after surgery. Total irrigation time, amount of irrigation fluid used, weight of resected tissue and presence of capsular perforation were recorded. Statistical analysis was performed to observe the effects of various factors on the amount of intraoperative fluid absorption. Of 53 patients studied 14 (26.41%) demonstrated fluid absorption in the range of 213 to 930 ml (mean 459). Preoperative prostate weight, total irrigation time, amount of irrigation fluid used and resected tissue weight were all significantly greater in absorbers. Similarly, absorbers had a statistically significant decrease in hemoglobin level postoperatively. There was no statistically significant change in serum electrolytes between absorbers and nonabsorbers. Preoperative weight of prostate, total irrigation time, amount of irrigation fluid used and weight of resected tissue all directly influence the amount of fluid absorption during HoLEP. There is no significant change in serum electrolytes and no risk of the transurethral resection syndrome.

Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model.

PubMed

Giangreco, Angeline A; Dambal, Shweta; Wagner, Dennis; Van der Kwast, Theodorus; Vieth, Reinhold; Prins, Gail S; Nonn, Larisa

2015-04-01

Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal-epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-α, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro-inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, the prostatic epithelium appears to be the main producer of 1,25(OH)2D. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma-epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of connexin 43 in the maintenance of spontaneous activity in the guinea pig prostate gland

PubMed Central

Dey, Anupa; Kusljic, Snezana; Lang, Richard J; Exintaris, Betty

2010-01-01

BACKGROUND AND PURPOSE To investigate the role of connexin 43 in the maintenance of spontaneous activity in prostate tissue from young and old guinea pigs. EXPERIMENTAL APPROACH Conventional intracellular microelectrode and tension recording techniques, coupled with Western blot analysis and immunohistochemistry for connexin 43 (CX43) were used. The effects of three gap junction uncouplers, 18β glycyrrhetinic acid (10 µM, 40 µM), carbenoxolone (10 µM, 50 µM) and octanol (0.5 mM, 1 mM), were studied in cells displaying slow wave activity and on spontaneously contracting tissue from prostate glands of young (2–5 months) and old (9–16 months) guinea pigs. KEY RESULTS 18β Glycyrrhetinic acid (40 µM), carbenoxolone (50 µM) or octanol (0.5 mM) abolished slow wave activity in prostate tissue from young and old guinea pigs and depolarized membrane potential by approximately 5 mV. These treatments also abolished all contractions in both sets of prostate tissue. These effects were reversed upon washout. Western blot analysis and CX43 immunohistochemistry showed that there was no age-related difference in the expression and distribution of CX43 in prostate tissues. CONCLUSION AND IMPLICATIONS When gap junctional communication via CX43 was disrupted, spontaneous activity was abolished at a cellular and whole tissue level; CX43 is therefore essential for the maintenance of spontaneous slow wave activity and subsequent contractile activity in the guinea pig prostate gland. PMID:20735413

Loss of miR-100 enhances migration, invasion, epithelial-mesenchymal transition and stemness properties in prostate cancer cells through targeting Argonaute 2.

PubMed

Wang, Min; Ren, Dong; Guo, Wei; Wang, Zeyu; Huang, Shuai; Du, Hong; Song, Libing; Peng, Xinsheng

2014-07-01

Evidence in literature has demonstrated that some microRNAs (miRNAs) play a pivotal role in most solid tumor metastasis. Previous studies have showed that miR-100 is downregulated in human prostate cancer tissue compared to normal prostate and also significantly decreased in bone metastatic prostate cancer samples compared with primary prostate cancer. Argonaute 2 (AGO2) is the core effector protein of the miRNA-induced silencing complex and overexpression of AGO2 might enhance tumor metastasis. However, it is unknown whether and how miR-100 and AGO2 regulates metastasis of prostate cancer. Here, we report that miR-100 negatively regulated migration, invasion, epithelial-mesenchymal transition (EMT), colony formation, spheroid formation and expression of the stemness factors c-Myc, Oct4 and Klf4 in PC-3 and DU145 cells. Furthermore, miR-100 expression was negatively correlated with bone metastasis of prostate cancer patients. Notably, luciferase assay showed that AGO2 was a direct target of miR-100. Downregulation of AGO2 repressed migration, invasion, EMT and stemness of prostate cancer cells, and reversed the effects seen with miR-100 downregulation. Downregulation of AGO2 enhanced expression of miR-34a and miR-125b which can suppress migration, invasion, EMT and stemness of cancer cells. Taken together, our findings indicate that loss of miR-100 promotes the metastatic ability of prostate cancer cells at least partially by upregulating AGO2 expression through modulating migration, invasion, EMT and stemness of cancer cells, and suggest that miR-100/AGO2 may play an important role in regulating the metastasis of prostate cancer and is a potential target of prevention and therapy.

A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer.

PubMed

Frigerio, B; Fracasso, G; Luison, E; Cingarlini, S; Mortarino, M; Coliva, A; Seregni, E; Bombardieri, E; Zuccolotto, G; Rosato, A; Colombatti, M; Canevari, S; Figini, M

2013-06-01

Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers. Published by Elsevier Ltd.

Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Jingjing; Xu, Chen; Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003

Abstracts: MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibitmore » apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3′UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. -- Highlights: •miR-182-5p is the mostly up-regulated miRNA in Chinese prostate cancer. •miR-182-5p is regulated by androgen receptor. •miR-182-5p promotes prostate cancer progression. •miR-182-5p regulates ARRDC3/ITGB4 pathway.« less

Up regulation of the steroid hormone synthesis regulator HSD3B2 is linked to early PSA recurrence in prostate cancer.

PubMed

Neubauer, Emily; Latif, Morwari; Krause, Jenny; Heumann, Asmus; Armbrust, Moritz; Luehr, Clara; Fraune, Christoph; Hube-Magg, Claudia; Kluth, Martina; Möller-Koop, Christina; Sauter, Guido; Simon, Ronald; Beyer, Burkhard; Pompe, Raisa S; Thederan, Imke; Schlomm, Thorsten; Büscheck, Franziska

2018-05-24

HSD3B2 plays a crucial role in steroid hormone biosynthesis and is thus of particular interest in hormone dependent tumors such as prostate cancer. To clarify the clinical relevance of HSD3B2 expression in prostate cancer, we analyzed HSD3B2 protein expression by immunohistochemistry on our preexisting tissue microarray with 12.247 annotated cancers. Compared with normal tissue cytoplasmic HSD3B2 staining was stronger in prostate cancers. In 9371 interpretable cancers, HSD3B2 expression was found in 95.5% of cancers and was considered weak in 29.9%, moderate in 40.7% and strong in 24.9%. HSD3B2 up regulation was linked to advanced pathological tumor stage (pT), high Gleason grade, elevated preoperative PSA levels (p < 0.0001 each), lymph node metastasis (p = 0.0019), accelerated cell proliferation (p < 0.0001), androgen receptor (AR) expression (p < 0.0001), and early biochemical recurrence (p < 0.0001). HSD3B2 up regulation was only marginally more frequent in ERG positive (98%) than in ERG negative cancers (94%; p < 0.0001) and was strongly linked to deletions of 5q and 6q (p < 0.0001 each). Multivariate analyses showed that the prognostic impact of HSD3B2 expression was independent of established preoperative, but not of postoperative prognostic parameters. In summary, the results of our study demonstrate that HSD3B2 is strongly up regulated in a fraction of prostate cancers that are characterized by increased AR signaling, adverse tumor phenotype and early biochemical recurrence. Copyright © 2018 Elsevier Inc. All rights reserved.

VPAC1 targeted 64Cu-TP3805 PET imaging of prostate cancer: preliminary evaluation in man

PubMed Central

Tripathi, Sushil; Trabulsi, Edouard J; Gomella, Leonard; Kim, Sung; McCue, Peter; Intenzo, Charles; Birbe, Ruth; Gandhe, Ashish; Kumar, Pardeep; Thakur, Mathew

2015-01-01

Objectives To evaluate 64Cu-TP3805 as a novel biomolecule, to PET image prostate cancer (PC), at the onset of which VPAC1, the superfamily of G-protein coupled receptors, is expressed in high density on PC cells, but not on normal cells. Methods 25 patients undergoing radical prostatectomy were PET/CT imaged preoperatively with 64Cu-TP3805. Standardized uptake values (SUVmax) were determined, malignant lesions (SUV > 1.0) counted, and compared with histologic findings. Whole mount pathology slides from 6 VPAC1 PET imaged patients, 3 BPH patients, one malignant and one benign lymph node underwent digital autoradiography (DAR) after 64Cu-TP3805 incubation and compared to H&E stained slides. Results In 25 patient PET imaging, 212 prostate gland lesions had SUVmax > 1.0 vs.127 lesions identified by histology of biopsy tissues. The status of the additional 85 PET identified prostate lesions remains to be determined. In 68 histological slides from 6 PET imaged patients, DAR identified 105/107 PC foci, 19/19 HGPIN, and ejaculatory ducts and verumontanum involved with cancer. Additionally, DAR found 9 PC lesions not previously identified histologically. The positive and negative lymph nodes were correctly identified and in 3/3 BPH patients and 5/5 cysts, DAR was negative. Conclusion This feasibility study demonstrated that 64Cu-TP3805 delineates PC in vivo and ex vivo, provided normal images for benign masses, and is worthy of further studies. PMID:26519886

Herniated Thoracic Spleen Mimicking Lung Metastasis on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT in a Patient With Prostate Cancer.

PubMed

Malik, Dharmender; Basher, Rajender K; Sood, Apurva; Devana, Sudheer Kumar; Bhattacharya, Anish; Mittal, Bhagwant Rai

2017-06-01

We report a case of clinically asymptomatic patient of prostate cancer who was previously subjected to radical prostatectomy presenting with a rising serum prostate-specific antigen level of 6.6 ng/mL. Whole-body PET/CT with Ga-labeled prostate-specific membrane antigen ligand was performed to assess for disease recurrence, which revealed an intense tracer uptake in a soft tissue mass in left hemithorax mimicking lung metastasis; which later turned out to be splenic tissue.

