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Sample records for hyperplastic human prostate

  1. Regressive changes in finasteride-treated human hyperplastic prostates correlate with an upregulation of TGF-beta receptor expression.

    PubMed

    Sáez, C; González-Baena, A C; Japón, M A; Giráldez, J; Segura, D I; Miranda, G; Rodríguez-Vallejo, J M; González-Esteban, J; Torrubia, F

    1998-10-01

    Prostatic atrophy has been documented histologically as a consequence of finasteride action on human hyperplastic prostates. An increase in apoptotic rates has also been reported in androgen-deprived hyperplastic prostates. Transforming growth factor beta (TGF-beta) signaling is implicated in apoptotic cell death. TGF-betas have been detected in normal and diseased human prostate. In the normal prostate, TGF-beta acts as a predominantly negative growth regulator. TGF-beta signaling receptors TbetaRI and TbetaRII have been shown to be negatively regulated by androgens. We studied the histological changes in 9 selected finasteride-treated patients with benign prostatic hyperplasia (BPH), and analyzed the levels of expression and localization of TGF-beta receptor types TbetaRI and TbetaRII in these patients as compared to selected BPH controls. The prostatic epithelial compartment seemed to be a primary target site for finasteride action, since we observed moderate to severe glandular atrophy after 4-6 months of treatment. TGF-beta receptors were upregulated in treated cases. We assessed a twofold increase in TbetaRII mRNA levels in treated cases as compared to controls. An increase in both TbetaRI and TbetaRII at the protein level by immunostaining was observed, which also provided a helpful means for detecting glands undergoing regression. We conclude that finasteride may modulate the TGF-beta signaling system to promote changes leading to apoptosis of epithelial cells and prostatic glandular atrophy.

  2. Influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer and benign hyperplastic cells.

    PubMed

    Soares, Nathalia da Costa Pereira; Teodoro, Anderson Junger; Oliveira, Felipe Leite; Santos, Carlos Antonio do Nascimento; Takiya, Christina Maeda; Junior, Oswaldo Saback; Bianco, Mario; Junior, Antonio Palumbo; Nasciutti, Luiz Eurico; Ferreira, Luciana Bueno; Gimba, Etel Rodrigues Pereira; Borojevic, Radovan

    2013-01-01

    Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related mortality in men of the Western world. Lycopene has received attention because of its expcted potential to prevent cancer. In the present study, we evaluated the influence of lycopene on cell viability, cell cycle, and apoptosis of human prostate cancer cells and benign prostate hyperplastic cells. Using MTT assay, we observed a decrease of cell viability in all cancer cell lines after treatment with lycopene, which decreased the percentage of cells in G0/G1 phase and increased in S and G2/M phases after 96 h of treatment in metastatic prostate cancer cell lineages. Flow citometry analysis of cell cycle revealed lycopene promoted cell cycle arrest in G0/G1 phase after 48 and 96 h of treatment in a primary cancer cell line. Using real time PCR assay, lycopene also induced apoptosis in prostate cancer cells with altered gene expression of Bax and Bcl-2. No effect was observed in benign prostate hyperplasia cells. These results suggest an effect of lycopene on activity of human prostate cancer cells.

  3. Alpha 2 adrenergic receptors in hyperplastic human prostate: identification and characterization using (/sup 3/H) rauwolscine

    SciTech Connect

    Shapiro, E.; Lepor, H.

    1986-05-01

    (/sup 3/H)Rauwolscine ((/sup 3/H)Ra), a selective ligand for the alpha 2 adrenergic receptor, was used to identify and characterize alpha 2 adrenergic receptors in prostate glands of men with benign prostatic hyperplasia. Specific binding of (/sup 3/H)Ra to prostatic tissue homogenates was rapid and readily reversible by addition of excess unlabelled phentolamine. Scatchard analysis of saturation experiments demonstrates a single, saturable class of high affinity binding sites (Bmax = 0.31 +/- 0.04 fmol./microgram. DNA, Kd = 0.9 +/- 0.11 nM.). The relative potency of alpha adrenergic drugs (clonidine, alpha-methylnorepinephrine and prazosin) in competing for (/sup 3/H)Ra binding sites was consistent with the order predicted for an alpha 2 subtype. The role of alpha 2 adrenergic receptors in normal prostatic function and in men with bladder outlet obstruction secondary to BPH requires further investigation.

  4. Upregulation of Phosphodiesterase type 5 in the Hyperplastic Prostate

    PubMed Central

    Zhang, Wenhao; Zang, Ning; Jiang, Yaoming; Chen, Ping; Wang, Xinghuan; Zhang, Xinhua

    2015-01-01

    Both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in the aging male. Numerous clinical trials have demonstrated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5-Is) for treating LUTS/BPH with/without ED. However, the influence of BPH on prostatic PDE5 expression has never been studied. A testosterone-induced rat model of BPH was developed and human hyperplastic prostate specimens were harvested during cystoprostatectomy. PDE5, nNOS, eNOS and α1-adrenoreceptor subtypes (α1aARs, α1bARs and α1dARs) were determined with real-time RT-PCR for rat tissues whilst PDE5 and α1-adrenoreceptor subtypes were determined in human samples. PDE5 was further analyzed with Western-blot and histological examination. Serum testosterone was measured with ELISA. The rat BPH model was validated as having a significantly enlarged prostate. PDE5 localized mainly in fibromuscular stroma in prostate. Our data showed a significant and previously undocumented upregulation of PDE5 in both rat and human BPH, along with increased expression of nNOS and α1dARs for rat tissues and α1aARs for human BPH. The upregulation of PDE5 in the hyperplastic prostate could explain the mechanism and contribute to the high effectiveness of PDE5-Is for treating LUTS/BPH. Fibromuscular stroma could be the main target for PDE5-Is within prostate. PMID:26657792

  5. Protein profiling of isolated leukocytes, myofibroblasts, epithelial, Basal, and endothelial cells from normal, hyperplastic, cancerous, and inflammatory human prostate tissues.

    PubMed

    Khamis, Zahraa I; Iczkowski, Kenneth A; Sahab, Ziad J; Sang, Qing-Xiang Amy

    2010-06-15

    In situ neoplastic prostate cells are not lethal unless they become invasive and metastatic. For cells to become invasive, the prostate gland must undergo degradation of the basement membrane and disruption of the basal cell layer underneath the luminal epithelia. Although the roles of proteinases in breaking down the basement membrane have been well-studied, little is known about the factors that induce basal cell layer disruption, degeneration, and its eventual disappearance in invasive cancer. It is hypothesized that microenvironmental factors may affect the degradation of the basal cell layer, which if protected may prevent tumor progression and invasion. In this study, we have revealed differential protein expression patterns between epithelial and stromal cells isolated from different prostate pathologies and identified several important epithelial and stromal proteins that may contribute to inflammation and malignant transformation of human benign prostate tissues to cancerous tissues using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and proteomics methods. Cellular retinoic acid-binding protein 2 was downregulated in basal cells of benign prostate. Caspase-1 and interleukin-18 receptor 1 were highly expressed in leukocytes of prostate cancer. Proto-oncogene Wnt-3 was downregulated in endothelial cells of prostatitis tissue and tyrosine phosphatase non receptor type 1 was only found in normal and benign endothelial cells. Poly ADP-ribose polymerase 14 was downregulated in myofibroblasts of prostatitis tissue. Interestingly, integrin alpha-6 was upregulated in epithelial cells but not detected in myofibroblasts of prostate cancer. Further validation of these proteins may generate new strategies for the prevention of basal cell layer disruption and subsequent cancer invasion.

  6. Role of IAPs in prostate cancer progression: immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate

    PubMed Central

    2010-01-01

    Background In this study was investigate IAPs in normal human prostate (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC), and their involvement in apoptosis/proliferation via NF-kB (TNF-α, IL-1) stimulation. Methods Immunohistochemical and Western blot analyses were performed in 10 samples of normal prostates, 35 samples of BPH, 27 samples diagnosis of PIN (with low-grade PIN or high-grade PIN) and 95 samples of PC (with low, medium or high Gleason grades). Results In NP, cytoplasm of epithelial cells were positive to c-IAP1/2 (80% of samples), c-IAP-2 (60%), ILP (20%), XIAP (20%); negative to NAIP and survivin. In BPH, epithelial cells were immunostained to c-IAP1/2 (57.57%), c-IAP-2 (57.57%), ILP (66.6%), NAIP (60.6%), XIAP (27.27%), survivin (9.1%). Whereas low-grade PIN showed intermediate results between NP and BPH; results in high-grade PIN were similar to those found in PC. In PC, epithelial cells were immunostained to c-IAP1/2, c-IAP-2, ILP, NAIP, XIAP (no Gleason variation) and survivin (increasing with Gleason). Conclusions IAPs could be involved in prostate disorder (BPH, PIN and PC) development since might be provoke inhibition of apoptosis and subsequently cell proliferation. At the same time, different transduction pathway such as IL-1/NIK/NF-kB or TNF/NF-kB (NIK or p38) also promotes proliferation. Inhibitions of IAPs, IL-1α and TNFα might be a possible target for PC treatment since IAPs are the proteins that inhibited apoptosis (favour proliferation) and IL-1α and TNFα would affect all the transduction pathway involucrate in the activation of transcription factors related to survival or proliferation (NF-kB, Elk-1 or ATF-2). PMID:20078866

  7. 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

  8. Differences between chemical element contents in hyperplastic and nonhyperplastic prostate glands investigated by neutron activation analysis.

    PubMed

    Zaichick, Vladimir; Zaichick, Sofia; Davydov, German

    2015-03-01

    In order to clarify the differences between Ag, Br, Ca, Co, Cr, Fe, Hg, K, Mg, Mn, Na, Rb, Sb, Sc, Se, and Zn contents in hyperplastic (patients with benign prostate hyperplasia (BPH), n = 32) and nonhyperplastic (control group of healthy male inhabitants, n = 32) prostates, an instrumental neutron activation analysis was performed. Mean values (M ± SΕΜ) for mass fraction (mg/kg, dry mass basis) of chemical elements in glands of patients with BPH were the following: Ag, 0.0346 ± 0.0060; Br, 30.4 ± 3.6; Ca, 2030 ± 165; Co, 0.0716 ± 0.0097; Cr, 1.073 ± 0.119; Fe, 130.0 ± 7.9; Hg, 0.232 ± 0.030; K, 14,470 ± 740; Mg, 1200 ± 80; Mn, 1.19 ± 0.09; Na, 11,610 ± 870; Rb, 14.7 ± 0.8; Sb, 0.163 ± 0.025; Sc, 0.0257 ± 0.0040; Se, 1.243 ± 0.079; and Zn, 1235 ± 92. It was observed that in BPH tissue, the mass fraction of Co (p < 0.015), Cr (p < 0.0002), Hg (p < 0.000007), K (p < 0.001), Rb (p < 0.048), Sb (p < 0.0001), and Se (p < 0.000001) were significantly higher than in controls. In the sixth to eighth decades, the mass fractions of almost all chemical elements in hyperplastic prostates did not depend from age. Our finding of correlation between pairs of prostatic chemical element mass fractions indicates that there is a great disturbance of prostatic chemical element relationships with a benign hyperplastic transformation. The results apparently confirm the disturbed homeostasis of Zn and Se and some other chemical elements in the etiology of BPH.

  9. Immunohistochemistry of the cytoskeleton of human prostatic epithelium. Evidence for disturbed organization in neoplasia.

    PubMed Central

    Purnell, D. M.; Heatfield, B. M.; Anthony, R. L.; Trump, B. F.

    1987-01-01

    An indirect immunoperoxidase technique was used to evaluate keratin, actin, tubulin, and calmodulin immunoreactivity in histologic sections of normal, hyperplastic, and neoplastic human prostate. Polyclonal as well as monoclonal keratin antibodies produced equivalent and intense staining of normal epithelium. The immunoreactivity of normal prostate with keratin antibodies was more pronounced than with antibodies to the other components of the cytoskeleton. Variation in staining for components of the cytoskeleton was minimal. The same findings applied to hyperplastic prostate. The immunoreactivity of prostate tumors with antibodies to these cytoskeletal proteins differed markedly from normal prostate. Prostatic carcinomas showed reduced keratin immunoreactivity with a panepithelial antibody, but unaltered or enhanced immunoreactivity with tubulin, actin, and calmodulin antibodies. Many tumors were unreactive with a monoclonal keratin antibody that was strongly reactive with tissues that contained cytokeratin 18 (45-kd) and which intensely stained normal and hyperplastic prostate. In addition, prostate carcinomas often yielded heterogeneous patterns of staining with actin, tubulin, and calmodulin antibodies in contrast to normal and hyperplastic prostate, which showed uniform staining. The results suggest that a disturbance in the organization of the cytoskeleton may accompany neoplastic transformation of human prostate. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2435158

  10. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis

    USDA-ARS?s Scientific Manuscript database

    The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation, and survival, and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF...

  11. Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva.

    PubMed

    Tang, Liang; Li, Nan; Xie, Han; Jin, Yan

    2011-03-01

    Human gingiva plays an important role in the maintenance of oral health and shows unique fetal-like scarless healing process after wounding. Here we isolate and characterize mesenchymal stem cells from human normal and hyperplastic gingival tissues (N-GMSC and H-GMSC, respectively). Immunocytochemical staining indicated that gingival lamina propria contained Stro-1 and SSEA-4 positive cells, implying existence of putative gingival MSC. Under attachment-based isolating and culturing condition, gingival MSC displayed highly clonogenic and long-term proliferative capability. By using single colony isolation and expansion approaches, we found both N-GMSC and H-GMSC possessed self-renewal and multipotent differentiation properties. N-GMSC and H-GMSC showed distinct immunoregulatory functions in a murine skin allograft setting via up-regulation of putative systemic regulatory T cells (Tregs). N-GMSC and H-GMSC were capable of regenerating collagenous tissue following in vivo transplantation, in which H-GMSC exhibited more robust regenerative capability. These findings suggest that gingival tissue contains tissue-specific mesenchymal stem cell population and is an ideal resource for immunoregulatory therapy due to its substantial availability and accessibility. In addition, gingival MSC over-activation may contribute to gingival hyperplastic phenotype.

  12. [The detection of the human papilloma virus during hyperplastic processes in the nose, ears and throat].

    PubMed

    Boiko, N V; Panchenko, S N

    The objective of the present work was to carry out the virological and histological studies of various neoplastic and hyperplastic processes in the nose, ears, and throat with a view to identifying the presence of human papilloma virus and Epstein-Barr virus. The brush biopsies and remote neoplasms obtained from 18 patients (including 2 children and 16 adults) presenting with various ENT diseases and tumours were available for the virological investigation with the use of the polymerase chain reaction (PCR) and a system MY09-MY11 degenerate primers . The histological study of biopsies and remote neoplasms was carried out by means of conventional light microscopy. The virological and histological studies conducted in parallel confirmed the diagnostic significance of morphological changes at the tissue and cellular levels caused by the human papilloma virus.

  13. Lectin binding patterns in hyperplastic and metaplastic bullock prostate tissues after diethylstilbestrol administration.

    PubMed

    Fernández, P E; Barbeito, C G; Portiansky, E L; Gimeno, E J

    2004-03-06

    Hyperplasia and squamous metaplasia of the prostatic epithelium are conditions induced by oestrogens. Diethylstilbestrol (DES) has been banned from cattle used for beef production because of the health risks. The potential use of molecular markers for the detection of illegal oestrogen administration was evaluated by taking samples of prostatic tissue from control bullocks, bullocks which had been treated with oestrogens, and bullocks sacrificed 21 and 90 days after a single dose of DES. The expression of the glycoconjugates was examined by lectinhistochemistry and the lectin binding pattern was characterised in epithelium and connective tissue. In the animals sacrificed after 21 days there was an increase in the binding of one lectin (JAC) and there was an increase in the binding of one of the other lectins (DBA) in the animals sacrificed after 90 days. An increase in SWGA lectin staining was observed in the bullocks that had probably been treated with oestrogen and in the animals sacrificed 90 days after the inoculation with DES. There were also differences between the binding of SWGA in the control bullocks and the other groups.

  14. Localization of angiotensin-converting enzyme in the human prostate: pathological expression in benign prostatic hyperplasia.

    PubMed

    Nassis, L; Frauman, A G; Ohishi, M; Zhuo, J; Casley, D J; Johnston, C I; Fabiani, M E

    2001-12-01

    Benign prostatic hyperplasia (BPH) is the most common hyperplastic disease in man and it is characterized by increased cellular growth (stromal and epithelial hyperplasia) and enhanced local sympathetic tone, both of which are known to be augmented by activation of the renin-angiotensin system (RAS) in other tissues. Angiotensin-converting enzyme (ACE) is an integral component of the RAS that is responsible for the production of the active peptide angiotensin II from the inactive precursor angiotensin I. The present study was undertaken to map the anatomical localization of ACE protein and messenger ribonucleic acid (mRNA) in the normal human prostate and to establish whether their expression is pathologically altered in BPH. Human prostate samples were obtained at post-mortem and histologically defined as normal or hyperplastic. ACE protein binding/expression was determined by in vitro autoradiography and immunohistochemistry using the ACE-specific radioligand [125I]-MK351A and a mouse anti-ACE polyclonal antibody, respectively, whereas the spatiotemporal distribution of ACE mRNA was determined by in situ hybridization using 35S-labelled oligonucleotide probes. ACE protein was localized to the glandular epithelium in the human prostate. ACE binding and immunostaining were increased in BPH compared with normal (non-hyperplastic) prostate specimens [X-ray film autoradiography: normal 873+/-48 dpm/mm2 (n=8) vs. BPH 1631+/-274 dpm/mm2 (n=6), p<0.05; emulsion autoradiography: normal 3.1+/-0.5 grains/mm2 (n=6) vs. BPH 32.8+/-8.6 grains/mm2 (n=5), p<0.01]. ACE mRNA was also localized to glandular epithelial cells in the human prostate with a significant increase in ACE mRNA expression in BPH compared with the normal prostate [normal 11.04+/-2.03 grains/cell (n=220 cells total) vs. BPH 22.29+/-1.34 grains/cell (n=198 cells total), p<0.05]. The findings of the present study suggest that ACE is localized to the glandular epithelium of the human prostate and that its

  15. P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

    PubMed Central

    Wang, Yiming; Gratzke, Christian; Tamalunas, Alexander; Wiemer, Nicolas; Ciotkowska, Anna; Rutz, Beata; Waidelich, Raphaela; Strittmatter, Frank; Liu, Chunxiao; Stief, Christian G.; Hennenberg, Martin

    2016-01-01

    Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under

  16. Langerhans cell homeostasis and activation is altered in hyperplastic human papillomavirus type 16 E7 expressing epidermis.

    PubMed

    Abd Warif, Nor Malia; Stoitzner, Patrizia; Leggatt, Graham R; Mattarollo, Stephen R; Frazer, Ian H; Hibma, Merilyn H

    2015-01-01

    It has previously been shown that expression of human papillomavirus type 16 (HPV) E7 in epidermis causes hyperplasia and chronic inflammation, characteristics of pre-malignant lesions. Importantly, E7-expressing epidermis is strongly immune suppressed and is not rejected when transplanted onto immune competent mice. Professional antigen presenting cells are considered essential for initiation of the adaptive immune response that results in graft rejection. Langerhans cells (LC) are the only antigen presenting cells located in normal epidermis and altered phenotype and function of these cells may contribute to the immune suppressive microenvironment. Here, we show that LC are atypically activated as a direct result of E7 expression in the epidermis, and independent of the presence of lymphocytes. The number of LC was significantly increased and the LC are functionally impaired, both in migration and in antigen uptake. However when the LC were extracted from K14E7 skin and matured in vitro they were functionally competent to present and cross-present antigen, and to activate T cells. The ability of the LC to present and cross-present antigen following maturation supports retention of full functional capacity when removed from the hyperplastic skin microenvironment. As such, opportunities are afforded for the development of therapies to restore normal LC function in hyperplastic skin.