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity

PubMed Central

Garcia, Emmanuel; Becker, Veronika G. C.; McCullough, Danielle J.; Stabley, John N.; Gittemeier, Elizabeth M.; Opoku-Acheampong, Alexander B.; Sieman, Dietmar W.

2016-01-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10−9 to 10−4 M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. PMID:27125846

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

PubMed

Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

2016-07-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

Concentration of ofloxacin in canine prostate tissue and prostate fluid after intraprostatic injection of biodegradable sustained-releasing microspheres containing ofloxacin.

PubMed

Bahk, J Y; Hyun, J S; Lee, J Y; Kim, J; Cho, Y H; Lee, J H; Park, J S; Kim, M O

2000-05-01

Excellent treatment results in chronic prostatitis by direct intra-prostatic injection of antibiotic were reported several decades ago with only minimal scientific background. We examined the distribution, in prostatic tissue and fluid, of the antibiotic in canines after intra-prostatic injection of biodegradable sustained-releasing microspheres containing 12 mg. of ofloxacin. A total of 36 male dogs, 12 controls and 24 experimental, older than 2 years, were used. Experimental dogs were given biodegradable sustained releasing microspheres containing ofloxacin 12 mg. and poly(D,L-lactic) acid 28 mg., designed to release over more than a 4 week period. The 12 control animals were divided into 2 groups, and oral ofloxacin 100 mg. was given twice a day for 2 and 4 weeks. The 24 experimental animals were divided into 4 subgroups of 6 dogs each, 4 for prostatic tissue and 2 for prostatic fluid level of ofloxacin determination. Anesthesia was initiated with ketamine HCl and xylazine, and maintained with intermittent ketamine HCl. In the experimental groups, 1 ml. of resolved formula was injected into one lobe of surgically exposed prostates. The concentration of ofloxacin was measured by high performance liquid chromatography (HPLC) of blood, prostatic tissue and prostatic fluid. Pilocarpine 0.5 mg./kg. was used for the collection of the prostatic fluid. The total ofloxacin of controls were 2,800 (2 weeks) and 5,600 (4 weeks) mg. In control groups, tissue concentrations of ofloxacin were relatively even at all segments of prostate, 7.4 +/- 0.8 (2 weeks) and 9.2 +/- 1.1 microg./ml. (4 weeks). The blood level ranged between 3.6 to 5.1 microg./ml. The prostatic fluid level ranged from 3.1 to 5.7 microg. /ml. In the experimental groups, the tissue levels of ofloxacin were 10.5 +/- 3.0 (1 week), 13.8 +/- 4.5 (2 weeks), 7.1 +/- 0.9 (3 weeks) and 7.7 +/- 3.0 microg./ml. (4 weeks) in the injected lobe. The opposite lobes were 8.0 +/- 1.1 (1 week), 10.2 +/- 4.2 (2 weeks), 5. 1 +/- 1.4 (3 weeks) and 7.6 +/- 0.8 (4 weeks) microg./ml. The blood level in the experimental groups ranged between 0.16 to 0.59 microg./ml. The prostate fluid level ranged from 2.9 to 6.1 microg./ml. in 8 dogs. Upon pathologic examination, the microspheres were interposed between prostate stroma and their size was reduced over time. Our study indicates that there is communication between the right and left prostate lobes. Direct injection of biodegradable sustained releasing ofloxacin formula into the prostate may be a substitute for long term antibiotic medication in humans for chronic prostatitis in the future without hurting the minimal inhibitory concentration(MIC)90.

SU-F-T-46: The Effect of Inter-Seed Attenuation and Tissue Composition in Prostate 125I Brachytherapy Dose Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tamura, K; Araki, F; Ohno, T

Purpose: To investigate the difference of dose distributions with/without the effect of inter-seed attenuation and tissue compositions in prostate {sup 125}I brachytherapy dose calculations, using Monte Carlo simulations of Particle and Heavy Ion Transport code System (PHITS). Methods: The dose distributions in {sup 125}I prostate brachytherapy were calculated using PHITS for non-simultaneous and simultaneous alignments of STM1251 sources in water or prostate phantom for six patients. The PHITS input file was created from DICOM-RT file which includes source coordinates and structures for clinical target volume (CTV) and organs at risk (OARs) of urethra and rectum, using in-house Matlab software. Photonmore » and electron cutoff energies were set to 1 keV and 100 MeV, respectively. The dose distributions were calculated with the kerma approximation and the voxel size of 1 × 1 × 1 mm{sup 3}. The number of incident photon was set to be the statistical uncertainty (1σ) of less than 1%. The effect of inter-seed attenuation and prostate tissue compositions was evaluated from dose volume histograms (DVHs) for each structure, by comparing to results of the AAPM TG-43 dose calculation (without the effect of inter-seed attenuation and prostate tissue compositions). Results: The dose reduction due to the inter-seed attenuation by source capsules was approximately 2% for CTV and OARs compared to those of TG-43. In additions, by considering prostate tissue composition, the D{sub 90} and V{sub 100} of CTV reduced by 6% and 1%, respectively. Conclusion: It needs to consider the dose reduction due to the inter-seed attenuation and tissue composition in prostate {sup 125}I brachytherapy dose calculations.« less

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality.

PubMed

Fiano, Valentina; Zugna, Daniela; Grasso, Chiara; Trevisan, Morena; Delsedime, Luisa; Molinaro, Luca; Gillio-Tos, Anna; Merletti, Franco; Richiardi, Lorenzo

2017-01-02

Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982-1988 and 1993-1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95-2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (<75%) vs. high (>80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03-21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression.

Histopathological classification criteria of rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, Xianjin; Zhong, Shan; Xu, Tianyuan; Xia, Leilei; Zhang, Xiaohua; Zhu, Zhaowei; Zhang, Minguang; Shen, Zhoujun

2015-02-01

A variety of murine models of experimental prostatitis that mimic the phenotype of human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been developed. However, there is still a lack of explicit diagnosis criteria about those animal model. Our study is to establish histopathological classification criteria, which will be conducive to evaluate the animal models. We firstly established a rat model of experimental autoimmune prostatitis that is considered a valid model for CP/CPPS. For modelling, male Sprague-Dawley rats were immunized with autologous prostate tissue homogenate supernatant emulsified with complete Freund's adjuvant by subcutaneous injection into abdominal flank and simultaneously immunized with pertussis-diphtheria-tetanus vaccine by intraperitoneal injection. Three immunizations were administered semimonthly. At the 45th day, animals were killed, and prostate tissues were examined for morphology. Histologically, the prostate tissues were characterized by lymphoproliferation, atrophy of acini, and chronic inflammatory cells infiltration in the stromal connective tissue around the acini or ducts. Finally, we built histopathological classification criteria incorporating inflammation locations (mesenchyme, glands, periglandular tissues), ranges (focal, multifocal, diffuse), and grades (grade I-IV). To verify the effectiveness and practicability of the histopathological classification criteria, we conducted the treatment study with one of the alpha blockers, tamsulosin. The histopathological classification criteria of rat model of CP/CPPS will serve for further research of the pathogenesis and treatment strategies of the disease.

Irradiation of the prostate and pelvic lymph nodes with an adaptive algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hwang, A. B.; Chen, J.; Nguyen, T. B.

2012-02-15

Purpose: The simultaneous treatment of pelvic lymph nodes and the prostate in radiotherapy for prostate cancer is complicated by the independent motion of these two target volumes. In this work, the authors study a method to adapt intensity modulated radiation therapy (IMRT) treatment plans so as to compensate for this motion by adaptively morphing the multileaf collimator apertures and adjusting the segment weights. Methods: The study used CT images, tumor volumes, and normal tissue contours from patients treated in our institution. An IMRT treatment plan was then created using direct aperture optimization to deliver 45 Gy to the pelvic lymphmore » nodes and 50 Gy to the prostate and seminal vesicles. The prostate target volume was then shifted in either the anterior-posterior direction or in the superior-inferior direction. The treatment plan was adapted by adjusting the aperture shapes with or without re-optimizing the segment weighting. The dose to the target volumes was then determined for the adapted plan. Results: Without compensation for prostate motion, 1 cm shifts of the prostate resulted in an average decrease of 14% in D-95%. If the isocenter is simply shifted to match the prostate motion, the prostate receives the correct dose but the pelvic lymph nodes are underdosed by 14% {+-} 6%. The use of adaptive morphing (with or without segment weight optimization) reduces the average change in D-95% to less than 5% for both the pelvic lymph nodes and the prostate. Conclusions: Adaptive morphing with and without segment weight optimization can be used to compensate for the independent motion of the prostate and lymph nodes when combined with daily imaging or other methods to track the prostate motion. This method allows the delivery of the correct dose to both the prostate and lymph nodes with only small changes to the dose delivered to the target volumes.« less

The Role of Stromally Produced Cathepsin D in Promoting Prostate Tumorigenesis

DTIC Science & Technology

2014-11-01

was related to TGF-β activity. It has been previously shown in in vitro experiments that CathD can liberate TGF-β from the latency inhibitor complex...was performed fol- lowing a protocol that was described previously [31]. CathepsinDandProstateCancer 3 The Prostate Tissue slides were then incubated... low grade and high grade malignant prostate tissue. P-values less than 0.05 were consid- ered statistically significant. RESULTS

Laser evaporation of the prostate: preliminary findings in canines

NASA Astrophysics Data System (ADS)

Kuntzman, R. S.; Malek, Reza S.; Barrett, David M.; Bostwick, David G.

1996-05-01

Purpose: We evaluated the ability of KTP laser to evaporate prostatic tissue in vivo and compared the results with historical Nd:YAG treated controls. Methods: Five dogs underwent anterograde transurethral evaporation of the prostate (TUEP) with KTP laser at 38 watts and were sacrificed 48 hours after surgery. Results: All procedures were hemostatic and without complications. Laser evaporation produced cavities within the prostate ranging from 2.5 to 3.2 cm in diameter (average equals 2.9 cm) that were free of necrotic tissue. Conclusions: Preliminary findings in this initial canine study of laser evaporation of the prostate, show that KTP laser produces large spherical cavities within the prostate in a hemostatic fashion. These cavities are free of necrotic tissue. In addition, these cavities are comparable in size to those that have been observed 4 to 8 weeks following Nd:YAG VLAP and are significantly larger than the acute cavities produced by Nd:YAG TUEP.

Impact of pelvic nodal irradiation with intensity-modulated radiotherapy on treatment of prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Robert A.; Hannoun-Levi, Jean-Michel; Horwitz, Eric

2006-10-01

Purpose: The aim of this study was to evaluate the feasibility of treating the pelvic lymphatic regions during prostate intensity-modulated radiotherapy (IMRT) with respect to our routine acceptance criteria. Methods and Materials: A series of 10 previously treated prostate patients were randomly selected and the pelvic lymphatic regions delineated on the fused magnetic resonance/computed tomography data sets. A targeting progression was formed from the prostate and proximal seminal vesicles only to the inclusion of all pelvic lymphatic regions and presacral region resulting in 5 planning scenarios of increasing geometric difficulty. IMRT plans were generated for each stage for two acceleratormore » manufacturers. Dose volume histogram data were analyzed with respect to dose to the planning target volumes, rectum, bladder, bowel, and normal tissue. Analysis was performed for the number of segments required, monitor units, 'hot spots,' and treatment time. Results: Both rectal endpoints were met for all targets. Bladder endpoints were not met and the bowel endpoint was met in 40% of cases with the inclusion of the extended and presacral lymphatics. A significant difference was found in the number of segments and monitor units with targeting progression and between accelerators, with the smaller beamlets yielding poorer results. Treatment times between the 2 linacs did not exhibit a clinically significant difference when compared. Conclusions: Many issues should be considered with pelvic lymphatic irradiation during IMRT delivery for prostate cancer including dose per fraction, normal structure dose/volume limits, planning target volumes generation, localization, treatment time, and increased radiation leakage. We would suggest that, at a minimum, the endpoints used in this work be evaluated before beginning IMRT pelvic nodal irradiation.« less

PSCA expression is associated with favorable tumor features and reduced PSA recurrence in operated prostate cancer.

PubMed

Heinrich, Marie-Christine; Göbel, Cosima; Kluth, Martina; Bernreuther, Christian; Sauer, Charlotte; Schroeder, Cornelia; Möller-Koop, Christina; Hube-Magg, Claudia; Lebok, Patrick; Burandt, Eike; Sauter, Guido; Simon, Ronald; Huland, Hartwig; Graefen, Markus; Heinzer, Hans; Schlomm, Thorsten; Heumann, Asmus

2018-05-31

Prostate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear. To clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry. PSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001). The absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests.

Dosimetric effects of patient rotational setup errors on prostate IMRT treatments

NASA Astrophysics Data System (ADS)

Fu, Weihua; Yang, Yong; Li, Xiang; Heron, Dwight E.; Saiful Huq, M.; Yue, Ning J.

2006-10-01

The purpose of this work is to determine dose delivery errors that could result from systematic rotational setup errors (ΔΦ) for prostate cancer patients treated with three-phase sequential boost IMRT. In order to implement this, different rotational setup errors around three Cartesian axes were simulated for five prostate patients and dosimetric indices, such as dose-volume histogram (DVH), tumour control probability (TCP), normal tissue complication probability (NTCP) and equivalent uniform dose (EUD), were employed to evaluate the corresponding dosimetric influences. Rotational setup errors were simulated by adjusting the gantry, collimator and horizontal couch angles of treatment beams and the dosimetric effects were evaluated by recomputing the dose distributions in the treatment planning system. Our results indicated that, for prostate cancer treatment with the three-phase sequential boost IMRT technique, the rotational setup errors do not have significant dosimetric impacts on the cumulative plan. Even in the worst-case scenario with ΔΦ = 3°, the prostate EUD varied within 1.5% and TCP decreased about 1%. For seminal vesicle, slightly larger influences were observed. However, EUD and TCP changes were still within 2%. The influence on sensitive structures, such as rectum and bladder, is also negligible. This study demonstrates that the rotational setup error degrades the dosimetric coverage of target volume in prostate cancer treatment to a certain degree. However, the degradation was not significant for the three-phase sequential boost prostate IMRT technique and for the margin sizes used in our institution.

Expression of basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma.

PubMed

Mydlo, J H; Michaeli, J; Heston, W D; Fair, W R

1988-01-01

In our previous work we demonstrated that prostate-derived growth factor (PrGF) is homologous to basic fibroblast growth factor (bFGF), not acidic fibroblast growth factor (aFGF). Using Northern blot analysis we now show that the messenger RNA for bFGF but not aFGF is expressed in benign prostatic hyperplastic (BPH) tissue as well as in carcinoma of the prostate (CAP). This not only corroborates our previous results, but suggests that PrGF is produced locally and not merely stored in the prostate. The demonstration of local production of bFGF by prostate tissue may indicate that this growth factor plays a role, either alone or in conjunction with other factors, in the etiology of benign hyperplasia or prostatic cancer.

Will metformin postpone high-fat diet promotion of TRAMP mouse prostate cancer development and progression?

PubMed

Xu, Hua; Hu, Meng-Bo; Bai, Pei-de; Zhu, Wen-Hui; Ding, Qiang; Jiang, Hao-Wen

2014-12-01

We aimed to examine the effect of high-fat diet (HFD) on prostate cancer (PCa) development and progression and to investigate whether metformin would postpone PCa development and progression promoted by HFD. TRAMP mice were randomly divided into three groups: normal diet group, HFD group and metformin-HFD (Met-HFD) group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24(th), and 28th week, respectively. Serum levels of insulin and IGF-1 were tested by ELISA. Prostate tissue of TRAMP mice was used for HE staining. A total of 17 deaths of TRAMP mice were observed, including 3 (10 %) from the normal diet group, 10 (33.33 %) from the HFD group, and 4 (13.33 %) from Met-HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P = 0.028), and metformin could moderately decrease the mortality rate by 60.01 % (P = 0.067). Tumor formation rates were not significantly different among the three groups. Levels of glucose, insulin, and IGF-1 tended to increase with TRAMP mice's age in HFD group. TRAMP mice from HFD group had higher serum insulin and IGF-1 levels. A moderate decrease in IGF-1 was also seen in Met-HFD group. HFD could promote TRAMP mouse PCa development and progression and metformin had moderate effect of reducing PCa mortality rate with a decrease in serum IGF-1 level.

Next-gen tissue: preservation of molecular and morphological fidelity in prostate tissue.

PubMed

Gillard, Marc; Tom, Westin R; Antic, Tatjana; Paner, Gladell P; Lingen, Mark W; VanderWeele, David J

2015-01-01

Personalization of cancer therapy requires molecular evaluation of tumor tissue. Traditional tissue preservation involves formalin fixation, which degrades the quality of nucleic acids. Strategies to bank frozen prostate tissue can interfere with diagnostic studies. PAXgene is an alternative fixative that preserves protein and nucleic acid quality. Portions of prostates obtained from autopsy specimens were fixed in either 10% buffered formalin or PAXgene, and processed and embedded in paraffin. Additional sections were immediately embedded in OCT and frozen. DNA and RNA were extracted from the formalin-fixed, PAXgene-fixed, or frozen tissue. Quantitative PCR was used to compare the quality of DNA and RNA obtained from all three tissue types. In addition, 5 μm sections were cut from specimens devoid of cancer and from prostate cancer specimens obtained at prostatectomy and fixed in PAXgene. They were either stained with hematoxylin and eosin or interrogated with antibodies for p63, PSA and p504. Comparable tissue morphology was observed in both the formalin and PAXgene-fixed specimens. Similarly, immunohistochemical expression of the P63, PSA and P504 proteins was comparable between formalin and PAXgene fixation techniques. DNA from the PAXgene-fixed tissue was of similar quality to that from frozen tissue. RNA was also amplified with up to 8-fold greater efficiency in the PAXgene fixed tissue compared to the formalin-fixed tissue. Prostate specimens fixed with PAXgene have preserved histologic morphology, stain appropriately, and have preserved quality of nucleic acids. PAXgene fixation facilitates the use of prostatectomy tissue for molecular biology techniques such as next-generation sequencing.

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

PubMed Central

Pirovano, Giacomo; Ashton, Thomas M; Herbert, Katharine J; Bryant, Richard J; Verrill, Clare L; Cerundolo, Lucia; Buffa, Francesca M; Prevo, Remko; Harrap, Iona; Ryan, Anderson J; Macaulay, Valentine; McKenna, William G; Higgins, Geoff S

2017-01-01

Background: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. Methods: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. Results: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G1/S transition and G2/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. Conclusions: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types. PMID:28677687

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy.

PubMed

Pirovano, Giacomo; Ashton, Thomas M; Herbert, Katharine J; Bryant, Richard J; Verrill, Clare L; Cerundolo, Lucia; Buffa, Francesca M; Prevo, Remko; Harrap, Iona; Ryan, Anderson J; Macaulay, Valentine; McKenna, William G; Higgins, Geoff S

2017-08-08

Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G 1 /S transition and G 2 /M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.

Selinexor in Treating Patients With Abiraterone Acetate and/or Enzalutamide Refractory Metastatic Castration-Resistant Prostate Cancer

ClinicalTrials.gov

2018-05-29

Castration Levels of Testosterone; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma in the Soft Tissue; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

PubMed Central

Ascui, Natasha; Frydenberg, Mark; Risbridger, Gail P.; Taylor, Renea A.; Watt, Matthew J.