  17. HUMAN PROSTATE CANCER RISK FACTORS

    EPA Science Inventory

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  18. HUMAN PROSTATE CANCER RISK FACTORS

    EPA Science Inventory

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  19. QUANTITATIVE STUDIES OF PROSTATIC SECRETION : II. THE EFFECT OF CASTRATION AND OF ESTROGEN INJECTION ON THE NORMAL AND ON THE HYPERPLASTIC PROSTATE GLANDS OF DOGS.

    PubMed

    Huggins, C; Clark, P J

    1940-11-30

    Cystic hyperplasia of the prostate occurs spontaneously in senile dogs only when they possess physiologically effective amounts of androgenic hormone. The cysts are closely grouped and radially arranged in a conical manner with the base of the cone at the periphery of the gland. Flattened and columnar epithelium, varying from about 5 to 25micro are seen in each cyst. The cysts communicate with the urethra by way of ducts. Both normal and cystic prostates undergo marked atrophy when the testes are removed, the chief difference 3 months after orchiectomy being the persistence of slightly dilated clefts and spaces at the site of the former cysts in the senile state. In the castrate dog whose prostate gland is being reconstructed as result of the influence of daily injections of androgen, certain doses of estrogen prevent increase of secretion and still larger doses greatly depress the output of the gland. In dogs so treated by daily injections of testosterone propionate, 10 mg., the amount of secretion is maintained from day to day at a level by daily injections of stilbestrol, 0.4 to 0.6 mg. and greatly depressed by doses of 1 to 1.5 mg. When the larger amounts of estrogen are used, together with androgen, squamous metaplasia occurs in the posterior lobe of the prostate while the epithelium of the acini decreases in height to cuboidal or low columnar form; these histological signs of activity of both androgen and estrogen on the prostate show that inhibition of the male hormone by stilbestrol is incomplete at these ratios. In dogs with either normal or cystic prostate glands, the prostate decreases in size when estrogen is injected in amounts to depress prostatic secretion profoundly. The gland is maintained in an atrophic state and overdosage avoided by controlled periodic injections of stilbestrol until secretion is reduced to the minimum, followed by free intervals, the estrogen being again administered when secretion measurably increases. The shrinkage is related

  20. Human Prostate Cancer Hallmarks Map.

    PubMed

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-08-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.

  1. An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer

    DTIC Science & Technology

    2005-06-01

    assess growth of the four cell lines, a Gompertz prostatectomy (n = 2), and six prostate cancer (PC) speci- growth model was fitted to each line. Day... Gompertz model with men (N), in hyperplastic (benign) tissue from men without line-specific asymptote and growth rate was estimated via Gauss-New...histologically confirmed tumor with histologically con- The plots and Gompertz fits were generated in R version 1.6.25.1 (36). firmed benign tissue obtained from

  2. Endometase in Androgen-Repressed Human Prostate Cancer

    DTIC Science & Technology

    2005-03-01

    intraepithelial neoplasia from multiple patients were significantly higher than those in prostatitis, benign prostate hyperplasia, and normal prostate glandular...prostate cancer cell invasion. 3. We showed that the levels of MMP-26 protein in human prostate carcinomas from multiple patients were significantly...inhibitors of MMP-26 block prostate cancer invasion. We have showed that the levels of MMP-26 protein in human prostate carcinomas from multiple patients were

  3. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  4. A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression

    PubMed Central

    Simons, Brian W; Durham, Nicholas M; Bruno, Tullia C; Grosso, Joseph F; Schaeffer, Anthony J; Ross, Ashley E; Hurley, Paula J; Berman, David M; Drake, Charles G; Thumbikat, Praveen; Schaeffer, Edward M

    2015-01-01

    Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate-derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles, with chronic inflammation lasting at least 1 year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist, despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1-infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed that distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma, with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression. PMID:25348195

  5. Inorganic Arsenic and Human Prostate Cancer

    PubMed Central

    Benbrahim-Tallaa, Lamia; Waalkes, Michael P.

    2008-01-01

    Objective We critically evaluated the etiologic role of inorganic arsenic in human prostate cancer. Data sources We assessed data from relevant epidemiologic studies concerning environmental inorganic arsenic exposure. Whole animal studies were evaluated as were in vitro model systems of inorganic arsenic carcinogenesis in the prostate. Data synthesis Multiple studies in humans reveal an association between environmental inorganic arsenic exposure and prostate cancer mortality or incidence. Many of these human studies provide clear evidence of a dose–response relationship. Relevant whole animal models showing a relationship between inorganic arsenic and prostate cancer are not available. However, cellular model systems indicate arsenic can induce malignant transformation of human prostate epithelial cells in vitro. Arsenic also appears to impact prostate cancer cell progression by precipitating events leading to androgen independence in vitro. Conclusion Available evidence in human populations and human cells in vitro indicates that the prostate is a target for inorganic arsenic carcinogenesis. A role for this common environmental contaminant in human prostate cancer initiation and/or progression would be very important. PMID:18288312

  6. Fluconazole penetration into the human prostate.

    PubMed Central

    Finley, R W; Cleary, J D; Goolsby, J; Chapman, S W

    1995-01-01

    Fluconazole concentrations in the serum and prostate of human volunteers undergoing transurethral resection for benign prostatic hypertrophy were measured. There was a high correlation (r = 0.783) between serum (mean = 6.6 micrograms/ml) and tissue (mean = 1.9 micrograms/g) fluconazole concentrations, and these data were used to construct a model for local tissue concentrations. PMID:7726532

  7. Subcellular concentrations of calcium, zinc, and magnesium in benign nodular hyperplasia of the human prostate: X-ray microanalysis of freeze-dried cryosections

    SciTech Connect

    Tvedt, K.E.; Kopstad, G.; Haugen, O.A.; Halgunset, J.

    1987-01-01

    Biopsies from human prostates were obtained from normal and hyperplastic glands. The intracellular concentrations of calcium, zinc, and magnesium were analyzed using X-ray microanalysis of freeze-dried cryosections. Two prostate biopsies were obtained from kidney donors, ages 19 and 50 years, without any sign of benign nodular hyperplasia. The normal tissues were frozen within 15 min after circulatory arrest. The central part of biopsies from eight elderly men suffering from benign nodular hyperplasia were frozen within 30 s after excision. Adjacent tissue was processed for light microscopy and histopathological diagnosis. All samples were fresh-frozen using liquid nitrogen cooled pliers, without the use of any freeze-protection, fixation, or staining. In both the normal and the hyperplastic prostates high concentrations (up to above 100 mmol/kg dry weight) of zinc were present in electron dense bodies in the cytoplasm of the epithelial cells. Together with zinc, about equal concentrations of magnesium were found. Calcium was detected in 4 to 8 times the concentration of zinc. Significant, positive correlation between calcium and zinc as well as between calcium and magnesium in the cytoplasm was a typical finding in both normal and hyperplastic glands. In six of eight patients, older than 60 years of age, high levels of calcium (17.0-38.8 mmol/kg dry weight) were observed in the nuclei of the epithelial cells, while very low values were found in the remaining two. In the two younger cases (19 and 50 years of age), the nuclear calcium level in prostatic epithelium was relatively low (about 10 mmol/kg dry weight). These observations suggest that an increase of intranuclear calcium with advancing age may be of pathogenetic significance to growth disturbances in the prostate.

  8. Glutathione transferase isoenzymes from human prostate.

    PubMed Central

    Di Ilio, C; Aceto, A; Bucciarelli, T; Angelucci, S; Felaco, M; Grilli, A; Federici, G

    1990-01-01

    By using affinity-chromatography and isoelectric-focusing techniques, several forms of glutathione transferase (GSTs) were resolved from human prostate cytosol. All the three major classes of GST, i.e. Alpha, Mu and Pi, are present in human prostate. However, large inter-individual variation in the qualitative and quantitative expression of different isoenzymes resulted in the samples investigated. The most abundant group of prostate isoenzymes showed acid (pI 4.3-4.7) behaviour and were classified as Pi class GSTs on the basis of their immunological and structural properties. Immunohistochemical staining of Pi class GSTs was prevalently distributed in the epithelial cells surrounding the alveolar lumen. Class Mu GSTs are also expressed, although in small amounts and in a limited number of samples, by human prostate. The major cationic isoenzyme purified from prostate, GST-9.6; (pI 9.6; apparent subunit molecular mass of 28 kDa), appears to be different from the cationic GST alpha-epsilon forms isolated from human liver and kidney as evidenced by its structural, kinetical and immunological properties. This enzyme, which accounts for about 20-30% (on protein basis) of total amount of GSTs, is expressed by only 40% of samples. GST-9.6 has the ability to cross-react in immunoblotting analysis with antisera raised against rat liver GST 2-2, rather than with antisera raised against members of human Alpha, Mu and Pi class GSTs. Although prostate GST-9.6 shows close relationship with the human skin GST pI 9.9, it does not correspond to any other known human GST. Images Fig. 2. Fig. 3. Fig. 4. PMID:2241927

  9. Response of Human Prostate Tissue to Hypofractionated Ionizing Radiation

    DTIC Science & Technology

    2011-07-01

    Summary01-07-2011 Response of Human Prostate Tissue to Hypofractionated Ionizing Radiation Dr. Thomas Sroka University of Arizona Tucson, AZ 85719 The aim...of this proposal is to determine the differences in radiobiological response of human prostate tissue to conventional and hypofractionated ...conventional and hypofractionated ionizing radiation. Data generated in the first year of study has shown that normal prostate tissue and prostate

  10. Constitutive Activation of NF-kappaB in Prostate Carcinoma Cells Through a Positive Feedback Loop: Implication of Inducible IKK-Related Kinase (IKKi)

    DTIC Science & Technology

    2006-08-01

    strongly suggests that GR is constitutively active in both normal and hyperplastic prostate glands. In contrast, GR levels were low or below detection... BPH ; (b) PC (Gleason score 7); (c) HGPIN and (d) prostate stroma. Note: Low GR expression in PC (B1) and high GR expression in apparently normal...was increased in human prostate carcinomas in comparison to BPH samples (see progress report for FY02), these recent results suggest an important

  11. Acoustic Radiation Force Impulse Imaging of Human Prostates ex vivo

    PubMed Central

    Zhai, Liang; Madden, John; Foo, Wen-Chi; Palmeri, Mark L.; Mouraviev, Vladimir; Polascik, Thomas J.; Nightingale, Kathryn R.

    2010-01-01

    It has been challenging for clinicians using current imaging modalities to visualize internal structures and detect lesions inside human prostates. Lack of contrast among prostatic tissues and high false positive or negative detection rates of prostate lesions have limited the use of current imaging modalities in the diagnosis of prostate cancer. In this study, Acoustic Radiation Force Impulse (ARFI) imaging is introduced to visualize the anatomic and abnormal structures in freshly excised human prostates. A modified Siemens Antares™ ultrasound scanner and a Siemens VF10-5 linear array were used to acquire ARFI images. The transducer was attached to a three-dimensional (3D) translation stage, which was programmed to automate volumetric data acquisition. A depth dependent gain (DDG) method was developed and applied to 3D ARFI datasets to compensate for the displacement gradients associated with spatially varying radiation force magnitudes as a function of depth. Nine human prostate specimens were collected and imaged immediately after surgical excision. Prostate anatomical structures such as seminal vesicles, ejaculatory ducts, peripheral zone, central zone, transition zone and verumontanum were visualized with high spatial resolution and in good agreement with McNeal's zonal anatomy. The characteristic appearance of prostate pathologies, such as prostate cancerous lesions, benign prostatic hyperplasia, calcified tissues and atrophy were identified in ARFI images based upon correlation with the corresponding histological slides. This study demonstrates that ARFI imaging can be used to visualize internal structures and detecting suspicious lesions in the prostate and appears promising for image guidance of prostate biopsy. PMID:20350685

  12. Co-expression and impact of prostate specific membrane antigen and prostate specific antigen in prostatic pathologies

    PubMed Central

    2010-01-01

    Background The present study was undertaken to relate the co-expression of prostate-associated antigens, PSMA and PSA, with the degree of vascularization in normal and pathologic (hyperplasia and cancer) prostate tissues to elucidate their possible role in tumor progression. Methods The study was carried out in 6 normal, 44 benign prostatic hyperplastic and 39 cancerous human prostates. Immunohistochemical analysis were performed using the monoclonal antibody CD34 to determine the angiogenic activity, and the monoclonal antibodies 3E6 and ER-PR8 to assess PSMA and PSA expression, respectively. Results In our study we found that in normal prostate tissue, PSMA and PSA were equally expressed (3.7 ± 0.18 and 3.07 ± 0.11). A significant difference in their expression was see in hyperplastic and neoplastic prostates tissues (16.14 ± 0.17 and 30.72 ± 0.85, respectively) for PSMA and (34.39 ± 0.53 and 17.85 ± 1.21, respectively) for PSA. Study of prostate tumor profiles showed that the profile (PSA+, PSMA-) expression levels decreased between normal prostate, benign prostatic tissue and primary prostate cancer. In the other hand, the profile (PSA-, PSMA+) expression levels increased from normal to prostate tumor tissues. PSMA overexpression was associated with high intratumoral angiogenesis activity. By contrast, high PSA expression was associated with low angiogenesis activity. Conclusion These data suggest that these markers are regulated differentially and the difference in their expression showed a correlation with malignant transformation. With regard to the duality PSMA-PSA, this implies the significance of their investigation together in normal and pathologic prostate tissues. PMID:21189143

  13. Intercellular communication and human prostate carcinogenesis.

    PubMed

    Carruba, Giuseppe; Stefano, Rosalba; Cocciadiferro, Letizia; Saladino, Francesca; Di Cristina, Antonietta; Tokar, Erik; Quader, Salmann T A; Webber, Mukta M; Castagnetta, Luigi

    2002-06-01

    Gap-junction-mediated intercellular communication (GJIC) is required for completion of embryonic development, tissue homeostasis, and regulation of cell proliferation and death. Although, as emphasized in several reports, defects or disruption of GJIC may be important in carcinogenesis, the potential role of GJIC in the onset and progression of human prostate cancer remains ill-defined. The gap junction channel-forming connexins (Cx) comprise a multigene family of highly conserved proteins that are differentially expressed in a tissue- and development-specific manner; changes in connexin expression are also commonly seen during cellular differentiation. However, when multiple connexins are concurrently expressed, gap junction channels may consist of more than one connexin species. This is important, because only certain pairings give rise to functional channels. In our studies, we investigated GJIC in a panel of both nontumorigenic (RWPE-1) and malignant (RWPE-2, LNCaP, DU-145) human prostate epithelial cells, compared to a normal rat liver epithelial F344 (WB-1) cell line, as it was found to be junctionally proficient. In addition, expression and regulation of Cx43 and Cx32 were also inspected using western blot analysis. The ability of hormones, antihormones, and the antihypertensive drug forskolin to restore GJIC in nontumorigenic and malignant human prostate epithelial cells was examined by the scrape-loading/dye transfer (SL/DT) or fluorescence recovery after photobleaching (FRAP) methods using an Ultima laser cytometer. Results from both assays showed that neither nontumorigenic nor malignant prostate cells have functional GJIC. However, both estrone (E1) and forskolin (FK) induced a significant increase (4.4- and 2.8-fold, respectively) in cell-cell communication only in the RWPE-1 cells. Interestingly, the use of Matrigel, a solubilized basement membrane, as substrate for cell attachment and growth resulted in the rescue of GJIC activity in RWPE-1 cells, as

  14. Is the phenotype mixed or mistaken? Hereditary nonpolyposis colorectal cancer and hyperplastic polyposis syndrome.

    PubMed

    Jarrar, Awad M; Church, James M; Fay, Susan; Kalady, Matthew F

    2009-12-01

    Hereditary nonpolyposis colorectal cancer is a hereditary syndrome defined by personal and family history of colorectal and other cancers. Some patients with this condition have multiple serrated polyps, which are the hallmark of hyperplastic polyposis syndrome, a rare colorectal cancer syndrome characterized by multiple hyperplastic/serrated polyps and an increased risk of colorectal cancer. We hypothesized that this may represent a unique group of patients, and this study investigates a possible association between the two syndromes. A hereditary colorectal cancer registry was reviewed for patients who fit hereditary nonpolyposis colorectal cancer or familial colorectal cancer and hyperplastic polyposis syndrome criteria. Twelve patients from seven families were identified. Four families had more than one person meeting the criteria. All patients were white, and four were women. Ten of 12 patients fit Amsterdam criteria, and two were designated with familial colorectal cancer. The median cumulative number of hyperplastic polyps resected per patient was 6, half of which were located in the right colon. Seven of the 12 patients developed colorectal cancer. Ten patients had personal or family history of other cancers: prostate, breast, testicular, salivary gland, lung, and Hodgkin's disease. Patients meeting criteria for hereditary nonpolyposis colorectal cancer may also carry a diagnosis of hyperplastic polyposis syndrome. Possible explanations include: 1) two hereditary syndromes are present in the same patient, 2) serrated polyps are part of the phenotype of hereditary nonpolyposis colorectal cancer, or 3) hereditary nonpolyposis colorectal cancer is potentially misdiagnosed in some families who do, in fact, have hyperplastic polyposis.

  15. Response of Human Prostate Tissue to Hypofractionated Ionizing Radiation

    DTIC Science & Technology

    2012-05-01

    hypofractionated ionizing radiation. PRINCIPAL INVESTIGATOR: Thomas C. Sroka, M.D., Ph.D...April 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Response of human prostate tissue to hypofractionated ionizing radiation. 5b. GRANT NUMBER...of this proposal was to determine the differences in radiobiological response of human prostate tissue to conventional and hypofractionated

  16. Altered expression of p53, but not Rb, is involved in canine prostatic carcinogenesis.

    PubMed

    Pagliarone, Simone; Frattone, Luca; Pirocchi, Valeria; Della Salda, Leonardo; Palmieri, Chiara

    2016-04-01

    Abnormalities in the retinoblastoma (Rb) and p53 tumour suppressor gene have been frequently detected in human and canine cancers, but never investigated in canine prostate cancer, considered a good model for the advanced and aggressive androgen-resistant prostate cancer in men. Therefore, the aim of this study was to evaluate the immunohistochemical expression of Rb and p53 in 6 normal canine prostates, 15 canine prostates with benign prostatic hyperplasia (BPH) and 10 prostatic carcinomas (PCs). In all normal samples, p53 was expressed in low number of epithelial cells, while a greater number of positive cells were observed in BPH and PC. The mean number of positive cells was statistically significantly higher in PCs than normal and hyperplastic prostates. A cytoplasmic or nucleo-cytoplasmic staining was observed in 5 out of 10 PCs. Rb protein was expressed in high number of normal, hyperplastic and neoplastic cells without a statistically significant differences. Considering that Rb is frequently lost in human prostate cancer, we suggest that Rb is not involved in canine prostatic carcinogenesis. On the other hand, the increased expression of p53 that corresponds to genetic defects in the p53 gene may be associated with the malignant growth of canine prostate cancer, conferring an apoptosis-resistant phenotype.

  17. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

    PubMed

    Lee, John K; Phillips, John W; Smith, Bryan A; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M; Shokat, Kevan M; Gustafson, W Clay; Huang, Jiaoti; Witte, Owen N

    2016-04-11

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.

  18. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

    PubMed Central

    Lee, John K.; Phillips, John W.; Smith, Bryan A.; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F.; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G.; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M.; Shokat, Kevan M.; Gustafson, W. Clay; Huang, Jiaoti; Witte, Owen N.

    2016-01-01

    SUMMARY MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. PMID:27050099

  19. Human papillomavirus and Epstein Barr virus in prostate cancer: Koilocytes indicate potential oncogenic influences of human papillomavirus in prostate cancer.

    PubMed

    Whitaker, Noel J; Glenn, Wendy K; Sahrudin, Arisha; Orde, Matthew M; Delprado, Warick; Lawson, James S

    2013-02-15

    The purpose of this study is to determine if high risk human papillomaviruses (HPV) and Epstein Barr virus (EBV) are both present in the same prostate cancer specimens. We used a range of analytical techniques including in situ polymerase chain reaction (IS-PCR) and standard liquid PCR followed by sequencing of the product to seek to identify HPV and EBV in normal, benign, and malignant prostate tissues. Both HPV type 18 and EBV gene sequences were identified in a high and approximately equal proportion of normal, benign, and prostate cancer specimens. These sequences were located in the nuclei of prostate epithelial cells. HPV associated koilocytes were identified in 24% of prostate cancer specimens. The presence of both HPV and EBV gene sequences in most of the same normal, benign, and malignant prostate specimens is particularly noteworthy because of recent experimental evidence demonstrating that EBV and HPV can collaborate to increase proliferation of cultured cervical cells. Because the presence of EBV and HPV in normal, benign, and malignant prostate tissues appears to be ubiquitous, it is possible that they are harmless. On the other hand HPV type 18 in particular, has high oncogenic potential and may be associated with some prostate cancers. The identification of HPV associated koilocytes in prostate cancer specimens is an indication of HPV infection and potential oncogenic influences of human papillomavirus in prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

  20. Emerging Roles of Human Prostatic Acid Phosphatase

    PubMed Central

    Kong, Hoon Young; Byun, Jonghoe

    2013-01-01

    Prostate cancer is one of the most prevalent non-skin related cancers. It is the second leading cause of cancer deaths among males in most Western countries. If prostate cancer is diagnosed in its early stages, there is a higher probability that it will be completely cured. Prostatic acid phosphatase (PAP) is a non-specific phosphomonoesterase synthesized in prostate epithelial cells and its level proportionally increases with prostate cancer progression. PAP was the biochemical diagnostic mainstay for prostate cancer until the introduction of prostate-specific antigen (PSA) which improved the detection of early-stage prostate cancer and largely displaced PAP. Recently, however, there is a renewed interest in PAP because of its usefulness in prognosticating intermediate to high-risk prostate cancers and its success in the immunotherapy of prostate cancer. Although PAP is believed to be a key regulator of prostate cell growth, its exact role in normal prostate as well as detailed molecular mechanism of PAP regulation is still unclear. Here, many different aspects of PAP in prostate cancer are revisited and its emerging roles in other environment are discussed. PMID:24009853

  1. Androgen Regulated Genes in Human Prostate Xenografts in Mice: Relation to BPH and Prostate Cancer

    PubMed Central

    Love, Harold D.; Booton, S. Erin; Boone, Braden E.; Breyer, Joan P.; Koyama, Tatsuki; Revelo, Monica P.; Shappell, Scott B.; Smith, Jeffrey R.; Hayward, Simon W.

    2009-01-01

    Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues. PMID:20027305

  2. Voltage-gated sodium channels were differentially expressed in human normal prostate, benign prostatic hyperplasia and prostate cancer cells.

    PubMed

    Shan, Bin; Dong, Mei; Tang, He; Wang, Na; Zhang, Jin; Yan, Changqing; Jiao, Xiaocui; Zhang, Hailin; Wang, Chuan

    2014-07-01

    Voltage-gated sodium channels (VGSCs) are expressed not only in excitable cells but also in numerous metastatic cells, particularly in certain types of cancer cells. In some types of cancer, including prostate cancer, the expression of VGSCs is associated with cancer migration, invasion and metastasis in vivo. However, the detailed expression profiles of VGSC α subunits in normal human prostate, in prostatic hyperplasia and prostatic cancer remain controversial. In the present study, quantitative polymerase chain reaction was used to systematically detect all subtypes of VGSC α subunits in normal human prostate, benign prostatic hyperplasia (BPH) and prostate cancer cells. The expression profile of VGSC α subunits was observed to differ between these cell types. Nav1.5 was the major isoform expressed in normal human prostate tissue, while Nav1.5 and Nav1.2 were the predominant isoforms in BPH tissue. However, in PC-3 and LNCaP cells, two typical prostate cancer cell lines, Nav1.6 and Nav1.7 were abundantly expressed. By comparing the relative expression levels of Nav1.5, Nav1.6 and Nav1.7 in these cells, the mRNA levels of Nav1.6 and Nav1.7 were identified to be 6- to 27-fold higher in PC-3 and LNCaP cells than in either normal or BPH samples (P<0.05); however, Nav1.5 mRNA levels were relatively lower compared with those of Nav1.6 or Nav1.7 in all cells analyzed. To confirm whether Nav1.6 and Nav1.7 expression in cancer cells was functional, a patch-clamp technique was used to record whole-cell currents. A tetrodotoxin-sensitive sodium current was successfully recorded in PC-3 cells, but not in LNCaP cells. It was concluded that although all types of VGSC α subunits exhibited low expression levels in normal prostate and BPH cells, both Nav1.6 and Nav1.7 were significantly upregulated in the prostate cancer cell lines, suggesting these subtypes may be potential diagnostic markers and therapeutic targets for certain types of prostate cancer in humans.

  3. Isolation and analysis of discreet human prostate cellular populations

    PubMed Central

    Strand, Douglas W.; Aaron, LaTayia; Henry, Gervaise; Franco, Omar E.; Hayward, Simon W.

    2015-01-01

    The use of lineage tracing in transgenic mouse models has revealed an abundance of subcellular phenotypes responsible for maintaining prostate homeostasis. The ability to use fresh human tissues to examine the hypotheses generated by these mouse experiments has been greatly enhanced by technical advances in tissue processing, flow cytometry and cell culture. We describe in detail the optimization of protocols for each of these areas to facilitate research on solving human prostate diseases through the analysis of human tissue. PMID:26546040

  4. The Isolation and Characterization of Human Prostate Cancer Stem Cells

    DTIC Science & Technology

    2015-05-01

    following significant findings/observations: i) 3D culture of human prostate cancer cells with magnetic nanoparticles is not optimal for tumor initiation...include: magnetic nanoparticles and using a stable (non-transformed) human prostate fibroblast cell line as a feeder layer. The former uses inert magnetic... nanoparticles (3D Biosciences, Inc.) that passively diffuse into live cells that then allow 3D growth in an applied magnetic field1. Such a

  5. Endocrine Disruption and Human Prostate Cancer

    DTIC Science & Technology

    2008-03-01

    described in Task 1, was to expose pregnant female rats to vinclozolin and test if the inductive and instructive properties of the prostate stroma is...ethane dimethane sulphonate ) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol Ind Health...BPH Benign prostate hyperplasia cDNA Complementary deoxyribonucleic acid DP Dorsal prostate EDC Endocrine disruptor E Estrogen FgF10

  6. Arachidonic acid metabolism in human prostate cancer

    PubMed Central

    YANG, PEIYING; CARTWRIGHT, CARRIE A.; LI, JIN; WEN, SIJIN; PROKHOROVA, INA N.; SHUREIQI, IMAD; TRONCOSO, PATRICIA; NAVONE, NORA M.; NEWMAN, ROBERT A.; KIM, JERI

    2012-01-01

    The arachidonic acid pathway is important in the development and progression of numerous malignant diseases, including prostate cancer. To more fully evaluate the role of individual cyclooxygenases (COXs), lipoxygenases (LOXs) and their metabolites in prostate cancer, we measured mRNA and protein levels of COXs and LOXs and their arachidonate metabolites in androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cell lines, bone metastasis-derived MDA PCa 2a and MDA PCa 2b cell lines and their corresponding xenograft models, as well as core biopsy specimens of primary prostate cancer and nonneoplastic prostate tissue taken ex vivo after prostatectomy. Relatively high levels of COX-2 mRNA and its product PGE2 were observed only in PC-3 cells and their xenografts. By contrast, levels of the exogenous 12-LOX product 12-HETE were consistently higher in MDA PCa 2b and PC-3 cells and their corresponding xenograft tissues than were those in LNCaP cells. More strikingly, the mean endogenous level of 12-HETE was significantly higher in the primary prostate cancers than in the nonneoplastic prostate tissue (0.094 vs. 0.010 ng/mg protein, respectively; p=0.019). Our results suggest that LOX metabolites such as 12-HETE are critical in prostate cancer progression and that the LOX pathway may be a target for treating and preventing prostate cancer. PMID:22895552

  7. High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer.

    PubMed

    Glenn, Wendy K; Ngan, Christopher C; Amos, Timothy G; Edwards, Richard J; Swift, Joshua; Lutze-Mann, Louise; Shang, Fei; Whitaker, Noel J; Lawson, James S

    2017-01-01

    Although high risk HPVs are associated with an increased risk of prostate cancer it is not known if they have a causal role. The purpose of this study is to investigate the potential role of human papilloma viruses (HPVs) in prostate cancer. The aims are (i) to investigate the presence and confirm the identity of high risk HPVs in benign prostate tissues prior to the development of HPV positive prostate cancer in the same patients, and (ii) to determine if HPVs are biologically active. We used polymerase chain reaction (PCR) to identify HPVs in specimens from 52 Australian men with benign prostate biopsies who 1 to 10 years later developed prostate cancer. Immunohistochemistry (IHC) was used to assess the expression of HPV E7 oncoproteins, cytokeratin and prostate specific antigen (PSA). We used RNASeq data from The Cancer Genome Atlas (TCGA) to identify possible HPV RNA sequences in prostate cancer. HPV screening using standard PCR was conducted on 28 of the 52 sets of benign and later prostate cancers. HPV L1 genes were identified in 13 (46%) benign and 8 (29%) of 28 later prostate cancers in the same patients. HPV E7 genes were identified in 23 (82%) benign and 19 (68%) of 28 subsequent prostate cancers in the same patients. The same HPV types were present in both the benign and subsequent prostate cancers in 9 sets of specimens. HPV type 16 was identified in 15% of benign and 3% of prostate cancers. HPV type 18 was identified in 26% of benign and 16% of prostate cancers. Small numbers of HPV types 45, 47, 76 and 115 were also identified. High confidence RNA-Seq evidence for high risk HPV types 16 and 18 was identified in 12 (2%) of the 502 TCGA prostate cancer transcriptomes. High risk HPV E7 oncoprotein was positively expressed in 23 (82%) of 28 benign prostate specimens but only in 8 (29%) of 28 of the later prostate cancer specimens. This difference is statistically significant (p = 0.001). Prostate specific antigen (PSA) was more highly expressed in 26

  8. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

    PubMed Central

    Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

    2005-01-01

    Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy. PMID:15824085

  9. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.

    PubMed

    Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

    2005-04-18

    Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

  10. Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk.

    PubMed Central

    Agúndez, J. A.; Martínez, C.; Olivera, M.; Gallardo, L.; Ladero, J. M.; Rosado, C.; Prados, J.; Rodriguez-Molina, J.; Resel, L.; Benítez, J.

    1998-01-01

    The role of two common polymorphisms of enzymes involved in the metabolism of drugs and carcinogens was studied in relation to prostate cancer. The gene encoding one of these enzymes (NAT2) is located in an area where frequent allelic loss occurs in prostate cancer. Mutations at the genes CYP2D6 and NAT2 were analysed by allele-specific polymerase chain reaction and restriction mapping in DNA from 94 subjects with prostate cancer and 160 male healthy control subjects. Eleven prostate specimens were analysed for genotype and enzymatic activities NAT2, CYP2D6 and CYP3A by using the enzyme-specific substrates sulphamethazine and dextromethorphan. Enzyme activities with substrate specificities corresponding to NAT2, CYP2D6 and CYP3A are present in human prostate tissue, with mean +/-s.d. activities of 4.8+/-4.4 pmol min(-1) mg(-1) protein, 156+/-91 and 112+/-72 nmol min(-1) mg(-1) protein respectively. The Km values for the prostate CYP2D6 and CYP3A enzyme activities corresponded to that of liver CYP2D6 and CYP3A activities, and the CYP2D6 enzyme activity is related to the CYP2D6 genotype. The N-acetyltransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyltransferase activity that is independent of the regulation of the NAT2 gene, are expressed in human prostate tissue. The presence of carcinogen-metabolizing enzymes in human prostate with a high interindividual variability may be involved in the regulation of local levels of carcinogens and mutagens and may underlie interindividual differences in cancer susceptibility. Images Figure 1 PMID:9823980

  11. 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

  12. Estrogen binding and estrogen receptor activity in the human prostate: a preliminary report.

    PubMed

    Fondo, E Y; Menendez-Botet, C J; Schwartz, M K; Whitmore, W F

    1981-03-01

    Assay of estrogen receptor activity in prostates from patients who ranged in age from 22 to 78 years and had not received any previous hormonal therapy was carried out by incubation of cytosols with (3)H-estradiol in the presence and absence of excess, nonradioactive estradiol. Hyperplastic prostatic tissues were used in the study. The kinetics of each reaction were studied and analysis of the data revealed 3.4 to 35.7 femtomoles of receptor protein per mg of cytosol protein; the dissociation constants obtained from a Scatchard plot ranged from 1.1 × 10(-10) to 1.2 × 10(-8)M.The small number of patients prevents realistic quantitative assessment of the apparent estrogen binding activity demonstrated in these preliminary studies, but the qualitative identification of such activity provides possible grounds for further insight into the hormonal mechanisms in the pathophysiology of prostatic diseases and of their responses to endocrine therapy.

  13. Involvement of human papillomavirus infections in prostate cancer progression.

    PubMed

    Al Moustafa, Ala-Eddin

    2008-08-01

    High-risk human papillomaviruses (HPVs) are sexually transmitted and have been associated with several human carcinomas especially cervical and colorectal. On the other hand, a small number of studies have examined the presence of high-risk HPV in human prostate cancer tissues. Currently, the presence and role of high-risk HPV infections in prostate carcinogenesis remain unclear because of the limited number of investigations. This raises the question whether high-risk HPV infections play any role in human prostate cancer development. However, other investigators and our group were able to immortalize normal and cancer prostate epithelial cells in vitro by E6/E7 of HPV type 16. In this paper, we propose the hypothesis that normal and cancer prostate epithelial cells are susceptible to persistent HPV infections; therefore, high-risk HPV infections play an important role in the progression of prostate cancer. We believe that an international collaboration of epidemiological studies and more molecular biology investigations are necessary to answer these important questions.

  14. Keratin immunoreactivity as an aid to the diagnosis of persistent adenocarcinoma in irradiated human prostates

    SciTech Connect

    Brawer, M.K.; Nagle, R.B.; Pitts, W.; Freiha, F.; Gamble, S.L.

    1989-02-01

    Postirradiation prostatic biopsy is believed by many to be the best measure of radiation effectiveness in prostatic cancer. Therapeutic irradiation may induce prostatic glandular atypia, which in its severe form can be confused with persistent adenocarcinoma on prostatic biopsies. In the current study, 37 postirradiation prostate biopsy specimens were evaluated by immunohistochemistry using a specific monoclonal anticytokeratin antibody (KA1) that reacts with the basal cells of normal or hyperplastic glands, but is nonreactive with the lumenal cells or with prostatic carcinoma cells. Persistent carcinoma was observed in 19 cases in which antibody staining was absent. The noncarcinomatous glands retained reactivity, but this reactivity appeared in a new and previously undescribed pattern. The irradiated lesion was characterized by cellular pleomorphisism, with enlargement of nuclei and loss of polarity. The immunoreactivity was seen in the enlarged basal cells and was seen to focally extend to involve the lumenal cell layer. In five of 37 cases, glands were seen that were so atypical on the routinely stained sections that a distinction from cancer could not be made. These same glands in the adjacent section reacted with KA1 in each case allowing us to conclude that the changes were benign. We conclude that the interpretation of postirradiation prostatic biopsy specimens may be aided by immunohistochemistry with this anticytokeratin antibody.

  15. In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

    PubMed Central

    Sakai, Monica; Martinez-Arguelles, Daniel B.; Patterson, Nathan H.; Chaurand, Pierre; Papadopoulos, Vassilios

    2015-01-01

    Degarelix is a gonadrotropin-releasing hormone (GnRH) receptor (GnRHR) antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration-resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH-1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK) pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i) the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii) MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii) the clusters of genes affected by degarelix suggest that

  16. Pre-clinical Orthotopic Murine Model of Human Prostate Cancer.

    PubMed

    Shahryari, Varahram; Nip, Hannah; Saini, Sharanjot; Dar, Altaf A; Yamamura, Soichiro; Mitsui, Yozo; Colden, Melissa; Bucay, Nathan; Tabatabai, Laura Z; Greene, Kirsten; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir; Majid, Shahana

    2016-08-29

    To study the multifaceted biology of prostate cancer, pre-clinical in vivo models offer a range of options to uncover critical biological information about this disease. The human orthotopic prostate cancer xenograft mouse model provides a useful alternative approach for understanding the specific interactions between genetically and molecularly altered tumor cells, their organ microenvironment, and for evaluation of efficacy of therapeutic regimens. This is a well characterized model designed to study the molecular events of primary tumor development and it recapitulates the early events in the metastatic cascade prior to embolism and entry of tumor cells into the circulation. Thus it allows elucidation of molecular mechanisms underlying the initial phase of metastatic disease. In addition, this model can annotate drug targets of clinical relevance and is a valuable tool to study prostate cancer progression. In this manuscript we describe a detailed procedure to establish a human orthotopic prostate cancer xenograft mouse model.

  17. Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer

    DTIC Science & Technology

    2006-08-01

    DAMD17-02-1-0060 TITLE: Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer PRINCIPAL INVESTIGATOR: Sarah Spiegel...Final 3. DATES COVERED (From - To) 2 Jan 2002 – 31 Jul 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Lysophosphatidic Acid Regulation and Roles ...important role in the pathophysiology of prostate cancer. Therefore, targeting this kinase, offers additional therapeutic benefits in treatment of

  18. Prediction of Aggressive Human Prostate Cancer by Cathepsin B

    DTIC Science & Technology

    2008-03-01

    for CB was added to the wells. Following several washes to remove unbound antibody-enzyme reagent, a substrate solution HRP (horse- radish ...prostate cancer. Clin Cancer Res 6: 3430-3433, 2000. 8 Guo Y, Sigman DB, Borkowski A and Kyprianou N: Racial differences in prostate cancer growth ...cystatins in tumor growth and progression. Biol Chem Hoppe Seyler 1990;371 Suppl:193-198. 39. Yan S, Sloane BF. Molecular regulation of human cathepsin B

  19. Differentially Expressed Genes and Signature Pathways of Human Prostate Cancer

    PubMed Central

    Myers, Jennifer S.; von Lersner, Ariana K.; Robbins, Charles J.; Sang, Qing-Xiang Amy

    2015-01-01

    Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The “transforming growth factor-beta signaling” and “Ran regulation of mitotic spindle formation” pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran) for investigation in prostate cancer pathogenesis. PMID:26683658

  20. Nonylphenol effects on human prostate non tumorigenic cells.

    PubMed

    Forte, Maurizio; Di Lorenzo, Mariana; Carrizzo, Albino; Valiante, Salvatore; Vecchione, Carmine; Laforgia, Vincenza; De Falco, Maria

    2016-05-16

    Nonylphenol (NP) is an industrial chemical with estrogenic activity both in vivo and in vitro; estrogens play a critical role in the development of prostate and may be the cause of some pathological states, including cancer. In this study we examined the effects of NP on human prostate non tumorigenic epithelial cells (PNT1A) investigating on cell proliferation, interaction with estrogen receptors (ERs) and gene expression of genes involved in prostate diseases. We found that NP affects cell proliferation at 10(-6)M, promoting a cytoplasm-nucleus translocation of ERα and not ERβ, like the natural estrogen 17β-estradiol (E2). Moreover, we showed that NP enhances gene expression of key regulators of cell cycle. Estrogen selective antagonist ICI182780 in part reverted the observed effects of NP. These results confirm the estrogenic activity of NP and suggest that other transduction pathways may be involved in NP action on prostate.

  1. High resolution regional elasticity mapping of the human prostate.

    PubMed

    Murayama, Yoshinobu; Omata, Sadao; Yajima, Toshikuni; Peng, Qiyu; Shishido, Keiichi; Peehl, Donna M; Constantinou, Christos E

    2007-01-01

    What is it that the clinician "feels" during a digital rectal examination? To answer this question, it is necessary to measure the elastic properties of the prostate and verify the stiffness values with histological examination. Therefore, we devised an Elasticity Mapping System to evaluate the elastic properties of various histopathological grades of prostate cancer in relation to benign prostatic hyperplasia (BPH) and normal tissue. The system consists of a micro tactile sensor, a three-axis (XYZ) with one (fine Z) micromanipulation stage, a stereoscope camera and a measurement chamber. Using this methodology we mapped the elasticity of human prostate cancer (CaP) and it was obviously observed that the node was significantly harder than surrounding normal tissues and had some textures.