2016-01-01

There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis. PMID:27351281

Expression of spermidine/spermine N(1) -acetyl transferase (SSAT) in human prostate tissues is related to prostate cancer progression and metastasis.

PubMed

Huang, Wei; Eickhoff, Jens C; Mehraein-Ghomi, Farideh; Church, Dawn R; Wilding, George; Basu, Hirak S

2015-08-01

Prostate cancer (PCa) in many patients remains indolent for the rest of their lives, but in some patients, it progresses to lethal metastatic disease. Gleason score is the current clinical method for PCa prognosis. It cannot reliably identify aggressive PCa, when GS is ≤ 7. It is shown that oxidative stress plays a key role in PCa progression. We have shown that in cultured human PCa cells, an activation of spermidine/spermine N(1) -acetyl transferase (SSAT; EC 2.3.1.57) enzyme initiates a polyamine oxidation pathway and generates copious amounts of reactive oxygen species in polyamine-rich PCa cells. We used RNA in situ hybridization and immunohistochemistry methods to detect SSAT mRNA and protein expression in two tissue microarrays (TMA) created from patient's prostate tissues. We analyzed 423 patient's prostate tissues in the two TMAs. Our data show that there is a significant increase in both SSAT mRNA and the enzyme protein in the PCa cells as compared to their benign counterpart. This increase is even more pronounced in metastatic PCa tissues as compared to the PCa localized in the prostate. In the prostatectomy tissues from early-stage patients, the SSAT protein level is also high in the tissues obtained from the patients who ultimately progress to advanced metastatic disease. Based on these results combined with published data from our and other laboratories, we propose an activation of an autocrine feed-forward loop of PCa cell proliferation in the absence of androgen as a possible mechanism of castrate-resistant prostate cancer growth. © 2015 Wiley Periodicals, Inc.

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

PubMed

Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

2012-02-01

Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer

DTIC Science & Technology

2005-01-01

that AGK is localized to the mitochondria . Using a matched human tumor/normal tissue expression array, we found that AGK expression was upregulated in...absence of yellow color in the merged images (Fig. 2A). On the other hand, AGK expression clearly co- localized with mitochondria stained with MitoTracker... localized to the mitochondria (Hiroyama and Takenawa, 1999). This LPA phosphatase has been suggested to regulate lipid metabolism in mitochondria by

Modulation of T-Cell Activation in an Experimental Model of Mammary Carcinoma

DTIC Science & Technology

1999-07-01

depigmentation, reminiscent of the vitiligo that occurs in melanoma patients undergoing immunotherapy (3). In the transgenic prostate cancer model, we...extrusion in the hair follicles that is not observed in unaffected areas of the coat. This depigmentation is reminiscent of the vitiligo syndrome observed in...and a GM-CSF-expressing Vaccine. manuscript submitted. 3. Rosenberg, S.A., and D.E. White. 1996. Vitiligo in patients with melanoma: normal tissue

WE-EF-210-07: Development of a Minimally Invasive Photo Acoustic Imaging System for Early Prostate Cancer Detection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sano, M; Yousefi, S; Xing, L

Purpose: The objective of this work is to design, implement and characterize a catheter-based ultrasound/photoacoustic imaging probe for early-diagnosis of prostate cancer and to aid in image-guided radiation therapy. Methods: The need to image across 6–10cm of tissue to image the whole prostate gland limits the resolution achievable with a transrectal ultrasound approach. In contrast, the urethra bisects the prostate gland, providing a minimally invasive pathway for deploying a high resolution ultrasound transducer. Utilizing a high-frequency (20MHz) ultrasound/photoacoustic probe, high-resolution structural and molecular imaging of the prostate tissue is possible. A custom 3D printed probe containing a high-frequency single-element ultrasoundmore » transducer is utilized. The diameter of the probe is designed to fit inside a Foley catheter and the probe is rotated around the central axis to achieve a circular B-scan. A custom ultrasound amplifier and receiver was set up to trigger the ultrasound pulse transmission and record the reflected signal. The reconstructed images were compared to images generated by traditional 5 MHz ultrasound transducers. Results: The preliminary results using the high-frequency ultrasound probe show that it is possible to resolve finely detailed information in a prostate tissue phantom that was not achievable with previous low-frequency ultrasound systems. Preliminary ultrasound imaging was performed on tissue mimicking phantom and sensitivity and signal-to-noise ratio of the catheter was measured. Conclusion: In order to achieve non-invasive, high-resolution, structural and molecular imaging for early-diagnosis and image-guided radiation therapy of the prostate tissue, a transurethral catheter was designed. Structural/molecular imaging using ultrasound/photoacoustic of the prostate tissue will allow for localization of hyper vascularized areas for early-stage prostate cancer diagnosis.« less

Maturation of the developing human fetal prostate in a rodent xenograft model

PubMed Central

Saffarini, Camelia M.; McDonnell, Elizabeth V.; Amin, Ali; Spade, Daniel J.; Huse, Susan M.; Kostadinov, Stefan; Hall, Susan J.; Boekelheide, Kim

2015-01-01

Background Prostate cancer is the most commonly diagnosed non-skin cancer in men. The etiology of prostate cancer is unknown, although both animal and epidemiologic data suggest that early life exposures to various toxicants, may impact DNA methylation status during development, playing an important role. Methods We have developed a xenograft model to characterize the growth and differentiation of human fetal prostate implants (gestational age 12-24 weeks) that can provide new data on the potential role of early life stressors on prostate cancer. The expression of key immunohistochemical markers responsible for prostate maturation was evaluated, including p63, cytokeratin 18, α-smooth muscle actin, vimentin, caldesmon, Ki-67, prostate specific antigen, estrogen receptor-α, and androgen receptor. Xenografts were separated into epithelial and stromal compartments using laser capture microdissection (LCM), and the DNA methylation status was assessed in >480,000 CpG sites throughout the genome. Results Xenografts demonstrated growth and maturation throughout the 200 days of post-implantation evaluation. DNA methylation profiles of laser capture micro-dissected tissue demonstrated tissue-specific markers clustered by their location in either the epithelium or stroma of human prostate tissue. Differential methylated promoter region CpG-associated gene analysis revealed significantly more stromal than epithelial DNA methylation in the 30 and 90-day xenografts. Functional classification analysis identified CpG-related gene clusters in methylated epithelial and stromal human xenografts. Conclusion This study of human fetal prostate tissue establishes a xenograft model that demonstrates dynamic growth and maturation, allowing for future mechanistic studies of the developmental origins of later life proliferative prostate disease. PMID:24038131

Using the epigenetic field defect to detect prostate cancer in biopsy negative patients.

PubMed

Truong, Matthew; Yang, Bing; Livermore, Andrew; Wagner, Jennifer; Weeratunga, Puspha; Huang, Wei; Dhir, Rajiv; Nelson, Joel; Lin, Daniel W; Jarrard, David F

2013-06-01

We determined whether a novel combination of field defect DNA methylation markers could predict the presence of prostate cancer using histologically normal transrectal ultrasound guided biopsy cores. Methylation was assessed using quantitative Pyrosequencing® in a training set consisting of 65 nontumor and tumor associated prostate tissues from University of Wisconsin. A multiplex model was generated using multivariate logistic regression and externally validated in blinded fashion in a set of 47 nontumor and tumor associated biopsy specimens from University of Washington. We observed robust methylation differences in all genes at all CpGs assayed (p <0.0001). Regression models incorporating individual genes (EVX1, CAV1 and FGF1) and a gene combination (EVX1 and FGF1) discriminated nontumor from tumor associated tissues in the original training set (AUC 0.796-0.898, p <0.001). On external validation uniplex models incorporating EVX1, CAV1 or FGF1 discriminated tumor from nontumor associated biopsy negative specimens (AUC 0.702, 0.696 and 0.658, respectively, p <0.05). A multiplex model (EVX1 and FGF1) identified patients with prostate cancer (AUC 0.774, p = 0.001) and had a negative predictive value of 0.909. Comparison between 2 separate cores in patients in this validation set revealed similar methylation defects, indicating detection of a widespread field defect. A widespread epigenetic field defect can be used to detect prostate cancer in patients with histologically negative biopsies. To our knowledge this assay is unique, in that it detects alterations in nontumor cells. With further validation this marker combination (EVX1 and FGF1) has the potential to decrease the need for repeat prostate biopsies, a procedure associated with cost and complications. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Relative mRNA expression of prostate-derived E-twenty-six factor and E-twenty-six variant 4 transcription factors, and of uridine phosphorylase-1 and thymidine phosphorylase enzymes, in benign and malignant prostatic tissue

PubMed Central

CAVAZZOLA, LUCIANE ROSTIROLA; CARVALHAL, GUSTAVO FRANCO; DEVES, CANDIDA; RENCK, DAIANA; ALMEIDA, RICARDO; SANTOS, DIóGENES SANTIAGO