  2. The role of human papillomavirus infection in prostate carcinoma.

    PubMed

    Aghakhani, Arezoo; Hamkar, Rasool; Parvin, Mahmoud; Ghavami, Nastaran; Nadri, Mahsa; Pakfetrat, Attesa; Banifazl, Mohammad; Eslamifar, Ali; Izadi, Nabiollah; Jam, Sara; Ramezani, Amitis

    2011-01-01

    Human papillomavirus (HPV) infections are associated with benign and malignant lesions of the female and male anogenital tract. Currently the possible role of HPV infections in prostate carcinogenesis is a subject of great controversy. In this study we aimed to investigate the role of HPV infection in prostate carcinoma (PCa). The study included formalin-fixed paraffin-embedded tissue samples of 104 primary prostate adenocarcinoma cases and 104 control tissues of benign prostatic hyperplasia (BPH). HPV-DNA was purified and amplified through MY09/MY11 and GP5(+)/GP6(+) primers and subsequently subjected to sequencing. HPV-DNA was found in 13 of 104 (12.5%) PCa and 8 of 104 (7.7%) BPH samples. High-risk HPVs were detected in 10 of 13 (76.9%) PCa and 5 of 8 (62.5%) BPH samples with positive HPV-DNA. Low-risk HPVs were detected in 3 of 13 (23.1%) PCa and 3 of 8 (37.5%) BPH specimens with positive HPV-DNA. There was no significant difference between PCa and BPH specimens regarding HPV-DNA presence or the detection of high-risk and low-risk types of HPV. Our data do not support the role of HPV infection in prostate carcinoma. Further studies are required to elucidate the role of HPV infection in human prostate carcinogenesis.

  3. Adenosine deaminase complexing protein (ADCP) expression and metastatic potential in prostatic adenocarcinomas.

    PubMed

    Dinjens, W N; Ten Kate, J; Kirch, J A; Tanke, H J; Van der Linden, E P; Van den Ingh, H F; Van Steenbrugge, G J; Meera Khan, P; Bosman, F T

    1990-03-01

    The expression of the adenosine deaminase complexing protein (ADCP) was investigated by immunohistochemistry in the normal and hyperplastic human prostate, in 30 prostatic adenocarcinomas, and in seven human prostatic adenocarcinoma cell lines grown as xenografts in athymic nude mice. In the normal and hyperplastic prostate, ADCP was localized exclusively in the apical membrane and the apical cytoplasm of the glandular epithelial cells. In prostatic adenocarcinomas, four distinct ADCP expression patterns were observed: diffuse cytoplasmic, membranous, both cytoplasmic and membranous, and no ADCP expression. The expression patterns were compared with the presence of metastases. We found an inverse correlation between membranous ADCP immunoreactivity and metastatic propensity. Exclusively membranous ADCP immunoreactivity occurred only in non-metastatic tumours. In contrast, the metastatic tumours showed no or diffuse cytoplasmic ADCP immunoreactivity. This suggests that immunohistochemical detection of ADCP might predict the biological behaviour of prostatic cancer. However, the occurrence of membranous ADCP immunoreactivity in the xenograft of a cell line (PC-EW), derived from a prostatic carcinoma metastasis, indicates that not only the tendency to metastasize modulates ADCP expression.

  4. Observations on human smooth muscle cell cultures from hyperplastic lesions of prosthetic bypass grafts: Production of a platelet-derived growth factor-like mitogen and expression of a gene for a platelet-derived growth factor receptor--a preliminary study

    SciTech Connect

    Birinyi, L.K.; Warner, S.J.; Salomon, R.N.; Callow, A.D.; Libby, P. )

    1989-08-01

    Prosthetic bypass grafts placed to the distal lower extremity often fail because of an occlusive tissue response in the perianastomotic region. The origin of the cells that comprise this occlusive lesion and the causes of the cellular proliferation are not known. To increase our understanding of this process we cultured cells from hyperplastic lesions obtained from patients at the time of reexploration for lower extremity graft failure, and we studied their identity and growth factor production in tissue culture. These cultures contain cells that express muscle-specific actin isoforms, shown by immunohistochemical staining, consistent with vascular smooth muscle origin. These cultures also released material that stimulated smooth muscle cell growth. A portion of this activity was similar to platelet-derived growth factor, since preincubation with antibody-to-human platelet-derived growth factor partially blocked the mitogenic effect of medium conditioned by human anastomotic hyperplastic cells. These conditioned media also contained material that competed with platelet-derived growth factor for its receptor, as measured in a radioreceptor assay. Northern blot analysis showed that these cells contain messenger RNA that encodes the A chain but not the B chain of platelet-derived growth factor. In addition, these cells contain messenger RNA that encodes a platelet-derived growth factor receptor. We conclude that cultured smooth muscle cells from human anastomotic hyperplastic lesions express genes for platelet-derived growth factor A chain and a platelet-derived growth factor receptor and secrete biologically active molecules similar to platelet-derived growth factor.

  5. Characterizing the stiffness of Human Prostates using Acoustic Radiation Force

    PubMed Central

    Zhai, Liang; Madden, John; Foo, Wen-Chi; Mouraviev, Vladimir; Polascik, Thomas J.; Palmeri, Mark L.; Nightingale, Kathryn R.

    2012-01-01

    Acoustic Radiation Force Impulse (ARFI) imaging has been previously reported to portray normal anatomic structures and pathologies in ex vivo human prostates with good contrast and resolution. These findings were based on comparison with histological slides and McNeal’s zonal anatomy. In ARFI images, the central zone (CZ) appears darker (smaller displacement) than other anatomic zones, and prostate cancer (PCa) is darker than normal tissue in the peripheral zone (PZ). Since displacement amplitudes in ARFI images are determined by both the underlying tissue stiffness and the amplitude of acoustic radiation force which varies with acoustic attenuation, one question that arises is: how are the relative displacements in prostate ARFI images related to the underlying prostatic tissue stiffness? In linear, isotropic elastic materials and in tissues that are relatively uniform in acoustic attenuation (e.g. liver), relative displacement in ARFI images has been shown to be correlated with underlying tissue stiffness. However, the prostate is known to be heterogeneous. Variations in acoustic attenuation of prostatic structures could confound the interpretation of ARFI images due to the associated variations in the applied acoustic radiation force. Therefore, in this study, co-registered three-dimensional (3D) ARFI datasets and quantitative shear wave elasticity imaging (SWEI) datasets were acquired in freshly excised human prostates to investigate the relationship between displacement amplitudes in ARFI prostate images and the matched reconstructed shear moduli. The lateral time-to-peak (LTTP) algorithm was applied to the SWEI data to compute the shear wave speed and reconstruct the shear moduli. Five types of prostatic tissue (PZ, CZ, transition zone (TZ) and benign prostatic hyperplasia (BPH), PCa, and atrophy) were identified, whose shear moduli were quantified to be 4.1±0.8 kPa, 9.9±0.9 kPa, 4.8±0.6 kPa, 10.0±1.0 kPa and 8.0 kPa, respectively. Linear regression was

  6. Characterizing stiffness of human prostates using acoustic radiation force.

    PubMed

    Zhai, Liang; Madden, John; Foo, Wen-Chi; Mouraviev, Vladimir; Polascik, Thomas J; Palmeri, Mark L; Nightingale, Kathryn R

    2010-10-01

    Acoustic Radiation Force Impulse (ARFI) imaging has been previously reported to portray normal anatomic structures and pathologies in ex vivo human prostates with good contrast and resolution. These findings were based on comparison with histological slides and McNeal's zonal anatomy. In ARFI images, the central zone (CZ) appears darker (smaller displacement) than other anatomic zones and prostate cancer (PCa) is darker than normal tissue in the peripheral zone (PZ). Since displacement amplitudes in ARFI images are determined by both the underlying tissue stiffness and the amplitude of acoustic radiation force that varies with acoustic attenuation, one question that arises is how the relative displacements in prostate ARFI images are related to the underlying prostatic tissue stiffness. In linear, isotropic elastic materials and in tissues that are relatively uniform in acoustic attenuation (e.g., liver), relative displacement in ARFI images has been shown to be correlated with underlying tissue stiffness. However, the prostate is known to be heterogeneous. Variations in acoustic attenuation of prostatic structures could confound the interpretation of ARFI images due to the associated variations in the applied acoustic radiation force. Therefore, in this study, co-registered three-dimensional (3D) ARFI datasets and quantitative shear wave elasticity imaging (SWEI) datasets were acquired in freshly-excised human prostates to investigate the relationship between displacement amplitudes in ARFI prostate images and the matched reconstructed shear moduli. The lateral time-to-peak (LTTP) algorithm was applied to the SWEI data to compute the shear-wave speed and reconstruct the shear moduli. Five types of prostatic tissue (PZ, CZ, transition zone (TZ) and benign prostatic hyperplasia (BPH), PCa and atrophy) were identified, whose shear moduli were quantified to be 4.1 +/- 0.8 kPa, 9.9 +/- 0.9 kPa, 4.8 +/- 0.6 kPa, 10.0 +/- 1.0 kPa and 8.0 kPa, respectively. Linear

  7. Isolation of cancer stem cells from human prostate cancer samples.

    PubMed

    Vidal, Samuel J; Quinn, S Aidan; de la Iglesia-Vicente, Janis; Bonal, Dennis M; Rodriguez-Bravo, Veronica; Firpo-Betancourt, Adolfo; Cordon-Cardo, Carlos; Domingo-Domenech, Josep

    2014-03-14

    The cancer stem cell (CSC) model has been considerably revisited over the last two decades. During this time CSCs have been identified and directly isolated from human tissues and serially propagated in immunodeficient mice, typically through antibody labeling of subpopulations of cells and fractionation by flow cytometry. However, the unique clinical features of prostate cancer have considerably limited the study of prostate CSCs from fresh human tumor samples. We recently reported the isolation of prostate CSCs directly from human tissues by virtue of their HLA class I (HLAI)-negative phenotype. Prostate cancer cells are harvested from surgical specimens and mechanically dissociated. A cell suspension is generated and labeled with fluorescently conjugated HLAI and stromal antibodies. Subpopulations of HLAI-negative cells are finally isolated using a flow cytometer. The principal limitation of this protocol is the frequently microscopic and multifocal nature of primary cancer in prostatectomy specimens. Nonetheless, isolated live prostate CSCs are suitable for molecular characterization and functional validation by transplantation in immunodeficient mice.

  8. Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk.

    PubMed

    Hu, Wen-Yang; Shi, Guang-Bin; Hu, Dan-Ping; Nelles, Jason L; Prins, Gail S

    2012-05-06

    Estrogen reprogramming of the prostate gland as a function of developmental exposures (aka developmental estrogenization) results in permanent alterations in structure and gene expression that lead to an increased incidence of prostatic lesions with aging. Endocrine disrupting chemicals (EDCs) with estrogenic activity have been similarly linked to an increased prostate cancer risk. Since it has been suggested that stem cells and cancer stem cells are potential targets of cancer initiation and disease management, it is highly possible that estrogens and EDCs influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this article, we review recent literature highlighting the effects of estrogens and EDCs on prostate cancer risk and discuss recent advances in prostate stem/progenitor cell research. Our laboratory has recently developed a novel prostasphere model using normal human prostate stem/progenitor cells and established that these cells express estrogen receptors (ERs) and are direct targets of estrogen action. Further, using a chimeric in vivo prostate model derived from these normal human prostate progenitor cells, we demonstrated for the first time that estrogens initiate and promote prostatic carcinogenesis in an androgen-supported environment. We herein discuss these findings and highlight new evidence using our in vitro human prostasphere assay for perturbations in human prostate stem cell self-renewal and differentiation by natural steroids as well as EDCs. These findings support the hypothesis that tissue stem cells may be direct EDC targets which may underlie life-long reprogramming as a consequence of developmental and/or transient adult exposures.

  9. Prostatitis

    PubMed Central

    Domingue, Gerald J.; Hellstrom, Wayne J. G.

    1998-01-01

    The laboratory diagnosis of acute bacterial prostatitis is straightforward and easily accomplished in clinical laboratories. Chronic bacterial prostatitis, and especially chronic idiopathic prostatitis (most often referred to as abacterial prostatitis), presents a real challenge to the clinician and clinical microbiologist. Clinically, the diagnosis of chronic idiopathic prostatitis is differentiated from that of acute prostatitis by a lack of prostatic inflammation and no “significant” (controversial) leukocytes or bacteria in the expressed prostatic secretions. Despite these diagnostic criteria, the etiology of chronic idiopathic prostatitis is unknown. While this review covers the entire spectrum of microbially caused acute prostatitis (including common and uncommon bacteria, viruses, fungi, and parasites) and microbially associated chronic prostatitis, a special focus has been given to chronic idiopathic prostatitis. The idiopathic syndrome is commonly diagnosed in men but is poorly treated. Recent data convincingly suggests a possible bacterial etiology for the condition. Provocative molecular studies have been published reporting the presence of 16S rRNA bacterial sequences in prostate biopsy tissue that is negative for ordinary bacteria by routine culture in men with chronic idiopathic prostatitis. Additionally, special culture methods have indicated that difficult-to-culture coryneforms and coagulase-negative staphylococci are present in expressed prostatic secretions found to be negative by routine culture techniques. Treatment failures are not uncommon in chronic prostatitis. Literature reports suggest that antimicrobial treatment failures in chronic idiopathic prostatitis caused by organisms producing extracellular slime might result from the virulent properties of coagulase-negative staphylococci or other bacteria. While it is difficult to definitively extrapolate from animal models, antibiotic pharmokinetic studies with a murine model have

  10. The Isolation and Characterization of Human Prostate Cancer Stem Cells

    DTIC Science & Technology

    2012-02-01

    magnetic field.1 This technique is based on the cellular uptake and magnetic levitation of a...culture based on magnetic cell levitation . Nature nanotechnology;5(4):291-6. Appendix None. ...have focused attention on two alternative strategies: magnetic nanoparticles and human prostate fibroblasts

  11. SEM and X-ray microanalysis of human prostatic calculi

    SciTech Connect

    Vilches, J.; Lopez, A.; De Palacio, L.; Munoz, C.; Gomez, J.

    1982-02-01

    Calculi removed from human prostates affected with nodular hyperplasia were analyzed with scanning electron microscopy and EDAX system. The general spectrum was made up of Na, Al, Mg, S, P, Ca and Zn. Two types of stone were identified morphostructurally and microanalytically: calculi type I of nodular surface with high peaks of S, and calculi type II polyfaceted with high peaks of P and Ca. Their formation from corpora amylacea and/or exogenous constituents is discussed. The superficial deposit of Zn suggests its incorporation from the prostatic liquid and does not seem to play an important role in the genesis.

  12. Potential Prognostic Markers for Human Prostate Cancer

    DTIC Science & Technology

    2001-03-01

    such as proliferation, differentiation and assay [15]. TGF[3 may be produced by metastatic motility. Upregulation of growth factor synthesis or prostate...via mod- ronment include neuroendocrine cells. These cells ulation of tumor cell receptor expression. Control of can secrete bombesin, a gastrin ...controls, indicating that addition ofT015 accelerates tumor expansion. TIl15 synthesis triggered a dramatic increase in cell motility, boosting serum

  13. Interleukin-Driven Insulin-Like Growth Factor Promotes Prostatic Inflammatory Hyperplasia

    PubMed Central

    Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee

    2014-01-01

    Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1–driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation. PMID:25292180

  14. Problems in outpatients with laryngeal hyperplastic lesions.

    PubMed

    Goldman, N C

    1997-01-01

    The care of outpatients with epithelial hyperplastic lesions of the larynx presents problems of classification, treatment, continued surveillance and prognosis. One hundred patients who underwent microlaryngoscopy and vocal cord stripping from 1990 through 1995 were studied retrospectively with a follow-up period of 8-156 months. Twenty-eight patients with biopsy proven epithelial hyperplastic lesions were given 21 different pathological diagnoses exclusive of invasive carcinoma following 52 operative microlaryngoscopies. Prognosis was inferred and treatment commenced primarily on the basis of the pathology report. Microlaryngoscopy and stripping with and without the carbon dioxide laser, "watchful waiting," radiation therapy, and partial laryngectomy were all used as treatment modalities. Controversy remains as of choice of treatment. Encouraging the patient to discontinue smoking is an integral part of treatment; however, most patients continue to smoke. Recent changes in the United States health care delivery system present additional problems in surveillance of the patient.

  15. Selective changes of retroelement expression in human prostate cancer.

    PubMed

    Goering, Wolfgang; Ribarska, Teodora; Schulz, Wolfgang A

    2011-10-01

    Retroelements constitute a large part of the human genome. These sequences are mostly silenced in normal cells, but genome-wide DNA hypomethylation in cancers might lead to their re-expression. Whether this re-expression really occurs in human cancers is largely unkown. We therefore investigated expression and DNA methylation of several classes of retroelements in human prostate cancer tissues and cell lines by quantitative reverse transcription-polymerase chain reaction and pyrosequencing, respectively. The most striking finding was strong and generalized increased expression of the HERV-K_22q11.23 provirus in cancers, including de novo expression of a spliced accessory Np9 transcript in some tumors. In parallel, DNA methylation in the long terminal repeat (LTR) decreased. Conversely, HERVK17 expression was significantly diminished in cancer tissues, but this decrease was unrelated to LTR methylation. Expression of both proviruses was restricted to androgen-responsive prostate cancer cell lines and LTRs sequences containing steroid hormone-responsive elements bound the androgen receptor and conferred androgen responsiveness to reporter constructs. Expression of LINE-1 5'-untranslated region (UTR) and 3'-UTR sequences in prostate cancers rather decreased, despite significant hypomethylation of the internal LINE-1 promoter. Increased expression of the young AluYa5 and AluYb8 families was restricted to individual tumors. Our findings demonstrate a surprising specificity of changes in expression and DNA methylation of retroelements in prostate cancer. In particular, LINE-1 hypomethylation does not lead to generalized overexpression, but specific human endogenous retrovirus-K proviruses display conspicuous changes in their expression hinting at significant functions during prostate carcinogenesis.

  16. Nasopharyngeal irradiation treatment of hyperplastic adenoids

    SciTech Connect

    Pratt, L.W.

    1981-01-01

    Radiotherapy treatment in childhood is an important cause of thyroid cancer. In the 1930 to 1950 era, radium irradiation of the nasopharynx was used to control hyperplastic adenoids. Because of the technical characteristics of this applicator, sufficient radiation was not applied to the thyroid by this technique to stimulate the development of thyroid malignancies. No malignancies have been reported thus far as a result of this treatment.

  17. Virus, Oncolytic virus and Human Prostate Cancer.

    PubMed

    Liu, Guang Bin; Zhao, Liang; Zhang, Lifang; Zhao, Kong-Nan

    2016-12-15

    Prostate cancer (PCa), a disease, is characterized by abnormal cell growth in the prostate - a gland in the male reproductive system. PCa is one of the leading causes of cancer death among men of all races. Although older age and a family history of the disease have been recognized as the risk factors of PCa, the cause of this cancer remains unclear. Mounting evidence suggests that infections with various viruses are causally linked to PCa pathogenesis. Published studies have provided strong evidence that at least two viruses (RXMV and HPV) contribute to prostate tumourigenicity and impact on the survival of patients with malignant PCa. Traditional therapies including chemotherapy and radiotherapy are unable to distinguish cancer cells from normal cells, which are a significant drawback and leads to toxicities for PCa patients undergoing treatment. So far, few other options are available for treating patients with advanced PCa. Virotherapy is being developed to be a novel therapy for cancers, which uses oncotropic and oncolytic viruses with their abilities to find and destroy malignant cells in the body. For PCa treatment, oncolytic virotherapy appears to be much more attractive, which uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cancer cell lysis through virus replication and expression of cytotoxic proteins. As oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents, several important barriers still exist on the road to the use of oncolytic viruses for PCa therapy. In this review, we first discuss the controversy of the contribution of virus infection to PCa, and subsequently summarize the development of oncolytic virotherapy for PCa in the past several years.