2015-01-01

Prostate cancer is the most frequent urological tumor, and the second most common cancer diagnosed in men. Incidence and mortality are variable and appear to depend on behavioral factors and genetic predisposition. The prostate-derived E-twenty-six factor (PDEF) and E-twenty-six variant 4 (ETV4) transcription factors, and the thymidine phosphorylase (TP) and uridine phosphorylase-1 (UP-1) enzymes, are reported to be components of the pathways leading to tumorigenesis and/or metastasis in a number of tumors. The present study aimed to analyze the mRNA expression levels of these proteins in prostatic cancerous and benign tissue, and their association with clinical and pathological variables. Using quantitative reverse transcription polymerase chain reaction, the mRNA expression levels of PDEF, ETV4, TP and UP-1 were studied in 52 tissue samples (31 of benign prostatic hyperplasia and 21 of prostate adenocarcinomas) obtained from patients treated by transurethral resection of the prostate or by radical prostatectomy. Relative expression was assessed using the ∆-CT method. Data was analyzed using Spearman's tests for correlation. P<0.05 was considered to indicate a statistically significant difference. The results revealed that PDEF, ETV4, UP-1 and TP were expressed in 85.7, 90.5, 95.2 and 100% of the prostate cancer samples, and in 90.3, 96.8, 90.3 and 96.8% of the benign samples, respectively. PDEF and ETV4 exhibited a significantly higher relative expression level in the tumor samples compared with their benign counterparts. The relative expression of TP and UP-1 did not differ significantly between benign and cancerous prostate tissues. The relative expression of TP was moderately and significantly correlated with the expression of ETV4 in the benign tissues. The relative expression of UP-1 was significantly lower in T3 compared with T1 and T2 cancers. These findings indicate that PDEF, ETV4, TP and UP-1 are typically expressed in benign and malignant prostatic tissues. Further studies are necessary to define the role of these proteins as therapeutic targets in prostate cancer. PMID:26137165

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

PubMed

Goto, Yusuke; Kurozumi, Akira; Arai, Takayuki; Nohata, Nijiro; Kojima, Satoko; Okato, Atsushi; Kato, Mayuko; Yamazaki, Kazuto; Ishida, Yasuo; Naya, Yukio; Ichikawa, Tomohiko; Seki, Naohiko

2017-07-25

Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Inflammasomes are important mediators of prostatic inflammation associated with BPH.

PubMed

Kashyap, Mahendra; Pore, Subrata; Wang, Zhou; Gingrich, Jeffrey; Yoshimura, Naoki; Tyagi, Pradeep

2015-01-01

There is mounting evidence to support the role of inflammation in benign prostate hyperplasia (BPH), and a recent study reported expression of inflammasome derived cytokine IL-18 in prostate biopsy of BPH patients. Here we examined the expression of inflammasome-derived cytokines and activation of nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP) 1 inflammasome in a rat model of prostatic inflammation relevant to BPH. Prostatic inflammation was experimentally induced in three-month-old male Sprague-Dawley rats by intraprostatic injection (50 μL) of either 5 % formalin or saline (sham) into the ventral lobes of prostate. 7 days later, prostate and bladder tissue was harvested for analysis of inflammasome by Western blot, immunohistochemistry and downstream cytokine production by Milliplex. Expression of interleukins, CXC and CC chemokines were elevated 2-15 fold in formalin injected prostate relative to sham. Significant expression of NLRP1 inflammasome components and caspase-1 in prostate were associated with significant elevation of pro and cleaved forms of IL-1β (25.50 ± 1.16 vs 3.05 ± 0.65 pg/mg of protein) and IL-18 (1646.15 ± 182.61 vs 304.67 ± 103.95 pg/mg of protein). Relative to prostate tissue, the cytokine expression in bladder tissue was much lower and did not involve inflammasome activation. Significant upregulation of NLRP1, caspase-1 and downstream cytokines (IL-18 and IL-1β) suggests that a NLRP1 inflammasome is assembled and activated in prostate tissue of this rat model . Recapitulation of findings from human BPH specimens suggests that the inflammasome may perpetuate the inflammatory state associated with BPH. Further clarification of these pathways may offer innovative therapeutic targets for BPH-related inflammation.

[A comparison between prostatic volume measured during suprapubic ultrasonography (TAUS) and volume of the enucleated gland after open prostatectomy].

PubMed

Szewczyk, Wojciech; Prajsner, Andrzej; Kozina, Janusz; Login, Tomasz; Kaczorowski, Marek

2004-01-01

General practitioner very often uses transabdominal ultrasonograpy (TAUS) in order to measure prostatic volume. Using this method it is rather impossible to distinguish between tissue of benign prostatic hyperplasia (BPH) and prostatic tissue which forms so called surgical capsule of BPH. The aim of this study was a comparison of prostatic volume measured during suprapubic (transabdominal) ultrasonography and volume of the enucleated gland after open prostatectomy. Regarding the results authors created a nomogram based on TAUS measurement of the prostate which helps to predict the volume of BPH. They also stated that surgical capsule of the BPH makes about 1/3 of the whole volume of the prostate measured by TAUS.

Atmospheric Pressure Photoionization Tandem Mass Spectrometry of Androgens in Prostate Cancer

PubMed Central

Lih, Fred Bjørn; Titus, Mark A.; Mohler, James L.; Tomer, Kenneth B.

2010-01-01

Androgen deprivation therapy is the most common treatment option for advanced prostate cancer. Almost all prostate cancers recur during androgen deprivation therapy, and new evidence suggests that androgen receptor activation persists despite castrate levels of circulating androgens. Quantitation of tissue levels of androgens is critical to understanding the mechanism of recurrence of prostate cancer during androgen deprivation therapy. A liquid chromatography atmospheric pressure photoionization tandem mass spectrometric method was developed for quantitation of tissue levels of androgens. Quantitation of the saturated keto-steroids dihydrotestosterone and 5-α-androstanedione required detection of a novel parent ion, [M + 15]+. The nature of this parent ion was explored and the method applied to prostate tissue and cell culture with comparison to results achieved using electrospray ionization. PMID:20560527

Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer

PubMed Central

Tsavachidou, Dimitra; McDonnell, Timothy J.; Wen, Sijin; Wang, Xuemei; Vakar-Lopez, Funda; Pisters, Louis L.; Pettaway, Curtis A.; Wood, Christopher G.; Do, Kim-Anh; Thall, Peter F.; Stephens, Clifton; Efstathiou, Eleni; Taylor, Robert; Menter, David G.; Troncoso, Patricia; Lippman, Scott M.; Logothetis, Christopher J.

2009-01-01

Background Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation. Methods Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 μg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided. Results The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051). Conclusions We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type– and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications. PMID:19244175

A Double Blind, Randomized, Neoadjuvant Study of the Tissue effects of POMx Pills in Men with Prostate Cancer Prior to Radical Prostatectomy

PubMed Central

Freedland, Stephen J.; Carducci, Michael; Kroeger, Nils; Partin, Alan; Rao, Jian-yu; Jin, Yusheng; Kerkoutian, Susan; Wu, Hong; Li, Yunfeng; Creel, Patricia; Mundy, Kelly; Gurganus, Robin; Fedor, Helen; King, Serina A.; Zhang, Yanjun; Heber, David; Pantuck, Allan J.

2013-01-01

Pomegranates slow prostate cancer xenograft growth and prolong PSA doubling times in single-arm human studies. Pomegranates’ effects on human prostate tissue are understudied. We hypothesized orally administered pomegranate extract (POMx; PomWonderful, Los Angeles, CA) would lower tissue 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative stress biomarker. 70 men were randomized to 2 tablets POMx or placebo daily up to 4 weeks prior to radical prostatectomy. Tissue was analyzed for intra-prostatic Urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NFκB, and Ki67. Primary end-point was differences in 8-OHdG powered to detect 30% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (p=0.095), which was not statistically significant. POMx was well-tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21/33 patient in the POMx group vs. 12/35 in the placebo group (p=0.031). Cancer pS6 kinase, NFκB, Ki67, and serum PSA changes were similar between arms. POMx prior to surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary end-point in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitely test whether POMx reduces prostate oxidative stress as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology. PMID:23985577

Prostate tissue metal levels and prostate cancer recurrence in smokers.

PubMed

Neslund-Dudas, Christine; Kandegedara, Ashoka; Kryvenko, Oleksandr N; Gupta, Nilesh; Rogers, Craig; Rybicki, Benjamin A; Dou, Q Ping; Mitra, Bharati

2014-02-01

Although smoking is not associated with prostate cancer risk overall, smoking is associated with prostate cancer recurrence and mortality. Increased cadmium (Cd) exposure from smoking may play a role in progression of the disease. In this study, inductively coupled plasma mass spectrometry was used to determine Cd, arsenic (As), lead (Pb), and zinc (Zn) levels in formalin-fixed paraffin embedded tumor and tumor-adjacent non-neoplastic tissue of never- and ever-smokers with prostate cancer. In smokers, metal levels were also evaluated with regard to biochemical and distant recurrence of disease. Smokers (N = 25) had significantly higher Cd (median ppb, p = 0.03) and lower Zn (p = 0.002) in non-neoplastic tissue than never-smokers (N = 21). Metal levels were not significantly different in tumor tissue of smokers and non-smokers. Among smokers, Cd level did not differ by recurrence status. However, the ratio of Cd ppb to Pb ppb was significantly higher in both tumor and adjacent tissue of cases with distant recurrence when compared with cases without distant recurrence (tumor tissue Cd/Pb, 6.36 vs. 1.19, p = 0.009, adjacent non-neoplastic tissue Cd/Pb, 6.36 vs. 1.02, p = 0.038). Tissue Zn levels were also higher in smokers with distant recurrence (tumor, p = 0.039 and adjacent non-neoplastic, p = 0.028). These initial findings suggest that prostate tissue metal levels may differ in smokers with and without recurrence. If these findings are confirmed in larger studies, additional work will be needed to determine whether variations in metal levels are drivers of disease progression or are simply passengers of the disease process.