  18. Prostate tissue stiffness as measured with a resonance sensor system: a study on silicone and human prostate tissue in vitro.

    PubMed

    Jalkanen, Ville; Andersson, Britt M; Bergh, Anders; Ljungberg, Börje; Lindahl, Olof A

    2006-07-01

    Prostate cancer is the most common form of cancer in men in Europe and in the USA. Some prostate tumours are stiffer than the surrounding normal tissue, and it could therefore be of interest to measure prostate tissue stiffness. Resonance sensor technology based on piezoelectric resonance detects variations in tissue stiffness due to a change in the resonance frequency. An impression-controlled resonance sensor system was used to detect stiffness in silicone rubber and in human prostate tissue in vitro using two parameters, both combinations of frequency change and force. Variations in silicone rubber stiffness due to the mixing ratio of the two components could be detected (p<0.05) using both parameters. Measurements on prostate tissue showed that there existed a statistically significant (MANOVA test, p<0.001) reproducible difference between tumour tissue (n=13) and normal healthy tissue (n=98) when studying a multivariate parameter set. Both the tumour tissue and normal tissue groups had variations within them, which were assumed to be related to differences in tissue composition. Other sources of error could be uneven surfaces and different levels of dehydration for the prostates. Our results indicated that the resonance sensor could be used to detect stiffness variations in silicone and in human prostate tissue in vitro. This is promising for the development of a future diagnostic tool for prostate cancer.

  19. Differential expression of human leukocyte antigen-G (HLA-G) messenger RNAs and proteins in normal human prostate and prostatic adenocarcinoma.

    PubMed

    Langat, Daudi K; Sue Platt, J; Tawfik, Ossama; Fazleabas, Asgerally T; Hunt, Joan S

    2006-08-01

    Human leukocyte antigen-G (HLA-G) is a major histocompatibility complex class Ib gene expressed in normal organs and in some tumors. The glycoproteins encoded by this gene are best known for their immunosuppressive properties. Because isoform-specific expression of HLA-G in male reproductive organs has not been reported, we investigated HLA-G1, -G2, -G5, -G6 mRNAs and proteins in four-to-five samples of normal prostate glands, prostates with benign prostatic hyperplasia and prostate adenocarcinomas using RT-PCR and immunohistochemistry. All tissues contained HLA-G1, -G2, -G5 and -G6 specific mRNAs, but only HLA-G5 protein was detectable. In normal prostate glands, HLA-G5 protein was prominent in the cytoplasm of tubuloglandular epithelia and in glandular secretions. Staining was reduced in samples of benign prostatic hyperplasia but remained localized to the cytoplasm of glandular epithelia and secretions. In prostatic adenocarcinomas, HLA-G5 protein was detectable mainly in the secretions. Thus, HLA-G5 but not HLA-G1, -G2 or -G6 is produced in the normal prostate and is present in prostatic secretions. In addition, normal cellular localization is disturbed in benign and malignant prostatic adenocarcinomas. The results are consistent with this molecule may influencing female immune receptivity to sperm and suggest that such immunosuppression could be disturbed in men with prostatic adenocarcinomas.

  20. Androgen Receptor Variants and Prostate Cancer in Humanized AR Mice

    PubMed Central

    Albertelli, Megan A.; O’Mahony, Orla A.

    2008-01-01

    SUMMARY Androgen, acting via the androgen receptor (AR), is central to male development, differentiation and hormone-dependent diseases such as prostate cancer. AR is actively involved in the initiation of prostate cancer, the transition to androgen independence, and many mechanisms of resistance to therapy. To examine genetic variation of AR in cancer, we created mice by germ-line gene targeting in which human AR sequence replaces that of the mouse. Since shorter length of a polymorphic N-terminal glutamine (Q) tract has been linked to prostate cancer risk, we introduced alleles with 12, 21 or 48 Qs to test this association. The three “humanized” AR mouse strains (h/mAR) are normal physiologically, as well as by cellular and molecular criteria, although slight differences are detected in AR target gene expression, correlating inversely with Q tract length. However, distinct allele-dependent differences in tumorigenesis are evident when these mice are crossed to a transgenic prostate cancer model. Remarkably, Q tract variation also differentially impacts disease progression following androgen depletion. This finding emphasizes the importance of AR function in androgen-independent as well as –dependent disease. These mice provide a novel genetic paradigm in which to dissect opposing functions of AR in tumor suppression vs. oncogenesis. PMID:17936615

  1. Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach.

    PubMed

    Cerasuolo, Marianna; Paris, Debora; Iannotti, Fabio A; Melck, Dominique; Verde, Roberta; Mazzarella, Enrico; Motta, Andrea; Ligresti, Alessia

    2015-08-01

    Prostate cancer is highly sensitive to hormone therapy because androgens are essential for prostate cancer cell growth. However, with the nearly invariable progression of this disease to androgen independence, endocrine therapy ultimately fails to control prostate cancer in most patients. Androgen-independent acquisition may involve neuroendocrine transdifferentiation, but there is little knowledge about this process, which is presently controversial. In this study, we investigated this question in a novel model of human androgen-dependent LNCaP cells cultured for long periods in hormone-deprived conditions. Strikingly, characterization of the neuroendocrine phenotype by transcriptomic, metabolomic, and other statistically integrated analyses showed how hormone-deprived LNCaP cells could transdifferentiate to a nonmalignantneuroendocrine phenotype. Notably, conditioned media from neuroendocrine-like cells affected LNCaP cell proliferation. Predictive in silico models illustrated how after an initial period, when LNCaP cell survival was compromised by an arising population of neuroendocrine-like cells, a sudden trend reversal occurred in which the neuroendocrine-like cells functioned to sustain the remaining androgen-dependent LNCaP cells. Our findings provide direct biologic and molecular support for the concept that neuroendocrine transdifferentiation in prostate cancer cell populations influences the progression to androgen independence.

  2. Prevalence of Helicobacter pylori in Gastric Hyperplastic Polyps.

    PubMed

    Horvath, Bela; Pai, Rish K

    2016-12-01

    Hyperplastic polyps of the stomach are routinely encountered during upper endoscopy and often arise in the setting of abnormal surrounding mucosa, particularly Helicobacter pylori, autoimmune gastritis, and reactive gastropathy. Not infrequently gastroenterologists fail to biopsy the surrounding mucosa, thus determining the underlying etiology of the gastric hyperplastic polyp can be difficult. Recently, the Rodger C. Haggitt Gastrointestinal Pathology Society published guidelines on the use of special stains. The society guidelines indicate that H pylori are not usually present in hyperplastic polyps and special stains in this setting may have limited utility. We analyzed the histologic features of 32 gastric hyperplastic polyps in which the nonpolypoid mucosa demonstrated H pylori gastritis. A consecutive series of 50 hyperplastic polyps in which no surrounding mucosa was sampled was also analyzed. When H pylori are identified in biopsies of the nonpolypoid mucosa, it is also commonly present within the polyp tissue (22/32, 69%). The majority of H pylori organisms were identified on routine hematoxylin and eosin stain (16/22, 72%). In contrast, H pylori were only seen in 2/50 consecutive hyperplastic polyps in which the surrounding mucosa was not sampled. Compared with the hyperplastic polyps that lack the organisms, H pylori associated hyperplastic polyps more commonly had dense lymphoplasmacytic inflammation (P = .0001) and neutrophils within gastric epithelium (P = .036). Polyp location, number, size, and presence of intestinal metaplasia was not associated with H pylori These results provide empirical data to guide evaluation of hyperplastic polyps for H pylori.

  3. Boric acid inhibits human prostate cancer cell proliferation.

    PubMed

    Barranco, Wade T; Eckhert, Curtis D

    2004-12-08

    The role of boron in biology includes coordinated regulation of gene expression in mixed bacterial populations and the growth and proliferation of higher plants and lower animals. Here we report that boric acid, the dominant form of boron in plasma, inhibits the proliferation of prostate cancer cell lines, DU-145 and LNCaP, in a dose-dependent manner. Non-tumorigenic prostate cell lines, PWR-1E and RWPE-1, and the cancer line PC-3 were also inhibited, but required concentrations higher than observed human blood levels. Studies using DU-145 cells showed that boric acid induced a cell death-independent proliferative inhibition, with little effect on cell cycle stage distribution and mitochondrial function.

  4. Sulphur XANES Analysis of Cultured Human Prostate Cancer Cells

    NASA Astrophysics Data System (ADS)

    Kwiatek, W. M.; Podgórczyk, M.; Paluszkiewicz, Cz.; Balerna, A.; Kisiel, A.

    2008-08-01

    Prostate cancer is one of the most commonly diagnosed cancers in men throughout the world. It is believed that changes to the structure of protein binding sites, altering its metabolism, may play an important role in carcinogenesis. Sulphur, often present in binding sites, can influence such changes through its chemical speciation. Hence there is a need for precise investigation of coordination environment of sulphur. X-ray absorption near edge structure spectroscopy offers such possibility. Cell culture samples offer histologically well defined areas of good homogeneity, suitable for successful and reliable X-ray absorption near edge structure analysis. This paper presents sulphur speciation data collected from three different human prostate cancer cell lines (PC-3, LNCaP and DU-145). Sulphur X-ray absorption near edge structure analysis was performed on K-edge structure. The spectra of cells were compared with those of cancerous tissue and with organic substances as well as inorganic compounds.

  5. A chemical relaxation study of human prostatic acid phosphatase.

    PubMed

    Shear, D B; Kustin, K

    1968-01-01

    Chemical relaxation methods and a dilution technique were applied to the study of the hydrolysis of p-nitrophenyl phosphate by human prostatic acid phosphatase. Although the reaction mechanism was not elucidated, rate constants and equilibrium constants were obtained for the reaction of enzyme and p-nitrophenol to form a complex. A slow, 2-sec relaxation effect which showed no concentration dependence was observed in various reaction mixtures, including some lacking the substrate and products of the hydrolytic reaction. The conclusion drawn is that there are two forms of the prostatic enzyme, which are normally in equilibrium with each other, but which undergo a relatively slow interconversion when this equilibrium is perturbed. A preliminary calculation indicates that these forms are present in the equilibrium ratio of 2:1.

  6. Bisphenol A Promotes Human Prostate Stem-Progenitor Cell Self-Renewal and Increases In Vivo Carcinogenesis in Human Prostate Epithelium

    PubMed Central

    Hu, Wen-Yang; Shi, Guang-Bin; Hu, Dan-Ping; Majumdar, Shyama; Li, Guannan; Huang, Ke; Nelles, Jason L.; Ho, Shuk-Mei; Walker, Cheryl Lyn; Kajdacsy-Balla, Andre; van Breemen, Richard B.

    2014-01-01

    Previous studies in rodent models have shown that early-life exposure to bisphenol A (BPA) reprograms the prostate and enhances its susceptibility to hormonal carcinogenesis with aging. To determine whether the human prostate is similarly sensitive to BPA, the current study used human prostate epithelial stem-like cells cultured from prostates of young, disease-free donors. Similar to estradiol-17β (E2), BPA increased stem-progenitor cell self-renewal and expression of stem-related genes in a dose-dependent manner. Further, 10 nM BPA and E2 possessed equimolar membrane-initiated signaling with robust induction of p-Akt and p-Erk at 15 minutes. To assess in vivo carcinogenicity, human prostate stem-progenitor cells combined with rat mesenchyme were grown as renal grafts in nude mice, forming normal human prostate epithelium at 1 month. Developmental BPA exposure was achieved through oral administration of 100 or 250 μg BPA/kg body weight to hosts for 2 weeks after grafting, producing free BPA levels of 0.39 and 1.35 ng/mL serum, respectively. Carcinogenesis was driven by testosterone plus E2 treatment for 2 to 4 months to model rising E2 levels in aging men. The incidence of high-grade prostate intraepithelial neoplasia and adenocarcinoma markedly increased from 13% in oil-fed controls to 33% to 36% in grafts exposed in vivo to BPA (P < .05). Continuous developmental BPA exposure through in vitro (200 nM) plus in vivo (250 μg/kg body weight) treatments increased high-grade prostate intraepithelial neoplasia/cancer incidence to 45% (P < .01). Together, the present findings demonstrate that human prostate stem-progenitor cells are direct BPA targets and that developmental exposure to BPA at low doses increases hormone-dependent cancer risk in the human prostate epithelium. PMID:24424067

  7. Is Human Papillomavirus Associated with Prostate Cancer Survival?

    PubMed Central

    Barbazza, Renzo; Marongiu, Barbara; Bonin, Serena; Stanta, Giorgio

    2013-01-01

    The role of human papillomavirus (HPV) in prostate carcinogenesis is highly controversial: some studies suggest a positive association between HPV infection and an increased risk of prostate cancer (PCa), whereas others do not reveal any correlation. In this study, we investigated the prognostic impact of HPV infection on survival in 150 primary PCa patients. One hundred twelve (74.67%) patients had positive expression of HPV E7 protein, which was evaluated in tumour tissue by immunohistochemistry. DNA analysis on a subset of cases confirmed HPV infection and revealed the presence of genotype 16. In Kaplan-Meier analysis, HPV-positive cancer patients showed worse overall survival (OS) (median 4.59 years) compared to HPV-negative (median 8.24 years, P = 0.0381). In multivariate analysis age (P < 0.001), Gleason score (P < 0.001), nuclear grading (P = 0.002), and HPV status (P = 0.034) were independent prognostic factors for OS. In our cohort, we observed high prevalence of HPV nuclear E7 oncoprotein and an association between HPV infection and PCa survival. In the debate about the oncogenic activity of HPV in PCa, our results further confirm the need for additional studies to clarify the possible role of HPV in prostate carcinogenesis. PMID:24288430

  8. ICRAC controls the rapid androgen response in human primary prostate epithelial cells and is altered in prostate cancer

    PubMed Central

    Holzmann, Christian; Kilch, Tatiana; Kappel, Sven; Armbrüster, Andrea; Jung, Volker; Stöckle, Michael; Bogeski, Ivan; Schwarz, Eva C.; Peinelt, Christine

    2013-01-01

    Labelled 5α-dihydrotestosterone (DHT) binding experiments have shown that expression levels of (yet unidentified) membrane androgen receptors (mAR) are elevated in prostate cancer and correlate with a negative prognosis. However, activation of these receptors which mediate a rapid androgen response can counteract several cancer hallmark functions such as unlimited proliferation, enhanced migration, adhesion and invasion and the inability to induce apoptosis. Here, we investigate the downstream signaling pathways of mAR and identify rapid DHT induced activation of store-operated Ca2+ entry (SOCE) in primary cultures of human prostate epithelial cells (hPEC) from non-tumorous tissue. Consequently, down-regulation of Orai1, the main molecular component of Ca2+ release-activated Ca2+ (CRAC) channels results in an almost complete loss of DHT induced SOCE. We demonstrate that this DHT induced Ca2+ influx via Orai1 is important for rapid androgen triggered prostate specific antigen (PSA) release. We furthermore identified alterations of the molecular components of CRAC channels in prostate cancer. Three lines of evidence indicate that prostate cancer cells down-regulate expression of the Orai1 homolog Orai3: First, Orai3 mRNA expression levels are significantly reduced in tumorous tissue when compared to non-tumorous tissue from prostate cancer patients. Second, mRNA expression levels of Orai3 are decreased in prostate cancer cell lines LNCaP and DU145 when compared to hPEC from healthy tissue. Third, the pharmacological profile of CRAC channels in prostate cancer cell lines and hPEC differ and siRNA based knock-down experiments indicate changed Orai3 levels are underlying the altered pharmacological profile. The cancer-specific composition and pharmacology of CRAC channels identifies CRAC channels as putative targets in prostate cancer therapy. PMID:24240085

  9. Unilateral persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous in a rabbit.

    PubMed

    Boillot, Thomas; Graille, Mélanie; Williams, David; Rosolen, Serge G

    2015-11-01

    A 3-month wild rabbit was presented for examination of ocular opacities in the left eye. A complete bilateral ocular examination including slit-lamp examination, indirect ophthalmoscopy, tonometry, and ultrasound biomicroscopy was performed. Biomicroscopy of the lens of the left eye showed a retrolental fibrovascular membrane causing leukocoria. The opacity prevented biomicroscopy of the vitreous and funduscopy OS. No other disorder was present in either eye. Ultrasound examination did not show any difference between the right and left eye. Histopathological examination showed a 50-μm thick, preretinal, retrolental, nonpigmented, fibrovascular tissue. Posterior synechiae were present, but no other lesion of the posterior segment was found in this eye. These ocular abnormalities are consistent with a persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous (PHTVL/PHPV), similar to those described in other species.

  10. Molecular pathogenesis of human prostate basal cell hyperplasia.

    PubMed

    Henry, Gervaise; Malewska, Alicia; Mauck, Ryan; Gahan, Jeffrey; Hutchinson, Ryan; Torrealba, Jose; Francis, Franto; Roehrborn, Claus; Strand, Douglas

    2017-05-01

    Understanding the molecular pathogenesis of distinct phenotypes in human benign prostatic hyperplasia (BPH) is essential to improving therapeutic intervention. Current therapies target smooth muscle and luminal epithelia for relief of lower urinary tract symptoms (LUTS) due to BPH, but basal cell hyperplasia (BCH) remains untargeted. The incidence of has been reported at 8-10%, but a molecular and cellular characterization has not been performed on this phenotype. Using freshly digested tissue from surgical specimens, we performed RNA-seq analysis of flow cytometry-purified basal epithelia from 3 patients with and 4 patients without a majority BCH phenotype. qPCR was performed on 28 genes identified as significant from 13 non-BCH and 7 BCH specimens to confirm transcriptomic analysis. IHC was performed on several non-BCH and BCH specimens for 3 proteins identified as significant by transcriptomic analysis. A total of 141 human BPH specimens were analyzed for the presence of BCH. Clinical characteristics of non-BCH and BCH cohorts revealed no significant differences in age, PSA, prostate volume, medical treatment, or comorbidities. Quantitation of cellular subsets by flow cytometry in 11 BCH patients vs. 11 non-BCH patients demonstrated a significant increase in the ratio of basal to luminal epithelia in patients with BCH (P <0.05), but no significant differences in the total number of leukocytes. RNA-seq data from flow cytometry isolated basal epithelia from patients with and without BCH were subjected to gene set enrichment analysis of differentially expressed genes, which revealed increased expression of members of the epidermal differentiation complex. Transcriptomic data were complemented by immunohistochemistry for members of the epidermal differentiation complex, revealing a morphological similarity to other stratified squamous epithelial layers. Increased expression of epidermal differentiation complex members and altered epithelial stratification resembles

  11. Gastric hyperplastic polyp with focal cancer.

    PubMed

    Markowski, Adam Roman; Guzinska-Ustymowicz, Katarzyna

    2016-05-01

    This paper reports a rare case of early adenocarcinoma within the gastric hyperplastic polyp, that was completely resected during an endoscopic procedure, and discusses current recommendations in such cases. Endoscopic resection of polyps with focal dysplasia or cancer is commonly indicated, as long as the procedure can be performed safely. After complete excision of a polyp with atypical focal lesion, endoscopic surveillance is suggested. The frequency of surveillance endoscopy should depend on the precise histopathological diagnosis and possibility of confirming the completeness of the endoscopic resection. If the completeness of the procedure is confirmed both macro- and microscopically, gastric resection does not have to be performed. A follow-up esophago-gastroduodenoscopy should be performed at 1 year and then at 3 years.

  12. Gastric hyperplastic polyp with focal cancer

    PubMed Central

    Markowski, Adam Roman; Guzinska-Ustymowicz, Katarzyna

    2016-01-01

    This paper reports a rare case of early adenocarcinoma within the gastric hyperplastic polyp, that was completely resected during an endoscopic procedure, and discusses current recommendations in such cases. Endoscopic resection of polyps with focal dysplasia or cancer is commonly indicated, as long as the procedure can be performed safely. After complete excision of a polyp with atypical focal lesion, endoscopic surveillance is suggested. The frequency of surveillance endoscopy should depend on the precise histopathological diagnosis and possibility of confirming the completeness of the endoscopic resection. If the completeness of the procedure is confirmed both macro- and microscopically, gastric resection does not have to be performed. A follow-up esophago-gastroduodenoscopy should be performed at 1 year and then at 3 years. PMID:25361760

  13. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia).

    PubMed

    Sitheeque, M A M; Samaranayake, L P

    2003-01-01

    Chronic hyperplastic candidosis/candidiasis (CHC; syn. candidal leukoplakia) is a variant of oral candidosis that typically presents as a white patch on the commissures of the oral mucosa. The major etiologic agent of the disease is the oral fungal pathogen Candida predominantly belonging to Candida albicans, although other systemic co-factors, such as vitamin deficiency and generalized immune suppression, may play a contributory role. Clinically, the lesions are symptomless and regress after appropriate antifungal therapy and correction of underlying nutritional or other deficiencies. If the lesions are untreated, a minor proportion may demonstrate dysplasia and develop into carcinomas. This review outlines the demographic features, etiopathogenesis, immunological features, histopathology, and the role of Candida in the disease process. In the final part of the review, newer molecular biological aspects of the disease are considered together with the management protocols that are currently available, and directions for future research.

  14. Protein Phosphatase 2A Signaling in Human Prostate Cancer

    DTIC Science & Technology

    2011-06-01

    been shown to be involved in androgen-independent growth of human prostate cancer cells (Carson et al., 1999; Grethe and Porn -Ares, 2006; Murillo et... Porn -Ares MI. (2006). p38 MAPK regulates phosphorylation of Bad via PP2A- dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-alpha...threonine phosphatases implicated in cell growth and sig- nalling. Biochem J 2001;353:417–39. 15. Grethe S, Porn -Ares MI. p38 MAPK regulates

  15. Functional Erythropoietin Receptors Expressed by Human Prostate Cancer Cells

    DTIC Science & Technology

    2006-10-01

    carcinoma cell line (PC-3). Invest Urol, 1979. 17(1): p. 16-23. 11. Yoshimura, A., A.D. D’Andrea, and H.F. Lodish , Friend spleen focus-forming virus...receptor expression in human prostate cancer. Mod Pathol, 2004. 13. Socolovsky, M., A.E. Fallon, S. Wang, C. Brugnara, and H.F. Lodish , Fetal anemia and...Socolovsky, M., H. Nam, M.D. Fleming, V.H. Haase, C. Brugnara, and H.F. Lodish , Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased

  16. Targeting the Human Complement Membrane Attack Complex to Selectively Kill Prostate Cancer Cells

    DTIC Science & Technology

    2014-12-01

    1 AD_________________ Award Number: W81XWH-11-1-0309 TITLE: Targeting the Human Complement Membrane Attack Complex to Selectively Kill Prostate...Attack Complex to Selectively Kill Prostate Cancer Cells 5b. GRANT NUMBER W81XWH-11-1-0309 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Samuel R...leading to the lytic death of PSA- producing prostate cancer cells as well as a significant bystander effect and killing of non-PSA producing cancer

  17. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18.

    PubMed

    Bello, D; Webber, M M; Kleinman, H K; Wartinger, D D; Rhim, J S

    1997-06-01

    Prostate cancer and benign tumors of the prostate are the two most common neoplastic diseases in men in the United States, however, research on their causes and treatment has been slow because of the difficulty in obtaining fresh samples of human tissue and a lack of well characterized cell lines which exhibit growth and differentiation characteristics of normal prostatic epithelium. Non-neoplastic adult human prostatic epithelial cells from a white male donor were immortalized with human papillomavirus 18 which resulted in the establishment of the RWPE-1 cell line. Cells from the RWPE-1 cell line were further transformed by v-Ki-ras to establish the RWPE-2 cell line. The objectives of this study were to: (1) establish the prostatic epithelial origin and androgen responsiveness of RWPE-1 and RWPE-2 cell lines; (2) examine their response to growth factors; and (3) establish the malignant characteristics of the RWPE-2 cell line. Immunoperoxidase staining showed that both RWPE-1 and RWPE-2 cells express cytokeratins 8 and 18, which are characteristic of luminal prostatic epithelial cells, but they also coexpress basal cell cytokeratins. These cell lines show growth stimulation and prostate specific antigen (PSA) and androgen receptor (AR) expression in response to the synthetic androgen mibolerone, which establishes their prostatic epithelial origin. Both cell lines also show a dose-dependent growth stimulation by EGF and bFGF and growth inhibition when exposed to TGF-beta, however, the transformed RWPE-2 cells are less responsive. RWPE-1 cells neither grow in agar nor form tumors when injected into nude mice with or without Matrigel. However, RWPE-2 cells form colonies in agar and tumors in nude mice. In the in vitro invasion assay, RWPE-1 cells are not invasive whereas RWPE-2 cells are invasive. Nuclear expression of p53 and Rb proteins was heterogeneous but detectable by immunostaining in both cell lines. The RWPE-1 cells, which show many normal cell

  18. Quantitative characterization of viscoelastic properties of human prostate correlated with histology.

    PubMed

    Zhang, Man; Nigwekar, Priya; Castaneda, Benjamin; Hoyt, Kenneth; Joseph, Jean V; di Sant'Agnese, Anthony; Messing, Edward M; Strang, John G; Rubens, Deborah J; Parker, Kevin J

    2008-07-01

    Quantification of mechanical properties of human prostate tissue is important for developing sonoelastography for prostate cancer detection. In this study, we characterized the frequency-dependent complex Young's modulus of normal and cancerous prostate tissues in vitro by using stress relaxation testing and viscoelastic tissue modeling methods. After radical prostatectomy, small cylindrical tissue samples were acquired in the posterior region of each prostate. A total of 17 samples from eight human prostates were obtained and tested. Stress relaxation tests on prostate samples produced repeatable results that fit a viscoelastic Kelvin-Voigt fractional derivative (KVFD) model (r(2)>0.97). For normal (n = 8) and cancerous (n = 9) prostate samples, the average magnitudes of the complex Young's moduli (|E*|) were 15.9 +/- 5.9 kPa and 40.4 +/- 15.7 kPa at 150 Hz, respectively, giving an elastic contrast of 2.6:1. Nine two-sample t-tests indicated that there are significant differences between stiffness of normal and cancerous prostate tissues in the same gland (p < 0.01). This study contributes to the current limited knowledge on the viscoelastic properties of the human prostate, and the inherent elastic contrast produced by cancer.

  19. Molecular effects of soy phytoalexin glyceollins in human prostate cancer cells LNCaP

    USDA-ARS?s Scientific Manuscript database

    Glyceollins are soy–derived phytoalexins that have been proposed to be candidate cancer preventive compounds. The effect of the glyceollins on prostate cancer is unknown. The present study examined the molecular effects of soy phytoalexins, glyceollins, on the human prostate cancer cell line LNCaP t...

  20. Tissue specific and androgen-regulated expression of human prostate-specific transglutaminase.

    PubMed Central

    Dubbink, H J; Verkaik, N S; Faber, P W; Trapman, J; Schröder, F H; Romijn, J C

    1996-01-01

    Transglutaminases (TGases) are calcium-dependent enzymes catalysing the post-translational cross-linking of proteins. In the prostate at least two TGases are present, the ubiquitously expressed tissue-type TGase (TGC), and a prostate-restricted TGase (TGP). This paper deals with the molecular cloning and characterization of the cDNA encoding the human prostate TGase (hTGP). For this purpose we have screened a human prostate cDNA library with a probe from the active-site region of TGC. The largest isolated cDNA contained an open reading frame encoding a protein of 684 amino acids with a predicted molecular mass of 77 kDa as confirmed by in vitro transcription-translation and subsequent SDS/PAGE. The hTGP gene was tissue-specifically expressed in the prostate, yielding an mRNA of approx. 3.5 kb. Furthermore, a 3-fold androgen-induced upregulation of hTGP mRNA expression has been demonstrated in the recently developed human prostate cancer cell line, PC346C. Other well established human prostate cancer cell lines, LNCaP and PC-3, showed no detectable hTGP mRNA expression on a Northern bolt. The gene coding for prostate TGase was assigned to chromosome 3. PMID:8645175

  1. Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

    PubMed Central

    Swift, Stephanie L.; Rivera, Guillermo C.; Dussupt, Vincent; Leadley, Regina M.; Hudson, Lucy C.; MA de Ridder, Corrina; Kraaij, Robert; Burns, Julie E.; Maitland, Norman J.; Georgopoulos, Lindsay J.

    2013-01-01

    Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can

  2. Association of hyperplastic polyposis syndrome, colorectal cancer and meningioma.

    PubMed

    Muzaffar, Mahvish; Irlam, John; Mohamed, Iman

    2011-01-01

    Recent research has provided compelling evidence that a subset of hyperplastic polyps may be associated with a risk of colorectal cancer. Colorectal cancer with extracolonic manifestation is usually seen in a hereditary syndrome setting, but some association with meningioma has been reported. The association of colorectal cancer with hyperplastic polyposis and meningioma is extremely rare. This report in a 57-year-old female with no family history of colon cancer or polyps, could be the first case of hyperplastic polyposis syndrome, colorectal cancer and meningioma. Hyperplastic polyposis syndrome was diagnosed as per WHO criteria at the time of colon cancer diagnosis. Within 4 months of colon cancer diagnosis she developed seizures. Imaging of the brain revealed meningioma of the left cerebellopontine angle. The patient underwent surgery followed by chemotherapy.

  3. Prediction of alpha1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia.

    PubMed

    Yamada, Shizuo; Kato, Yasuhiro; Okura, Takashi; Kagawa, Yoshiyuki; Kawabe, Kazuki

    2007-07-01

    Alpha1-adrenoceptor antagonists are clinically useful for the improvement of urinary obstruction due to benign prostatic hyperplasia (BPH), and their therapeutic effects are mediated through the blockade of prostatic alpha(1)-adrenoceptors. The present study was undertaken to predict the magnitude and duration of alpha(1)-adrenoceptor occupancy in the human prostate after oral alpha(1)-adrenoceptor antagonists. Prostatic alpha(1)-adrenoceptor-binding parameters of silodosin were estimated by measuring specific [(3)H]prazosin binding in rat prostate after oral administration of this drug. The plasma concentration of silodosin after oral administration in rats and healthy volunteers was measured using a high-performance liquid chromatographic method. The alpha(1)-adrenoceptor-binding affinities (K(i)) of silodosin, tamsulosin, and terazosin in the human prostate and plasma concentrations of tamsulosin and terazosin were obtained from the literature. Using the alpha(1)-adrenoceptor binding parameters of silodosin in rat prostate, alpha(1)-adrenoceptor occupancy in the human prostate was estimated to be around 60-70% at 1-6 h after oral administration of silodosin at doses of 3.0, 8.1, and 16.1 micromol. Thereafter, the receptor occupancy was periodically decreased, to 24% (8.1 micromol) and 54% (16.1 micromol) 24 h later. A similar magnitude and time course of alpha(1)-adrenoceptor occupancy by silodosin in the human prostate were estimated using alpha(1)-adrenoceptor-binding affinities (K(i)) in the human prostate. Despite about two orders of differences in the plasma unbound concentrations after clinically effective oral dosages of silodosin, tamsulosin, and terazosin, there was a comparable magnitude of prostatic alpha(1)-adrenoceptor occupancy by these drugs. In conclusion, the prediction of alpha(1)-adrenoceptor occupancy in the human prostate by alpha(1)-adrenoceptor antagonists may provide the rationale for the optimum dosage regimen of these drugs in the

  4. [Chavanprash in the treatment of hyperplastic processes in the endometrium].

    PubMed

    Kokhanevich, E V; Chervak, N M

    2001-01-01

    Hyperplastic processes in the endometrium are classified as a common gynecological pathology. The drug chavanprash has been shown to improve general bodily resistance, to enhance vital tone of the body. It is endowed with a manifest hepatotropic and antitoxic activity, which fact permits recommending it for use in the combination therapy of hyperplastic processes in the endometrium as well as during the period of rehabilitation in the wake of the course of hormonotherapy.

  5. Quantitative pathology of laryngeal epithelial hyperplastic lesions.

    PubMed

    Cör, A; Gale, N; Kambic, V

    1997-01-01

    We studied 40 laryngeal biopsies samples in order to ascertain the reliability of light microscopical criteria for subdividing laryngeal epithelial hyperplastic lesions (EHL) and carcinoma in situ as well as to determine the relationship between proliferative activity of their epithelial cells and the histological grade. The biopsies were divided into four groups in accordance with the Kambic-Lenart classification: simple, abnormal and atypical hyperplasia and carcinoma in situ. 10 cases in each group were included. The morphometrical analysis was carried out by a semiautomatic image analysis system. The proliferative activity was determined by the high percentage of cell nuclear antigen (PCNA) and Ki-67 positive epithelial cells and with counting nucleolar organizer regions (Ag-NORs) per nucleus. Our results suggest that measuring the nuclear area of the basal cells. augmented with basaloid cells and carcinomatous cells, is the most useful morphometrical method of differentiating three types of laryngeal EHL and carcinoma in situ, while the proliferative activity progressively increased with the degree of epithelial hyperplasia. Morphometrical methods and proliferative activity should be regarded as useful in conjunction with the traditional histopathological methods allowing more of objective grading of EHL.

  6. Targeting Stromal Androgen Receptor Suppresses Prolactin-Driven Benign Prostatic Hyperplasia (BPH)

    PubMed Central

    Lai, Kuo-Pao; Huang, Chiung-Kuei; Fang, Lei-Ya; Izumi, Kouji; Lo, Chi-Wen; Wood, Ronald; Kindblom, Jon; Yeh, Shuyuan

    2013-01-01

    Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, led to the reduction of prostate size, which could be used in future therapy. PMID:23893956

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

    PubMed Central

    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.

    2016-01-01

    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. PMID:27835867

  8. 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.

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

    PubMed

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

    1999-01-01

    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. 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. 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. 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.

  10. 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.

  11. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model

    PubMed Central

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-01-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer. PMID:26840261

  12. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model.

    PubMed

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-03-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer.

  13. Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model.

    PubMed

    Triest, J A; Grignon, D J; Cher, M L; Kocheril, S V; Montecillo, E J; Talati, B; Tekyi-Mensah, S; Pontes, J E; Hillman, G G

    1998-08-01

    Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.

  14. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue.

    PubMed

    Ribeiro, Ricardo; Monteiro, Cátia; Catalán, Victoria; Hu, Pingzhao; Cunha, Virgínia; Rodríguez, Amaia; Gómez-Ambrosi, Javier; Fraga, Avelino; Príncipe, Paulo; Lobato, Carlos; Lobo, Francisco; Morais, António; Silva, Vitor; Sanches-Magalhães, José; Oliveira, Jorge; Pina, Francisco; Lopes, Carlos; Medeiros, Rui; Frühbeck, Gema

    2012-09-25

    Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients. Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks. In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression.

  15. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue

    PubMed Central

    2012-01-01

    Background Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients. Methods Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks. Results In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Conclusions Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for

  16. Differentiation of Neonatal Human-Induced Pluripotent Stem Cells to Prostate Epithelial Cells: A Model to Study Prostate Cancer Development

    DTIC Science & Technology

    2014-06-01

    expression by RT-PCR showed that while human dermal fibroblasts have higher constitutive expression of Nanog, Oct4 and Sox2 compared to IMP90 cells...REPORT U b . ABSTRACT U c. THIS PAGE U UU 12 19b. TELEPHONE NUMBER (include area code) 4 TABLE OF CONTENTS: Item...mechanistic insights into prostate epithelial cell development can be gained. 8 a. DPYS DAY!O b . c. Fig. 1. Differentiation of human iPSC to

  17. Role of antibodies to human papillomavirus 16 in prostate cancer: A seroscreening by peptide microarray.

    PubMed

    Zhao, Xiaojun; Zhou, Zheng; Chen, Ye; Chen, Wen; Ma, Hongwei; Pu, Jinxian

    2017-06-01

    Evidence is accumulating in estimating the potential role of human papillomavirus infection in prostate carcinogenesis. However, the results remain inconclusive. We measured the serostatus of antibodies to one of the high-risk human papillomaviruses, human papillomavirus 16, with a newly developed peptide microarray. Serum samples were collected from 75 untreated prostate cancer patients, along with 80 control subjects. We identified 12 peptides with significant differences in prostate cancer samples from all 241 peptides derived from human papillomavirus 16. Our results showed human papillomavirus 16 infection in 64.0% of prostate cancer serum samples, which is significantly different compared with the controls ( p < 0.01) because only 17.5% of the control serum was considered seropositive. The area under the receiver operator characteristic curve was 0.793 (95% confidence interval 0.721-0.864), indicating that the new microarray technique may have diagnostic value. The results showed an association between serological evidence for human papillomavirus 16 infection and risk of prostate cancer. The different serostatus of antibodies in the two subgroups indicated that human papillomavirus 16 infection might occur and play a potential role of progression in a minority of prostate cancer.

  18. 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...

  19. Prediction of Aggressive Human Prostate Cancer by Cathepsin B

    DTIC Science & Technology

    2006-03-01

    microdisection (LCM) in this task is in progress. Prostate cancer (PC), and benign prostatic hyperplasia ( BPH ) as control samples, were collected at the...antigen (PSA) levels in less than five years even though the post-RP pathology report did not detect cancer cell invasion to prostate margin/capsule...design of prospective studies. Biopsies showed significantly higher levels of CB to SA ratios than BPH . 15. SUBJECT TERMS African and White American Men

  20. Identification of haemopoietic biglycan in hyperplastic thymus associated with myasthenia gravis.

    PubMed

    Tomoyasu, H; Kikuchi, A; Kamo, I

    1998-08-14

    Generally biglycan, a small proteoglycan, has been thought to play a role as an extracellular matrix and/or a reservoir for other factors, such as TGF-beta and collagens. Recently, we have found that a soluble 100 kDa biglycan, produced from the rat thymic myoid cells and the brain glial cells, predominantly stimulates growth and differentiation of monocytic lineage cells from various lymphatic organs, including microglias. In the present study, we attempted to identify biological significance of the corresponding molecules in human, using five myasthenic thymuses (three with hyperplasia and two with thymoma) that had been surgically removed for therapeutic purpose. With immunohistochemistry, many biglycan positive cells were detected in the germinal center of the three hyperplastic thymuses, but not in the two thymuses associated with lymphocytic thymoma. Biglycan purified from the hyperplastic thymuses by an immunoaffinity column was found as a monomer with apparent molecular size of 95-100 kDa and self associated oligomers of greater than 201 kDa. The purified biglycan markedly stimulated the growth and differentiation of monocytic cells from haemopoietic stem cells of the rat bone marrow. These results suggest that particular cells, which produce haemopoietic biglycan, play significant roles in generation and maintenance of the hyperplastic changes associated with myasthenia gravis.

  1. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

    PubMed Central

    Sun, Shihua; Sprenger, Cynthia C.T.; Vessella, Robert L.; Haugk, Kathleen; Soriano, Kathryn; Mostaghel, Elahe A.; Page, Stephanie T.; Coleman, Ilsa M.; Nguyen, Holly M.; Sun, Huiying; Nelson, Peter S.; Plymate, Stephen R.

    2010-01-01

    Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand. PMID:20644256

  2. Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures.

    PubMed

    Passer, B J; Wu, C-l; Wu, S; Rabkin, S D; Martuza, R L

    2009-12-01

    Oncolytic herpes simplex viruses type 1 (oHSVs) such as G47Delta and G207 are genetically engineered for selective replication competence in cancer cells. Several factors can influence the overall effectiveness of oHSV tropism, including HSV-1 receptor expression, extracellular matrix milieu and cellular permissiveness. We have taken advantage of human prostate organ cultures derived from radical prostatectomies to investigate oHSV tropism. In this study, we show that both G47Delta and G207 specifically replicate in epithelial cells of the prostatic glands but not in the surrounding stroma. In contrast, both the epithelial and stromal cell compartments were readily infected by wild-type HSV-1. Analysis of oHSV replication in prostate surgical specimens 3 days post infection showed that G47Delta generated approximately 30-fold more viral progeny than did G207. This correlated with the enhanced expression of G47Delta-derived glycoprotein gB protein levels as compared with G207. In benign prostate tissues, G207 and G47Delta titers were notably reduced, whereas strain F titers were maintained at similar levels compared with prostate cancer specimens. Overall, our results show that these oncolytic herpes vectors show both target specificity and replication competence in human prostate cancer specimens and point to the utility of using human prostate organ cultures in assessing oHSV tropism and cellular specificity.