Identification and Validation of Potential New Biomarkers for Prostate Cancer Diagnosis and Prognosis Using 2D-DIGE and MS

PubMed Central

Geisler, Cordelia; Gaisa, Nadine T.; Pfister, David; Fuessel, Susanne; Kristiansen, Glen; Braunschweig, Till; Gostek, Sonja; Beine, Birte; Diehl, Hanna C.; Jackson, Angela M.; Borchers, Christoph H.; Heidenreich, Axel; Meyer, Helmut E.; Knüchel, Ruth; Henkel, Corinna

2015-01-01

This study was designed to identify and validate potential new biomarkers for prostate cancer and to distinguish patients with and without biochemical relapse. Prostate tissue samples analyzed by 2D-DIGE (two-dimensional difference in gel electrophoresis) and mass spectrometry (MS) revealed downregulation of secernin-1 (P < 0.044) in prostate cancer, while vinculin showed significant upregulation (P < 0.001). Secernin-1 overexpression in prostate tissue was validated using Western blot and immunohistochemistry while vinculin expression was validated using immunohistochemistry. These findings indicate that secernin-1 and vinculin are potential new tissue biomarkers for prostate cancer diagnosis and prognosis, respectively. For validation, protein levels in urine were also examined by Western blot analysis. Urinary vinculin levels in prostate cancer patients were significantly higher than in urine from nontumor patients (P = 0.006). Using multiple reaction monitoring-MS (MRM-MS) analysis, prostatic acid phosphatase (PAP) showed significant higher levels in the urine of prostate cancer patients compared to controls (P = 0.012), while galectin-3 showed significant lower levels in the urine of prostate cancer patients with biochemical relapse, compared to those without relapse (P = 0.017). Three proteins were successfully differentiated between patients with and without prostate cancer and patients with and without relapse by using MRM. Thus, this technique shows promise for implementation as a noninvasive clinical diagnostic technique. PMID:25667921

Multiphoton Microscopy of Prostate and Periprostatic Neural Tissue: A Promising Imaging Technique for Improving Nerve-Sparing Prostatectomy

PubMed Central

Yadav, Rajiv; Mukherjee, Sushmita; Hermen, Michael; Tan, Gerald; Maxfield, Frederick R.; Webb, Watt W.

2009-01-01

Abstract Background and Purpose Various imaging modalities are under investigation for real-time tissue imaging of periprostatic nerves with the idea of improving the results of nerve-sparing radical prostatectomy. We explored multiphoton microscopy (MPM) for real-time tissue imaging of the prostate and periprostatic neural tissue in a male Sprague-Dawley rat model. The unique advantage of this technique is the acquisition of high-resolution images without necessitating any extrinsic labeling agent and with minimal phototoxic effect on tissue. Materials and Methods The prostate and cavernous nerves were surgically excised from male Sprague-Dawley rats. The imaging was carried out using intrinsic fluorescence and scattering properties of the tissues without any exogenous dye or contrast agent. A custom-built MPM, consisting of an Olympus BX61WI upright frame and a modified MRC 1024 scanhead, was used. A femtosecond pulsed titanium/sapphire laser at 780-nm wavelength was used to excite the tissue; laser power under the objective was modulated via a Pockels cell. Second harmonic generation (SHG) signals were collected at 390 (±35 nm), and broadband autofluorescence was collected at 380 to 530 nm. The images obtained from SHG and from tissue fluorescence were then merged and color coded during postprocessing for better appreciation of details. The corresponding tissues were subjected to hematoxylin and eosin staining for histologic confirmation of the structures. Results High-resolution images of the prostate capsule, underlying acini, and individual cells outlining the glands were obtained at varying magnifications. MPM images of adipose tissue and the neural tissues were also obtained. Histologic confirmation and correlation of the prostate gland, fat, cavernous nerve, and major pelvic ganglion validated the findings of MPM. Conclusion Real-time imaging and microscopic resolution of prostate and periprostatic neural tissue using MPM is feasible without the need for any extrinsic labeling agents. Integration of this imaging modality with operative technique has the potential to improve the precision of nerve-sparing prostatectomy. PMID:19425823

Anatomy and Histology of the Human and Murine Prostate.

PubMed

Ittmann, Michael

2018-05-01

The human and murine prostate glands have similar functional roles in the generation of seminal fluid to assist in reproduction. There are significant differences in the anatomy and histology of murine and human prostate and knowledge of the normal anatomy and histology of the murine prostate is essential to interpreting changes in genetically engineered mouse models. In this review, the normal anatomy and histology of both human and mouse prostate will be described. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

PubMed Central

Kote-Jarai, Zsofia; Saunders, Edward J.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Jugurnauth-Little, Sarah; Ross-Adams, Helen; Al Olama, Ali Amin; Benlloch, Sara; Halim, Silvia; Russel, Roslin; Dunning, Alison M.; Luccarini, Craig; Dennis, Joe; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Muir, Ken; Giles, Graham G.; Severi, Gianluca; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Le Marchand, Loic; Lindstrom, Sara; Kraft, Peter; Hunter, David J.; Gapstur, Susan; Chanock, Stephen; Berndt, Sonja I.; Albanes, Demetrius; Andriole, Gerald; Schleutker, Johanna; Weischer, Maren; Canzian, Federico; Riboli, Elio; Key, Tim J.; Travis, Ruth C.; Campa, Daniele; Ingles, Sue A.; John, Esther M.; Hayes, Richard B.; Pharoah, Paul; Khaw, Kay-Tee; Stanford, Janet L.; Ostrander, Elaine A.; Signorello, Lisa B.; Thibodeau, Stephen N.; Schaid, Dan; Maier, Christiane; Vogel, Walther; Kibel, Adam S.; Cybulski, Cezary; Lubinski, Jan; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong Y.; Kaneva, Radka; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A.; Sawyer, Emma J.; Morgan, Angela; Dicks, Ed; Baynes, Caroline; Conroy, Don; Bojesen, Stig E.; Kaaks, Rudolf; Vincent, Daniel; Bacot, François; Tessier, Daniel C.; Easton, Douglas F.; Eeles, Rosalind A.

2013-01-01

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease. PMID:23535824

Deep learning as a tool for increased accuracy and efficiency of histopathological diagnosis

NASA Astrophysics Data System (ADS)

Litjens, Geert; Sánchez, Clara I.; Timofeeva, Nadya; Hermsen, Meyke; Nagtegaal, Iris; Kovacs, Iringo; Hulsbergen-van de Kaa, Christina; Bult, Peter; van Ginneken, Bram; van der Laak, Jeroen

2016-05-01

Pathologists face a substantial increase in workload and complexity of histopathologic cancer diagnosis due to the advent of personalized medicine. Therefore, diagnostic protocols have to focus equally on efficiency and accuracy. In this paper we introduce ‘deep learning’ as a technique to improve the objectivity and efficiency of histopathologic slide analysis. Through two examples, prostate cancer identification in biopsy specimens and breast cancer metastasis detection in sentinel lymph nodes, we show the potential of this new methodology to reduce the workload for pathologists, while at the same time increasing objectivity of diagnoses. We found that all slides containing prostate cancer and micro- and macro-metastases of breast cancer could be identified automatically while 30-40% of the slides containing benign and normal tissue could be excluded without the use of any additional immunohistochemical markers or human intervention. We conclude that ‘deep learning’ holds great promise to improve the efficacy of prostate cancer diagnosis and breast cancer staging.

MicroRNAs as New Characters in the Plot between Epigenetics and Prostate Cancer.

PubMed

Paone, Alessio; Galli, Roberta; Fabbri, Muller

2011-01-01

Prostate cancer (PCA) still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs), a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR), a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in PCA and on the fine regulation of AR expression, as mediated by this miRNA-epigenetics interaction.

The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease

PubMed Central

Evans, James C; Malhotra, Meenakshi; Cryan, John F

2016-01-01

Prostate specific membrane antigen (PSMA) otherwise known as glutamate carboxypeptidase II (GCPII) is a membrane bound protein that is highly expressed in prostate cancer and in the neovasculature of a wide variety of tumours including glioblastomas, breast and bladder cancers. This protein is also involved in a variety of neurological diseases including schizophrenia and ALS. In recent years, there has been a surge in the development of both diagnostics and therapeutics that take advantage of the expression and activity of PSMA/GCPII. These include gene therapy, immunotherapy, chemotherapy and radiotherapy. In this review, we discuss the biological roles that PSMA/GCPII plays, both in normal and diseased tissues, and the current therapies exploiting its activity that are at the preclinical stage. We conclude by giving an expert opinion on the future direction of PSMA/GCPII based therapies and diagnostics and hurdles that need to be overcome to make them effective and viable. PMID:27526115

Dissecting the expression of EEF1A1/2 genes in human prostate cancer cells: the potential of EEF1A2 as a hallmark for prostate transformation and progression.

PubMed

Scaggiante, B; Dapas, B; Bonin, S; Grassi, M; Zennaro, C; Farra, R; Cristiano, L; Siracusano, S; Zanconati, F; Giansante, C; Grassi, G

2012-01-03

In prostate adenocarcinoma, the dissection of the expression behaviour of the eukaryotic elongation factors (eEF1A1/2) has not yet fully elucidated. The EEF1A1/A2 expressions were investigated by real-time PCR, western blotting (cytoplasmic and cytoskeletal/nuclear-enriched fractions) and immunofluorescence in the androgen-responsive LNCaP and the non-responsive DU-145 and PC-3 cells, displaying a low, moderate and high aggressive phenotype, respectively. Targeted experiments were also conducted in the androgen-responsive 22Rv1, a cell line marking the progression towards androgen-refractory tumour. The non-tumourigenic prostate PZHPV-7 cell line was the control. Compared with PZHPV-7, cancer cells showed no major variations in EEF1A1 mRNA; eEF1A1 protein increased only in cytoskeletal/nuclear fraction. On the contrary, a significant rise of EEF1A2 mRNA and protein were found, with the highest levels detected in LNCaP. Eukaryotic elongation factor 1A2 immunostaining confirmed the western blotting results. Pilot evaluation in archive prostate tissues showed the presence of EEF1A2 mRNA in near all neoplastic and perineoplastic but not in normal samples or in benign adenoma; in contrast, EEF1A1 mRNA was everywhere detectable. Eukaryotic elongation factor 1A2 switch-on, observed in cultured tumour prostate cells and in human prostate tumour samples, may represent a feature of prostate cancer; in contrast, a minor involvement is assigned to EEF1A1. These observations suggest to consider EEF1A2 as a marker for prostate cell transformation and/or possibly as a hallmark of cancer progression.

Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer.

PubMed

Nguyen, Han Christine Ngoc; Xie, Wanling; Yang, Ming; Hsieh, Chen-Lin; Drouin, Sarah; Lee, Gwo-Shu Mary; Kantoff, Philip W

2013-03-01

Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investigated circulating miRNAs in prostate cancer that may be associated with the progression of hormone-sensitive primary tumors to metastatic castration resistant prostate cancer (CRPC) after androgen deprivation therapy. Using genome-wide expression profiling by TaqMan Human MicroRNA Arrays (Applied Biosystems) and/or quantitative real-time polymerase chain reaction, we compared the expression levels of miRNAs in serum samples from 28 patients of low-risk localized disease, 30 of high-risk localized disease and 26 of metastatic CRPC. We demonstrated that serum samples from patients of low risk, localized prostate cancer and metastatic CRPC patients exhibit distinct circulating miRNA signatures. MiR-375, miR-378*, and miR-141 were significantly over-expressed in serum from CRPC patients compared with serum from low-risk localized patients, while miR-409-3p was significantly under-expressed. In prostate primary tumor samples, miR-375 and miR-141 also had significantly higher expression levels compared with those in normal prostate tissue. Circulating miRNAs, particularly miR-375, miR-141, miR-378*, and miR-409-3p, are differentially expressed in serum samples from prostate cancer patients. In the search for improved minimally invasive methods to follow cancer pathogenesis, the correlation of disease status with the expression patterns of circulating miRNAs may indicate the potential importance of circulating miRNAs as prognostic markers for prostate cancer progression. Copyright © 2012 Wiley Periodicals, Inc.

Prostate tissue ablation with MRI guided transurethral therapeutic ultrasound and intraoperative assessment of the integrity of the neurovascular bundle

NASA Astrophysics Data System (ADS)

Sammet, Steffen; Partanen, Ari; Yousuf, Ambereen; Wardrip, Craig; Niekrasz, Marek; Antic, Tatjana; Razmaria, Aria; Sokka, Sham; Karczmar, Gregory; Oto, Aytekin

2017-03-01

OBJECTIVES: Evaluation of the precision of prostate tissue ablation with MRI guided therapeuticultrasound by intraoperative objective assessment of the neurovascular bundle in canines in-vivo. METHODS: In this ongoing IACUC approved study, eight male canines were scanned in a clinical 3T Achieva MRI scanner (Philips) before, during, and after ultrasound therapy with a prototype MR-guided ultrasound therapy system (Philips). The system includes a therapy console to plan treatment, to calculate real-time temperature maps, and to control ultrasound exposures with temperature feedback. Atransurethral ultrasound applicator with eight transducer elements was used to ablate canine prostate tissue in-vivo. Ablated prostate tissue volumes were compared to the prescribed target volumes to evaluate technical effectiveness. The ablated volumes determined by MRI (T1, T2, diffusion, dynamic contrast enhanced and 240 CEM43 thermal dose maps) were compared to H&E stained histological slides afterprostatectomy. Potential nerve damage of the neurovascular bundle was objectively assessed intraoperativelyduring prostatectomy with a CaverMap Surgical Aid nerve stimulator (Blue Torch Medical Technologies). RESULTS: Transurethral MRI -guided ultrasound therapy can effectively ablate canine prostate tissue invivo. Coronal MR-imaging confirmed the correct placement of the HIFU transducer. MRI temperature maps were acquired during HIFU treatment, and subsequently used for calculating thermal dose. Prescribed target volumes corresponded to the 240 CEM43 thermal dose maps during HIFU treatment in all canines. Ablated volumes on high resolution anatomical, diffusion weighted, and contrast enhanced MR images matched corresponding histological slides after prostatectomy. MRI guidance with realtime temperature monitoring showed no damage to surrounding tissues, especially to the neurovascular bundle (assessed intra-operatively with a nerve stimulator) or to the rectum wall. CONCLUSIONS: Our study demonstrates the effectiveness and precision of transurethral ultrasound ablation of prostatic tissue in canines with MRI monitoring and guidance. The canine prostate is an excellent model for the human prostate with similar anatomical characteristics and diseases. MRI guidance with real-time, intraoperative temperature monitoring reduces the risk of damaging critical surrounding anatomical structures in ultrasound therapy of the prostate.

Microgravity

NASA Image and Video Library

1996-01-01

Electronics control module for the NASA Bioreactor. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Microgravity

NASA Image and Video Library

1996-01-01

Interior view of the gas supply for the NASA Bioreactor. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

NASA Bioreactor

NASA Technical Reports Server (NTRS)

1996-01-01

Electronics control module for the NASA Bioreactor. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

NASA Bioreactor

NASA Technical Reports Server (NTRS)

1996-01-01

Interior view of the gas supply for the NASA Bioreactor. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Tumor formation of prostate cancer cells influenced by stromal cells from the transitional or peripheral zones of the normal prostate

PubMed Central

Zhao, Fu-Jun; Han, Bang-Min; Yu, Sheng-Qiang; Xia, Shu-Jie

2009-01-01

This study was designed to investigate the different involvements of prostatic stromal cells from the normal transitional zone (TZ) or peripheral zone (PZ) in the carcinogenesis of prostate cancer (PCa) epithelial cells (PC-3) in vitro and in vivo co-culture models. Ultra-structures and gene expression profiles of primary cultures of human prostatic stromal cells from the normal TZ or PZ were analyzed by electron microscopy and microarray analysis. In vitro and in vivo co-culture models composed of normal TZ or PZ stromal cells and human PCa PC-3 cells were established. We assessed tumor growth and weight in the in vivo nude mice model. There are morphological and ultra-structural differences in stromal cells from TZ and PZ of the normal prostate. In all, 514 differentially expressed genes were selected by microarray analysis; 483 genes were more highly expressed in stromal cells from TZ and 31 were more highly expressed in those from PZ. Co-culture with PZ stromal cells and transforming growth factor-β1 (TGF-β1) increased the tumor growth of PC-3 cells in vitro and in vivo, as well as Bcl-2 expression. On the other hand, stromal cells of TZ suppressed PC-3 cell tumor growth in the mouse model. We conclude that ultra-structures and gene expression differ between the stromal cells from TZ or PZ of the normal prostate, and stroma–epithelium interactions from TZ or PZ might be responsible for the distinct zonal localization of prostate tumor formation. PMID:19122679

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2

PubMed Central

Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

2013-01-01

Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography – X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. PMID:22889168

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2.

PubMed

Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

2013-01-01

The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. © 2012 Genentech, Inc.. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Microgravity

NASA Image and Video Library

2001-06-01

Cells cultured on Earth (left) typically settle quickly on the bottom of culture vessels due to gravity. In microgravity (right), cells remain suspended and aggregate to form three-dimensional tissue. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Microgravity

NASA Image and Video Library

1998-01-01

Dr. Lisa E. Freed of the Massachusetts Institute of Technology and her colleagues have reported that initially disc-like specimens tend to become spherical in space, demonstrating that tissues can grow and differentiate into distinct structures in microgravity. The Mir Increment 3 (Sept. 16, 1996 - Jan. 22, 1997) samples were smaller, more spherical, and mechanically weaker than Earth-grown control samples. These results demonstrate the feasibility of microgravity tissue engineering and may have implications for long human space voyages and for treating musculoskeletal disorders on earth. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Bioreactor principles

NASA Technical Reports Server (NTRS)

2001-01-01

Cells cultured on Earth (left) typically settle quickly on the bottom of culture vessels due to gravity. In microgravity (right), cells remain suspended and aggregate to form three-dimensional tissue. The NASA Bioreactor provides a low turbulence culture environment which promotes the formation of large, three-dimensional cell clusters. The Bioreactor is rotated to provide gentle mixing of fresh and spent nutrient without inducing shear forces that would damage the cells. Due to their high level of cellular organization and specialization, samples constructed in the bioreactor more closely resemble the original tumor or tissue found in the body. The work is sponsored by NASA's Office of Biological and Physical Research. The bioreactor is managed by the Biotechnology Cell Science Program at NASA's Johnson Space Center (JSC). NASA-sponsored bioreactor research has been instrumental in helping scientists to better understand normal and cancerous tissue development. In cooperation with the medical community, the bioreactor design is being used to prepare better models of human colon, prostate, breast and ovarian tumors. Cartilage, bone marrow, heart muscle, skeletal muscle, pancreatic islet cells, liver and kidney are just a few of the normal tissues being cultured in rotating bioreactors by investigators.

Quantitative Time-Resolved Fluorescence Imaging of Androgen Receptor and Prostate-Specific Antigen in Prostate Tissue Sections.

PubMed

Krzyzanowska, Agnieszka; Lippolis, Giuseppe; Helczynski, Leszek; Anand, Aseem; Peltola, Mari; Pettersson, Kim; Lilja, Hans; Bjartell, Anders

2016-05-01

Androgen receptor (AR) and prostate-specific antigen (PSA) are expressed in the prostate and are involved in prostate cancer (PCa). The aim of this study was to develop reliable protocols for reproducible quantification of AR and PSA in benign and malignant prostate tissue using time-resolved fluorescence (TRF) imaging techniques. AR and PSA were detected with TRF in tissue microarrays from 91 PCa patients. p63/ alpha-methylacyl-CoA racemase (AMACR) staining on consecutive sections was used to categorize tissue areas as benign or cancerous. Automated image analysis was used to quantify staining intensity. AR intensity was significantly higher in AMACR+ and lower in AMACR- cancer areas as compared with benign epithelium. The PSA intensity was significantly lower in cancer areas, particularly in AMACR- glands. The AR/PSA ratio varied significantly in the AMACR+ tumor cells as compared with benign glands. There was a trend of more rapid disease progression in patients with higher AR/PSA ratios in the AMACR- areas. This study demonstrates the feasibility of developing reproducible protocols for TRF imaging and automated image analysis to study the expression of AR and PSA in benign and malignant prostate. It also highlighted the differences in AR and PSA protein expression within AMACR- and AMACR+ cancer regions. © 2016 The Histochemical Society.