  3. Bradykinin promotes vascular endothelial growth factor expression and increases angiogenesis in human prostate cancer cells.

    PubMed

    Yu, Hsin-Shan; Wang, Shih-Wei; Chang, An-Chen; Tai, Huai-Ching; Yeh, Hung-I; Lin, Yu-Min; Tang, Chih-Hsin

    2014-01-15

    Prostate cancer is the most commonly diagnosed malignancy in men and shows a tendency for metastasis to distant organs. Angiogenesis is required for metastasis. Bradykinin (BK) is an inflammatory mediator involved in tumor growth and metastasis, but its role in vascular endothelial growth factor (VEGF) expression and angiogenesis in human prostate cancer remains unknown. The aim of this study was to examine whether BK promotes prostate cancer angiogenesis via VEGF expression. We found that exogenous BK increased VEGF expression in prostate cancer cells and further promoted tube formation in endothelial progenitor cells and human umbilical vein endothelial cells. Pretreatment of prostate cancer with B2 receptor antagonist or small interfering RNA (siRNA) reduced BK-mediated VEGF production. The Akt and mammalian target of rapamycin (mTOR) pathways were activated after BK treatment, and BK-induced VEGF expression was abolished by the specific inhibitor and siRNA of the Akt and mTOR cascades. BK also promoted nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) activity. Importantly, BK knockdown reduced VEGF expression and abolished prostate cancer cell conditional medium-mediated angiogenesis. Taken together, these results indicate that BK operates through the B2 receptor, Akt, and mTOR, which in turn activate NF-κB and AP-1, activating VEGF expression and contributing to angiogenesis in human prostate cancer cells.

  4. Evidence for a Proapoptotic Role of Matrix Metalloproteinase-26 in Human Prostate Cancer Cells and Tissues

    PubMed Central

    Khamis, Zahraa I.; Iczkowski, Kenneth A.; Man, Yan-Gao; Bou-Dargham, Mayassa J.; Sang, Qing-Xiang Amy

    2016-01-01

    Matrix metalloproteinases (MMPs) play intricate roles in cancer progression; some promote invasion and angiogenesis while others suppress tumor growth. For example, human MMP-26/endometase/matrilysin-2 was reported to be either protective or pro-tumorigenic. Our previous reports suggested pro-invasion and anti-inflammation properties in prostate cancer. Here, we provide evidence for a protective role of MMP-26 in the prostate. MMP-26 expression levels in androgen-repressed human prostate cancer (ARCaP) cells, transfected with sense or anti-sense MMP-26 cDNA, are directly correlated with those of the pro-apoptotic marker Bax. Immunohistochemical staining of prostate cancer tissue samples shows similar protein expression patterns, correlating the expression levels of MMP-26 and Bax in benign, neoplastic, and invasive prostate cancer tissues. The MMP-26 protein levels were upregulated in high grade prostate intraepithelial neoplasia (HGPIN) and decreased during the course of disease progression. Further analysis using an indirect terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that many tumor cells expressing MMP-26 were undergoing apoptosis. This study showed that the high level of MMP-26 expression is positively correlated with the presence of apoptotic cells. This pro-apoptotic role of MMP-26 in human prostate cancer cells and tissues may enhance our understanding of the paradoxical roles of MMP-26 in tumor invasion and progression. PMID:26722363

  5. Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate.

    PubMed

    Carducci, M A; Nelson, J B; Chan-Tack, K M; Ayyagari, S R; Sweatt, W H; Campbell, P A; Nelson, W G; Simons, J W

    1996-02-01

    Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.

  6. Laser Treatment of Benign Prostatic Hyperplasia: Dosimetric and Thermodynamic Considerations

    NASA Astrophysics Data System (ADS)

    Anvari, Bahman

    1993-01-01

    Benign prostatic hyperplasia (BPH) is the most commonly occurring neoplastic disease in the aging human male. Currently, surgical treatment of BPH is the primary therapeutic method. However, due to surgical complications, less invasive methods of treatment are desirable. In recent years, thermal coagulation of the hyperplastic prostate by a laser has received a considerable amount of attention. Nevertheless, the optimum laser irradiation parameters that lead to a successful and safe treatment of BPH have not been determined. This dissertation studies the physics of laser coagulation of prostate from both basic science and practical perspectives. Optical properties of prostatic tissue are determined over a spectrum of wavelengths. Knowledge of these properties allows for selection of appropriate laser wavelengths and provides a basis for performing dose equivalency studies among various types of lasers. Furthermore, knowledge of optical properties are needed for development of computer simulation models that predict the extent of thermal injury during laser irradiation of prostate. A computer model of transurethral heating of prostate that can be used to guide the clinical studies in determining an optimum dosimetry is then presented. Studies of the effects of non-laser heating devices, optical properties, blood perfusion, surface irrigation, and beam geometry are performed to examine the extent of heat propagation within the prostate. An in vitro model for transurethral laser irradiation of prostate is also presented to examine the effects of an 810 nm diode laser, thermal boundary conditions, and energy deposition rate during Nd:YAG laser irradiation. Results of these studies suggest that in the presence of laminar irrigation, the convective boundary condition is dominated by thermal diffusion as opposed to the bulk motion of the irrigation fluid. Distinct phases of thermal events are also identified during the laser irradiation. The in vivo studies of

  7. Establishment and Genomic Characterization of Mouse Xenografts of Human Primary Prostate Tumors

    PubMed Central

    Priolo, Carmen; Agostini, Michelle; Vena, Natalie; Ligon, Azra H.; Fiorentino, Michelangelo; Shin, Eyoung; Farsetti, Antonella; Pontecorvi, Alfredo; Sicinska, Ewa; Loda, Massimo

    2010-01-01

    Serum prostate-specific antigen screening has led to earlier detection and surgical treatment of prostate cancer, favoring an increasing incidence-to-mortality ratio. However, about one third of tumors that are diagnosed when still confined to the prostate can relapse within 10 years from the first treatment. The challenge is therefore to identify prognostic markers of aggressive versus indolent tumors. Although several preclinical models of advanced prostate tumors are available, a model that recapitulates the genetic and growth behavior of primary tumors is still lacking. Here, we report a complete histopathological and genomic characterization of xenografts derived from primary localized low- and high-grade human prostate tumors that were implanted under the renal capsule of immunodeficient mice. We obtained a tumor take of 56% and show that these xenografts maintained the histological as well as most genomic features of the parental tumors. Serum prostate-specific antigen levels were measurable only in tumor xenograft-bearing mice, but not in those implanted with either normal prostate tissue or in tumors that likely regressed. Finally, we show that a high proliferation rate, but not the pathological stage or the Gleason grade of the original tumor, was a fundamental prerequisite for tumor take in mice. This mouse xenograft model represents a useful preclinical model of primary prostate tumors for their biological characterization, biomarker discovery, and drug testing. PMID:20167861

  8. Isolation and Growth of Prostate Stem Cells and Establishing Cancer Cell Lines from Human Prostate Tumors

    DTIC Science & Technology

    2008-05-01

    Kim, Y., Dubey, P., and Witte , O. N. In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital...R. U., Cheng, D., and Witte , O. N. Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci U S A, 2006. 34...of Medicine Flow Sorting Facility) for their expert assistance and Jessica Hicks and Yuko Konishi (Johns Hopkins Department of Pathology) for the

  9. 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

  10. Human fucosyltransferase 6 enables prostate cancer metastasis to bone

    PubMed Central

    Li, J; Guillebon, A D; Hsu, J-w; Barthel, S R; Dimitroff, C J; Lee, Y-F; King, M R

    2013-01-01

    Background: The interaction between human prostate cancer (PCa) cells and bone marrow (BM) endothelium follows a rolling-and-adhesion cascade mediated by E-selectin ligand (ESL): E-selectin. This adhesion is enabled by elevated expression of α-1,3-fucosyltransferases (FTs), enzymes responsible for ESL-mediated bone metastasis in humans. In contrast, the incidence of bone metastasis in mice is rare. Methods: FT 3, 6 and 7 were overexpressed in mouse PCa cells. The rolling cell number, cell-rolling velocity and transendothelial migration were characterised in vitro. Fucosyltransferases-transduced mouse PCa cells expressing luciferase were inoculated into mice via left ventricle to compare the capability of bone metastasis. Mass spectrometry and immunoprecipitation were utilised for identification of ESLs. Results: Overexpression of FT3, FT6 or FT7 restored ESLs and enabled mouse PCa cells to roll and adhere in E-selectin-functionalised microtubes, similar to trafficking of circulating PCa cells in BM vessels. Following intracardiac inoculation, FT6-transduced cells induced robust bone metastasis in mice. Inhibition of FT6 by a fucose mimetic significantly reduced bone metastasis. Importantly, comparison of FT3, FT6 and FT7 gene expression in existing clinical samples showed significant upregulation of FT6 in PCa-distant metastases. Conclusion: FT6 is a key mediator of PCa cells trafficking to the BM. It may serve as a viable drug target in preclinical tests of therapeutics for reduction of PCa bone metastasis. PMID:24178760

  11. Penetration of orally administered prulifloxacin into human prostate tissue.

    PubMed

    Giberti, Claudio; Gallo, Fabrizio; Rosignoli, Maria T; Ruggieri, Alessandro; Barattè, Simona; Picollo, Rossella; Dionisio, Paolo

    2009-01-01

    Prulifloxacin, a fluoroquinolone antibacterial agent, may be a useful addition to the antimicrobial armamentarium against prostatitis once the ability of its active metabolite, ulifloxacin, to penetrate prostatic tissue has been determined. This study set out to evaluate ulifloxacin penetration into the prostate following administration of the oral fluoroquinolone prodrug prulifloxacin in patients undergoing transurethral resection of the prostate (TURP). This was a phase I, randomized, open-label, single-centre study involving 20 male Caucasian patients (mean age 63.1 years) requiring TURP for treatment of benign prostatic hyperplasia. Sixteen patients were randomized to receive prulifloxacin; the other four patients were not treated (controls) in order to validate the bioanalytical method. Patients in the active treatment groups were randomized to receive one or three once-daily doses of prulifloxacin 600 mg, with the last administration 3 hours prior to surgery. Central/transitional and peripheral zone prostatic tissue samples were obtained from the 6 o'clock and 9 o'clock positions in the prostate, and blood samples were collected concurrently. Ulifloxacin concentrations were determined in the tissue samples and plasma using liquid chromatography-tandem mass spectrometry. Safety was also assessed. Prostatic tissue concentrations of ulifloxacin always exceeded those in plasma. Mean ulifloxacin concentrations measured in samples collected from the 6 o'clock central/transitional zone of the prostate were higher in patients who received prulifloxacin for 3 days than in those who received a single dose. Mean prostatic tissue/plasma ulifloxacin concentration ratios after single and repeated prulifloxacin administration ranged from 3.8 to 7.1 and from 3.9 to 9.5, respectively. The highest mean ratio was found in the 6 o'clock central/transitional zone after repeated dosing. Prostatic levels of ulifloxacin were above the minimum inhibitory concentrations for the most

  12. Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver.

    PubMed

    Yamada, Tomoya; Okuda, Yu; Kushida, Masahiko; Sumida, Kayo; Takeuchi, Hayato; Nagahori, Hirohisa; Fukuda, Takako; Lake, Brian G; Cohen, Samuel M; Kawamura, Satoshi

    2014-11-01

    High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1-week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation, and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats, and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500-ppm NaPB resulted in plasma levels around 3-5-fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose-dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated that the responses to NaPB in the human liver were clearly different from those in rodents. Although NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45β, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. However, increases in hepatocyte replicative DNA synthesis were observed in chimeric mice both in vivo and in vitro after treatment epidermal growth factor. Thus, although NaPB could activate CAR in both rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans.

  13. HGF and the regulation of tight junctions in human prostate cancer cells.

    PubMed

    Martin, Tracey A; Mason, Malcolm D; Jiang, Wen G

    2014-07-01

    Hepatocyte growth factor (HGF) may impact the metastasis of prostate cancer via its action on prostate stem cells or their progeny. Tight junctions (TJs) are crucial to the process of metastasis and have been previously shown to be regulated by HGF. The present study aimed to evaluate the effect of HGF on the function of TJs in human prostate epithelial, prostate stem cell-like and prostate cancer cell lines. Four human prostate cancer cell lines (PC-3, DU-145, PZHPV-7, CaHPV-10), normal adult prostate parental epithelial cells (RWPE-1) and a stem cell-like derivative of RWPE-1 (WPE-STEM) were used to assess HGF-induced changes in TJs. A significant difference was noted in the behaviour between the WPE-STEM, RWPE-1 and the cancer cell lines which was HGF concentration-dependent. However, in the WPE-STEM cells, the effect was biphasic, with the cells seemingly resistant to HGF-modulated TJ disruption. Closer examination revealed that HGF affected the redistribution of ZO-1, ZO-2 and ZO-3 away from the TJs of confluent cells with concurrent loss of claudin-1 and claudin-5, and western blot analysis revealed a loss in TJ protein expression of ZO-1 and ZO-2. We demonstrated for the first time that HGF regulates TJ function in human prostate cells. Moreover, this regulation was dependent on the tumourigenicity of the cells, with the most aggressive cells most susceptible and the stem cell-like cells least susceptible. These data offer an intriguing glimpse of how TJs affect the behaviour of prostate cancer cells and how HGF modulates the expression and function of the molecules maintaining TJ structure and function.

  14. Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer

    PubMed Central

    Lefort, Karine; Ostano, Gian Paola; Mello-Grand, Maurizia; Calpini, Valérie; Scatolini, Maria; Farsetti, Antonella; Dotto, Gian Paolo; Chiorino, Giovanna

    2016-01-01

    Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer. PMID:27384993

  15. Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer.

    PubMed

    Lefort, Karine; Ostano, Paola; Mello-Grand, Maurizia; Calpini, Valérie; Scatolini, Maria; Farsetti, Antonella; Dotto, G Paolo; Chiorino, Giovanna

    2016-07-26

    Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer.

  16. Contractile properties of human prostate adenomas and the development of infravesical obstruction.

    PubMed

    Gup, D I; Shapiro, E; Baumann, M; Lepor, H

    1989-01-01

    The contractile response of human prostate adenomas to KCl, phenylephrine (alpha 1 adrenergic agonist), UK 14304 (alpha 2 adrenergic agonist), and carbachol (muscarinic cholinergic agonist) was evaluated in tissue specimens obtained from men with symptomatic and asymptomatic BPH. Prostate specimens were obtained from 5 men with asymptomatic BPH undergoing cystoprostatectomy, 11 men with symptomatic BPH undergoing open prostatectomy, and 11 men with symptomatic BPH undergoing transurethral resection of the prostate (TURP). Quantitative symptom score analysis and urinary flow rate determination documented the absence of bladder outlet obstruction in men undergoing cystoprostatectomy and confirmed the presence of bladder outlet obstruction in men undergoing prostatectomy. The magnitude of the contractile response (Emax) and the potency of phenylephrine-induced contractions (EC50) in prostatic preparations obtained from men with symptomatic and asymptomatic BPH were similar. The IC50 for the inhibition of phenylephrine-induced contractions by prazosin was 3.2 nM, confirming that phenylephrine-induced contraction in the human prostate is mediated by the alpha 1 adrenoceptor. The contractile responses of prostate adenomas to muscarinic cholinergic and alpha 2 agonists were negligible. This study demonstrates that the development of bladder outlet obstruction in men with BPH is not related to alterations in the functional response of the smooth muscle component of the prostate adenoma.

  17. Carcinoma in gastric hyperplastic polyps: A phenotypic study

    SciTech Connect

    Zea-Iriarte, W.L.; Sekine, Ichiro; Itsuno, Minoru

    1996-02-01

    One-hundred twelve hyperplastic polyps were analyzed. The aim was to study their malignant transformation. Among them, four hyperplastic polyps harbored adenocarcinoma; two were from our own institution (1.8%). The majority were pedunculated and located in the antrum with an average of 14.5 mm in diameter. The four polyps bore well-differentiated adenocarcinoma. Dysplasia and intestinal metaplasia were detected in two and three polyps, respectively. The cancer and dysplastic foci shared the same type of neutral and acid mucosubstances. p53 oncoprotein was positive in three cancer foci and in the dysplastic areas, and nucleolar organizer region counts were higher in the cancer foci. In conclusion, hyperplastic polyps have malignant potential. Such possibility increases in polyps larger than 14.5 mm. In our cases, the carcinoma foci may have arisen from dysplastic areas. Once the neoplastic changes occur, the cancer cells proliferate and behave as other adenocarcinomas of the stomach. 40 refs., 7 figs., 5 tabs.

  18. Human prostatic cancer cells, PC3, elaborate mitogenic activity which selectively stimulates human bone cells

    SciTech Connect

    Perkel, V.S.; Mohan, S.; Herring, S.J.; Baylink, D.J.; Linkhart, T.A. )

    1990-11-01

    Prostatic cancer typically produces osteoblastic metastases which are not attended by marrow fibrosis. In the present study we sought to test the hypothesis that prostatic cancer cells produce factor(s) which act selectively on human osteoblasts. Such a paracrine mechanism would explain the observed increase in osteoblasts, unaccompanied by an increase in marrow fibroblasts. To test this hypothesis we investigated the mitogenic activity released by the human prostatic tumor cell line, PC3. PC3 cells have been reported previously to produce mitogenic activity for cells that was relatively specific for rat osteoblasts compared to rat fibroblasts. However, the effects of this activity on human cells has not been examined previously. PC3-conditioned medium (CM) (5-50 micrograms CM protein/ml) stimulated human osteoblast proliferation by 200-950% yet did not stimulate human fibroblast proliferation ((3H)thymidine incorporation). PC3 CM also increased cell numbers in human osteoblast but not fibroblast cell cultures. To determine whether the osteoblast-specific mitogenic activity could be attributed to known bone growth factors, specific assays for these growth factors were performed. PC3 CM contained 10 pg insulin-like growth factor (IGF) I, less than 2 pg IGF II, 54 pg basic fibroblast growth factor, and 16 pg transforming growth factor beta/microgram CM protein. None of these growth factors alone or in combination could account for the observed osteoblast-specific PC3 cell-derived mitogenic activity. Furthermore, when 5 micrograms/ml PC3 CM was tested in combination with maximally effective concentrations of either basic fibroblast growth factor, IGF I, IGF II, or transforming growth factor beta, it produced an additive effect suggesting that PC3 CM stimulates osteoblast proliferation by a mechanism independent of these bone mitogens.

  19. Pharmacological and functional characterization of bradykinin B2 receptor in human prostate.

    PubMed

    Srinivasan, Dinesh; Kosaka, Alan H; Daniels, Donald V; Ford, Anthony P D W; Bhattacharya, Anindya

    2004-11-19

    The objective of this study was to pharmacologically characterize bradykinin receptors, a component of the kallikrein-kinin system, in normal human prostate cells. In primary cultured human prostate stromal cells, bradykinin, but not [des-Arg9]bradykinin or [des-Arg10]kallidin, produced calcium mobilization or inositol phosphates accumulation with potencies (pEC50) of 8.8+/-0.2 and 8.2+/-0.2, respectively. This was consistent with abundance of bradykinin B2 mRNA over bradykinin B1 mRNA in prostate stromal cells. Although the prostate epithelial cells (prostate epithelium, BPH-1, and PC-3) expressed mRNA for bradykinin B2 receptors (albeit in lesser amounts than stromal cells), bradykinin was not functionally efficacious in the epithelial cells. Increasing concentrations of D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahhydro-3-isoquinolinecarbonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE-140), a bradykinin B2-selective peptide antagonist, attenuated bradykinin concentration-response curves in human prostate stromal cells with apparent estimate of affinity similar to that for the human bradykinin B2 receptor. Bradykinin (10 nM) caused proliferation of prostate stromal cells and phosphorylated extracellular signal-regulated kinases (ERK-1 and ERK-2) that were blocked by HOE-140 (1 microM). This study demonstrated that, in primary cultures of normal human prostate stromal cells, bradykinin activates bradykinin B2 receptors that may play a significant role in proliferation via activation of ERK-1/2 pathways.