The Accumulation of Versican in the Nodules of Benign Prostatic Hyperplasia

PubMed Central

True, Lawrence D.; Hawley, Sarah; Norwood, Thomas H.; Braun, Kathleen R.; Evanko, Stephen P.; Chan, Christina K.; LeBaron, Richard C.; Wight, Thomas N.

2014-01-01

Background Proteoglycans, a complex group of extracellular matrix (ECM) molecules, are elevated in benign prostatic hyperplasia (BPH). Versican is a stromal proteoglycan present in prostate tissue. Versican expression is elevated in tissues with increased proliferation. Based on these observations, we determined the extent and distribution of versican expression in prostates with BPH. Methods The involvement of versican in BPH nodules was compared with levels in non-nodular transition (TZ) and peripheral zone (PZ) tissues from 18 human prostate glands using immunohistochemistry, Northern blots and/or QRTPCR to localize versican and quantify versican mRNA transcript levels, and Western blots to assess gene product levels. Results Increased versican immunoreactivity was observed in the stroma of BPH nodules. Higher steady state levels of versican variants V0, V1, and V3 mRNA transcript and gene product were detected in the nodular tissues than in the non-nodular TZ or PZ parenchyma. Conclusions These results suggest that versican may play a role in nodule formation in BPH. PMID:18819099

Image-guided urologic surgery: intraoperative optical imaging and tissue interrogation (Conference Presentation)

NASA Astrophysics Data System (ADS)

Liao, Joseph C.

2017-02-01

Emerging optical imaging technologies can be integrated in the operating room environment during minimally invasive and open urologic surgery, including oncologic surgery of the bladder, prostate, and kidney. These technologies include macroscopic fluorescence imaging that provides contrast enhancement between normal and diseased tissue and microscopic imaging that provides tissue characterization. Optical imaging technologies that have reached the clinical arena in urologic surgery are reviewed, including photodynamic diagnosis, near infrared fluorescence imaging, optical coherence tomography, and confocal laser endomicroscopy. Molecular imaging represents an exciting future arena in conjugating cancer-specific contrast agents to fluorophores to improve the specificity of disease detection. Ongoing efforts are underway to translate optimal targeting agents and imaging modalities, with the goal to improve cancer-specific and functional outcomes.

Prostate Cancer: Serum and Tissue Markers

PubMed Central

Miller, Gary J; Brawer, Michael K; Sakr, Wael A; Thrasher, J Brantley; Townsend, Ronald

2001-01-01

The detection of prostate cancer, its clinical staging, and the prediction of its prognosis remain topics of paramount importance in clinical management. The digital rectal exam, although once the “gold standard,” has been largely supplanted by a variety of techniques including serum and tissue-based assays. This article reviews recent progress in the development of prostate-specific antigen assays with greater specificity; molecular markers for prostate cancer (DNA ploidy, nuclear morphometry, markers of proliferation, and cell adhesion molecules); the link between vitamin D deficiency and the clinical emergence of prostate cancer; the possible correlation of serum insulin-like growth factor levels with the risk for developing prostate cancer; and the latest advances in radiologic staging. PMID:16985995

Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination.

PubMed

Roebuck, Joseph R; Haker, Steven J; Mitsouras, Dimitris; Rybicki, Frank J; Tempany, Clare M; Mulkern, Robert V

2009-05-01

Quantitative, apparent T(2) values of suspected prostate cancer and healthy peripheral zone tissue in men with prostate cancer were measured using a Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence in order to assess the cancer discrimination potential of tissue T(2) values. The CPMG imaging sequence was used to image the prostates of 18 men with biopsy-proven prostate cancer. Whole gland coverage with nominal voxel volumes of 0.54 x 1.1 x 4 mm(3) was obtained in 10.7 min, resulting in data sets suitable for generating high-quality images with variable T(2)-weighting and for evaluating quantitative T(2) values on a pixel-by-pixel basis. Region-of-interest analysis of suspected healthy peripheral zone tissue and suspected cancer, identified on the basis of both T(1)- and T(2)-weighted signal intensities and available histopathology reports, yielded significantly (P<.0001) longer apparent T(2) values in suspected healthy tissue (193+/-49 ms) vs. suspected cancer (100+/-26 ms), suggesting potential utility of this method as a tissue specific discrimination index for prostate cancer. We conclude that CPMG imaging of the prostate can be performed in reasonable scan times and can provide advantages over T(2)-weighted fast spin echo (FSE) imaging alone, including quantitative T(2) values for cancer discrimination as well as proton density maps without the point spread function degradation associated with short effective echo time FSE sequences.

Carr-Purcell-Meiboom-Gill (CPMG) Imaging of Prostate Cancer: Quantitative T2 Values for Cancer Discrimination

PubMed Central

Roebuck, Joseph R.; Haker, Steven J.; Mitsouras, Dimitris; Rybicki, Frank J.; Tempany, Clare M.; Mulkern, Robert V.

2009-01-01

Quantitative, apparent T2 values of suspected prostate cancer and healthy peripheral zone tissue in men with prostate cancer were measured using a Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence in order to assess the cancer discrimination potential of tissue T2 values. The CPMG imaging sequence was used to image the prostates of 18 men with biopsy proven prostate cancer. Whole gland coverage with nominal voxel volumes of 0.54 × 1.1 × 4 mm3 was obtained in 10.7 minutes, resulting in data sets suitable for generating high quality images with variable T2-weighting and for evaluating quantitative T2 values on a pixel-by-pixel basis. Region-of-interest analysis of suspected healthy peripheral zone tissue and suspected cancer, identified on the basis of both T1- and T2-weighted signal intensities and available histopathology reports, yielded significantly (p < 0.0001) longer apparent T2 values in suspected healthy tissue (193 ± 49 ms) vs. suspected cancer (100 ± 26 ms), suggesting potential utility of this method as a tissue specific discrimination index for prostate cancer. We conclude that CPMG imaging of the prostate can be performed in reasonable scan times and can provide advantages over T2-weighted fast spin echo imaging alone, including quantitative T2 values for cancer discrimination as well as proton density maps without the point spread function degradation associated with short effective echo time fast spin echo (FSE) sequences. PMID:18823731

Ablative efficiency of lithium triborate laser vaporization and conventional transurethral resection of the prostate: a comparison using transrectal three-dimensional ultrasound volumetry

NASA Astrophysics Data System (ADS)

Gross, Oliver; Sulser, Tullio; Hefermehl, Lukas J.; Strebel, Daniel D.; Largo, Remo; Mortezavi, Ashkan; Poyet, Cédric; Eberli, Daniel; Zimmermann, Matthias; Müller, Alexander; Michel, Maurice S.; Müntener, Michael; Seifert, Hans-Helge; Hermanns, Thomas

2011-03-01

Introduction and objectives: It is unknown if tissue ablation following 120W lithium triborate (LBO) laser vaporization (LV) of the prostate is comparable to that following transurethral resection of the prostate (TURP). Therefore, transrectal 3D-ultrasound volumetry of the prostate was performed to compare the efficiency of tissue ablation between LBO-LV and TURP. Methods: Between 03/2008 and 03/2010 110 patients underwent routine LBO-LV (n=61) or TURP (n=49). Transrectal 3D-ultrasound with planimetric volumetry of the prostate was performed pre-operatively, after catheter removal, 6 weeks and 6 months. Results: Median prostate volume was 52.5ml in the LV group and 46.9ml in the TURP group. After catheter removal, median absolute volume reduction (LV: 7.05ml, TURP: 15.8ml) and relative volume reduction (15.9% vs. 34.2%) were significantly lower in the LV group (p<0.001). After 6 weeks/ 6 months, the relative volume reduction but not the absolute remained significantly lower in the LV group. Conclusions: LBO-LV is an efficient procedure evidenced by an absolute tissue ablation not significantly different to that after TURP. However, TURP seems to be superior due to a higher relative tissue ablation. The differences in tissue ablation had no impact on the early clinical outcome. Delayed volume reduction indicates that prostatic swelling occurs early after LV and then decreases subsequently.

SSeCKS/AKAP12 induces repulsion between human prostate cancer and microvessel endothelial cells through the activation of Semaphorin 3F.

PubMed

Xie, Wen; Su, Wei; Zhang, Lijuan; Shang, Qingkun; Su, Bing

2017-09-02

Metastasis remains the primary cause of prostate cancer related death. Cancer cells need to contact endothelial cells and disrupt endothelial junctions to cross the endothelium for invasion and metastasis. The suppression of heterotypic repulsion between cancer and endothelial cells allows cancer cells to invade into the surrounding tissue. Here, we demonstrate that SSeCKS/AKAP12 induced repulsion between human prostate cancer and microvessel endothelial cells, which was mediated by an angiogenesis inhibitor Semaphorin 3F. Moreover, we examined AKAP12 and Semaphorin 3F mRNA expression in 42 prostate cancer and 30 benign prostatic hyperplasia tissue samples, and found that the expression of AKAP12 and Semaphorin 3F mRNA was inversely associated with the degree of aggressiveness of prostate cancer cells and tissues. An ordinal logistic regression analysis indicates that there is a positive association between the expression of AKAP12 and Semaphorin 3F in prostate cancer, suggesting that the activation of Semaphorin 3F by SSeCKS/AKAP12 may be involved in prostate cancer progression and metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

PubMed Central

Delsedime, Luisa; Molinaro, Luca; Gillio-Tos, Anna

2017-01-01

ABSTRACT Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982–1988 and 1993–1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95–2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (<75%) vs. high (>80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03–21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression. PMID:27892790