  20. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation

    SciTech Connect

    Meeran, Syed M.; Katiyar, Suchitra; Katiyar, Santosh K.

    2008-05-15

    Phytochemicals show promise as potential chemopreventive or chemotherapeutic agents against various cancers. Here we report the chemotherapeutic effects of berberine, a phytochemical, on human prostate cancer cells. The treatment of human prostate cancer cells (PC-3) with berberine induced dose-dependent apoptosis but this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. This effect of berberine on prostate cancer cells was initiated by the generation of reactive oxygen species (ROS) irrespective of their androgen responsiveness, and the generation of ROS was through the increased induction of xanthine oxidase. Treatment of cells with allopurinol, an inhibitor of xanthine oxidase, inhibited berberine-induced oxidative stress in cancer cells. Berberine-induced apoptosis was blocked in the presence of antioxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. In conclusion, the present study reveals that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer.

  1. Prostatic penetration of meropenem in humans, and dosage considerations for prostatitis based on a site-specific pharmacokinetic/pharmacodynamic evaluation.

    PubMed

    Nishikawa, Genya; Ikawa, Kazuro; Nakamura, Kogenta; Yamada, Yoshiaki; Zennami, Kenji; Mitsui, Kenji; Narushima, Masahiro; Ikeda, Kayo; Morikawa, Norifumi; Sumitomo, Makoto

    2013-03-01

    The aims of this study were to investigate the penetration of meropenem (MER) into human prostate tissue and to assess MER regimens for prostatitis by performing a site-specific pharmacokinetic/pharmacodynamic evaluation. Patients with prostatic hypertrophy (n=49) prophylactically received a 0.5-h infusion of MER (250 mg or 500 mg) before transurethral resection of the prostate. MER concentrations in plasma (0.5-5h) and prostate tissue (0.5-1.5h) were measured chromatographically. Concentration data were analysed pharmacokinetically with a three-compartment model and were used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24h) in prostate tissue, an indicator for antibacterial effects at the site of action. The prostate tissue/plasma ratio was 16.6% for the maximum drug concentration and 17.7% for the area under the drug concentration-time curve, irrespective of the dose. Against MIC distributions for clinical isolates of Escherichia coli, Klebsiella spp. and Proteus spp., 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue. However, against the Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability of attaining the bacteriostatic or bactericidal targets. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  2. Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model

    PubMed Central

    Liu, Ming-Che; Chen, Wei-Hong; Chiou, Chi-Sheng; Lo, Wen-Cheng; Dubey, Navneet Kumar; Chen, Yu-Chin; Lai, Wen-Fu T.; Yeh, Shauh-Der; Chiang, Han-Sun; Deng, Win-Ping

    2017-01-01

    Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future. PMID:28558037

  3. A Vector-Based Short Hairpin RNA Targeting Aurora B Suppresses Human Prostatic Carcinoma Growth.

    PubMed

    Cao, Mei; Qi, Panpan; Chen, Chong; Song, Liju; Wang, Xuege; Li, Ningzhe; Wu, Daoyan; Hu, Guoku; Zhao, Jian

    2017-02-01

    Aurora kinase B, playing a vital, important role in mitosis, is frequently detected to be overexpressed in many cancer cell lines and various tumor tissues, including prostatic carcinoma. Given the essential function of Aurora kinase B in mitosis and its association with tumorigenesis, it might be a drug target for prostatic carcinoma treatment. In our study, short hairpin RNA targeting Aurora kinase B was cloned into a pGPU6 plasmid vector and then transfected into human prostatic carcinoma cells. The expression level of Aurora kinase B was verified by reverse transcription-polymerase chain reaction and Western blot. At the same time, cell apoptosis was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, fluorescent staining, and flow cytometric analysis. Furthermore, prostate carcinoma cells were injected into mice to establish a tumor xenograft model. Previous studies have shown the effect of pGPU6-shAURKB plasmid on tumor growth in a prostate carcinoma xenogenic implantation model. From the study, we knew that the Aurora kinase B was significantly downregulated in prostate carcinoma cells, and cell apoptosis was also detected higher in treated groups than that in control groups. Moreover, in the prostate carcinoma xenogenic implantation model, compared with the control groups, the tumor growth was inhibited about 78.7% in the pGPU6-shAURKB plasmid-treated group, and cell apoptosis in the experimental group was notably higher than that in control groups. The average duration of tumor-bearing mice was prolonged to about 35 days. The results of experiment indicated that specific knockdown of Aurora kinase B led to prostate carcinoma cells apoptosis and inhibited tumor growth. Our data clearly confirmed that specific knockdown of Aurora kinase B expression by vector-based short hairpin RNA/liposome may be a potential new approach to treat human prostatic carcinoma.

  4. Zinc transporter mRNA expression in the RWPE-1 human prostate epithelial cell line.

    PubMed

    Albrecht, Amy L; Somji, Seema; Sens, Mary Ann; Sens, Donald A; Garrett, Scott H

    2008-08-01

    The human prostate gland undergoes a prominent alteration in Zn+2 homeostasis during the development of prostate cancer. The goal of the present study was to determine if the immortalized human prostate cell line (RWPE-1) could serve as a model system to study the role of zinc in prostate cancer. The study examined the expression of mRNA for 19 members of the zinc transporter gene family in normal prostate tissue, the prostate RWPE-1 cell line, and the LNCaP, DU-145 and PC-3 prostate cancer cell lines. The study demonstrated that the expression of the 19 zinc transporters was similar between the RWPE-1 cell line and the in situ prostate gland. Of the 19 zinc transporters, only 5 had levels that were different between the RWPE-1 cells and the tissue samples; all five being increased (ZnT-6, Zip-1, Zip-3A, Zip-10, and Zip-14). The response of the 19 transporters was also determined when the cell lines were exposed to 75 microM Zn+2 for 24 h. It was shown for the RWPE-1 cells that only 5 transporters responded to Zn+2 with mRNA for ZnT-1 and ZnT-2 being increased while mRNA for ZnT-7, Zip-7 and Zip-10 transporters were decreased. It was shown for the LNCaP, DU-145 and PC-3 cells that Zn+2 had no effect on the mRNA levels of all 19 transporters except for an induction of ZnT-1 in PC-3 cells. Overall, the study suggests that the RWPE-1 cells could be a valuable model for the study of the zinc transporter gene family in the prostate.

  5. Targeting the Human Complement Membrane Attack Complex to Selectively Kill Prostate Cancer Cells

    DTIC Science & Technology

    2012-10-01

    Kill Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Samuel R. Denmeade, MD CONTRACTING ORGANIZATION: Johns Hopkins University...Annual 3. DATES COVERED t 2011- 29 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER . Targeting the Human Complement Membrane Attack Complex to...Support: DOD Idea Award W81XWH-10-PCRP-IDA to SRD; DOD Predoctoral Fellowship W81XWH-09-1-0219 to MLM ; DOD Post-Doctoral Fellowship to MBK; Prostate

  6. Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

    DTIC Science & Technology

    2010-05-01

    For each Q tract allele, we have currently obtained at least 30 experimental and 30 control mice . Some have reached their time points and tissues...overexpression of ETV1). Experimental mice have been generated and prostates are being microdissected as animals reach their time points. Initial...TITLE: Humanized Androgen Receptor Mice : A Genetic Model for Differential Response to Prostate Cancer Therapy PRINCIPAL INVESTIGATOR: Diane M

  7. Implications of pleiotrophin in human PC3 prostate cancer cell growth in vivo.

    PubMed

    Tsirmoula, Sotiria; Dimas, Kostas; Hatziapostolou, Maria; Lamprou, Margarita; Ravazoula, Panagiota; Papadimitriou, Evangelia

    2012-10-01

    Pleiotrophin (PTN) is a heparin-binding growth factor with diverse functions related to tumor growth, angiogenesis, and metastasis. Pleiotrophin seems to have a significant role in prostate cancer cell growth and to mediate the stimulatory actions of other factors that affect prostate cancer cell functions. However, all studies carried out up to date are in vitro, using different types of human prostate cancer cell lines. The aim of the present work was to study the role of endogenous PTN in human prostate cancer growth in vivo. For this purpose, human prostate cancer PC3 cells were stably transfected with a plasmid vector, bearing the antisense PTN sequence, in order to inhibit PTN expression (AS-PC3). Migration, apoptosis, and adhesion on osteoblastic cells were measured in vitro. In vivo, PC3 cells were s.c. injected into male NOD/SCID mice, and tumor growth, survival rates, angiogenesis, apoptosis, and the number of metastasis were estimated. Pleiotrophin depletion resulted in a decreased migration capability of AS-PC3 cells compared with the corresponding mock-transfected or the non-transfected PC3 cells, as well as increased apoptosis and decreased adhesiveness to osteoblastic cells in vitro. In prostate cancer NOD/SCID mouse xenografts, PTN depletion significantly suppressed tumor growth and angiogenesis and induced apoptosis of cancer cells. In addition, PTN depletion decreased the number of metastases, providing a survival benefit for the animals bearing AS-PC3 xenografts. Our data suggest that PTN is implicated in human prostate cancer growth in vivo and could be considered a potential target for the development of new therapeutic approaches for prostate cancer. © 2012 Japanese Cancer Association.

  8. Quantification of Protein Signatures in Archived Human Prostate Tissues Using Shotgun Proteomic Methods

    DTIC Science & Technology

    2011-06-01

    proteins were subsequently incubated with wheat - germ agglutinin (WGA) and con canavalin- A (ConA) beads, washed, and el uted with sol uble n-acetyl...prostate radial prostatectomies and have focused on optimizing protocols to extract and profile proteins in matched normal and dise ased tissue s...human prostate cancer using label-free, quantitative mass spectrometry. Last year we were able to extract up to 1 00 micrograms of total protein

  9. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter–Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth

    PubMed Central

    Sung, Shian-Ying; Chang, Junn-Liang; Chen, Kuan-Chou; Yeh, Shauh-Der; Liu, Yun-Ru; Su, Yen-Hao; Hsueh, Chia-Yen; Chung, Leland W. K.; Hsieh, Chia-Ling

    2016-01-01

    Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor–promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter–driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers. PMID:27054343

  10. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.

    PubMed

    Sung, Shian-Ying; Chang, Junn-Liang; Chen, Kuan-Chou; Yeh, Shauh-Der; Liu, Yun-Ru; Su, Yen-Hao; Hsueh, Chia-Yen; Chung, Leland W K; Hsieh, Chia-Ling

    2016-01-01

    Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.

  11. Effect of gyromagnetic fields on human prostatic adenocarcinoma cells

    PubMed Central

    Lei, Hongen; Xu, Yongde; Guan, Ruili; Li, Meng; Hui, Yu; Gao, Zhezhu; Yang, Bicheng; Xin, Zhongcheng

    2015-01-01

    Purpose To investigate the biological effect of gyromagnetic fields (GMFs) on cell proliferation and apoptosis of human prostatic adenocarcinoma cells and explore the underlying mechanisms. Methods PC-3 cells were grouped into normal control (NC) and GMF treatment groups. Cell proliferation was analyzed with kit-8 and Ki67 immunofluorescence staining, while cell apoptosis was analyzed with flow cytometry double staining of Annexin V-PE/7-AAD. The Akt and p38 MAPK/Caspase signaling pathways were analyzed by western blotting and immunofluorescence staining, and cell polarization was analyzed with PARD3. Results Cell proliferation and activity of the Akt pathway were significantly decreased by the GMF, while cell apoptosis, activity of p38 MAPK, and PARD3-positive cell number were significantly increased in the GMF group compared to the NC group. Conclusion GMFs inhibit cell proliferation, induce apoptosis, and regulate tumor cell polarity conditions, potentially through down-regulating Akt, activating the p38 MAPK/Caspase pathway, and promoting PARD3 expression in PC-3 cells. PMID:26648740

  12. The human (PEDB) and mouse (mPEDB) Prostate Expression Databases.

    PubMed

    Nelson, Peter S; Pritchard, Colin; Abbott, Denise; Clegg, Nigel

    2002-01-01

    The Prostate Expression Databases (PEDB and mPEDB) are online resources designed to allow researchers to access and analyze gene expression information derived from the human and murine prostate, respectively. Human PEDB archives more than 84 000 Expressed Sequence Tags (ESTs) from 38 prostate cDNA libraries in a curated relational database that provides detailed library information including tissue source, library construction methods, sequence diversity and sequence abundance. The differential expression of each EST species can be viewed across all libraries using a Virtual Expression Analysis Tool (VEAT), a graphical user interface written in Java for intra- and inter-library sequence comparisons. Recent enhancements to PEDB include (i) the development of a murine prostate expression database, mPEDB, that complements the human gene expression information in PEDB, (ii) the assembly of a non-redundant sequence set or 'prostate unigene' that represents the diversity of gene expression in the prostate, and (iii) an expanded search tool that supports both text-based and BLAST queries. PEDB and mPEDB are accessible via the World Wide Web at http://www.pedb.org and http://www.mpedb.org.

  13. Immunocytochemistry of epithelial markers in citral-induced prostate hyperplasia in rats.

    PubMed

    Massas, R; Servadio, C; Sandbank, U; Abramovici, A

    1991-04-01

    Immunocytochemical characterization of several epithelial markers using the PAP technique was analyzed during different stages of induced prostatic hyperplasia in rats. Intact adolescent rats (42 days old) were treated with citral (3,7 dimethyl-2,6 octadienal) for 10, 30 and 100 days and their ventral prostate compared to untreated, matched-age animals. Among the epithelial markers studied the prostatic specific acid phosphatase was present in hyperplastic prostates of rats. The immunoreaction showed a fair correlation with the severity of lesion and duration of treatment. The prostatic specific antigen showed equally immunoreactive in both control and treated rats. The hyperplastic and normal rat prostates did not show immunoreactivity towards the other epithelial cell markers such as epithelial membrane antigen, carcinoembrionic antingen and alpha-fetoprotein antisera. It is concluded that prostatic specific acid phosphatase, and to a lesser extent prostatic specific antigen, might represent valuable markers for comparative studies of prostatic hyperplasia in rodents.

  14. Detection of prostate stem cell antigen expression in human prostate cancer using quantum-dot-based technology.

    PubMed

    Ruan, Yuan; Yu, Weimin; Cheng, Fan; Zhang, Xiaobin; Larré, Stéphane

    2012-01-01

    Quantum dots (QDs) are a new class of fluorescent labeling for biological and biomedical applications. In this study, we detected prostate stem cell antigen (PSCA) expression correlated with tumor grade and stage in human prostate cancer by QDs-based immunolabeling and conventional immunohistochemistry (IHC), and evaluated the sensitivity and stability of QDs-based immunolabeling in comparison with IHC. Our data revealed that increasing levels of PSCA expression accompanied advanced tumor grade (QDs labeling, r = 0.732, p < 0.001; IHC, r = 0.683, p < 0.001) and stage (QDs labeling, r = 0.514, p = 0.001; IHC, r = 0.432, p = 0.005), and the similar tendency was detected by the two methods. In addition, by comparison between the two methods, QDs labeling was consistent with IHC in detecting the expression of PSCA in human prostate tissue correlated with different pathological types (K = 0.845, p < 0.001). During the observation time, QDs exhibited superior stability. The intensity of QDs fluorescence remained stable for two weeks (p = 0.083) after conjugation to the PSCA protein, and nearly 93% of positive expression with their fluorescence still could be seen after four weeks.

  15. Lack of detection of human papillomavirus DNA in prostate carcinomas in patients from northeastern Brazil

    PubMed Central

    Araujo-Neto, Ari P.; Ferreira-Fernandes, Hygor; Amaral, Carolina M.M.; Santos, Lina G.; Freitas, Antônio C.; Silva-Neto, Jacinto C.; Rey, Juan A.; Burbano, Rommel R.; da Silva, Benedito B.; Yoshioka, France K.N.; Pinto, Giovanny R.

    2016-01-01

    Abstract Prostate cancer is the second most common cancer among men in western populations, and despite its high mortality, its etiology remains unknown. Inflammatory processes are related to the etiology of various types of tumors, and prostate inflammation, in particular, has been associated with prostate cancer carcinogenesis and progression. Human papillomavirus (HPV) is associated with benign and malignant lesions in the anogenital tract of both females and males. The possible role of HPV in prostate carcinogenesis is a subject of great controversy. In this study, we aimed to examine the prevalence of HPV infections in prostate carcinomas of patients from northeastern Brazil. This study included 104 tissue samples from primary prostate carcinoma cases. HPV DNA was purified and then amplified using MY09/11 and GP5+/GP6+ degenerate primer sets that detect a wide range of HPV types, and with specific PCR primers sets for E6 and E7 HPV regions to detect HPV 16. None of the samples showed amplification products of HPV DNA for primer sets MY09/11 and GP5+/GP6+, or the specific primer set for the E6 and E7 HPV regions. HPV infection, thus, does not seem to be one of the causes of prostate cancer in the population studied. PMID:27007894

  16. Lack of detection of human papillomavirus DNA in prostate carcinomas in patients from northeastern Brazil.

    PubMed

    Araujo-Neto, Ari P; Ferreira-Fernandes, Hygor; Amaral, Carolina M M; Santos, Lina G; Freitas, Antônio C; Silva-Neto, Jacinto C; Rey, Juan A; Burbano, Rommel R; Silva, Benedito B da; Yoshioka, France K N; Pinto, Giovanny R

    2016-03-01

    Prostate cancer is the second most common cancer among men in western populations, and despite its high mortality, its etiology remains unknown. Inflammatory processes are related to the etiology of various types of tumors, and prostate inflammation, in particular, has been associated with prostate cancer carcinogenesis and progression. Human papillomavirus (HPV) is associated with benign and malignant lesions in the anogenital tract of both females and males. The possible role of HPV in prostate carcinogenesis is a subject of great controversy. In this study, we aimed to examine the prevalence of HPV infections in prostate carcinomas of patients from northeastern Brazil. This study included 104 tissue samples from primary prostate carcinoma cases. HPV DNA was purified and then amplified using MY09/11 and GP5+/GP6+ degenerate primer sets that detect a wide range of HPV types, and with specific PCR primers sets for E6 and E7 HPV regions to detect HPV 16. None of the samples showed amplification products of HPV DNA for primer sets MY09/11 and GP5+/GP6+, or the specific primer set for the E6 and E7 HPV regions. HPV infection, thus, does not seem to be one of the causes of prostate cancer in the population studied.

  17. Selective expression of myosin IC Isoform A in mouse and human cell lines and mouse prostate cancer tissues.

    PubMed

    Ihnatovych, Ivanna; Sielski, Neil L; Hofmann, Wilma A

    2014-01-01

    Myosin IC is a single headed member of the myosin superfamily. We recently identified a novel isoform and showed that the MYOIC gene in mammalian cells encodes three isoforms (isoforms A, B, and C). Furthermore, we demonstrated that myosin IC isoform A but not isoform B exhibits a tissue specific expression pattern. In this study, we extended our analysis of myosin IC isoform expression patterns by analyzing the protein and mRNA expression in various mammalian cell lines and in various prostate specimens and tumor tissues from the transgenic mouse prostate (TRAMP) model by immunoblotting, qRT-PCR, and by indirect immunohistochemical staining of paraffin embedded prostate specimen. Analysis of a panel of mammalian cell lines showed an increased mRNA and protein expression of specifically myosin IC isoform A in a panel of human and mouse prostate cancer cell lines but not in non-cancer prostate or other (non-prostate-) cancer cell lines. Furthermore, we demonstrate that myosin IC isoform A expression is significantly increased in TRAMP mouse prostate samples with prostatic intraepithelial neoplasia (PIN) lesions and in distant site metastases in lung and liver when compared to matched normal tissues. Our observations demonstrate specific changes in the expression of myosin IC isoform A that are concurrent with the occurrence of prostate cancer in the TRAMP mouse prostate cancer model that closely mimics clinical prostate cancer. These data suggest that elevated levels of myosin IC isoform A may be a potential marker for the detection of prostate cancer.

  18. Human Prostate Side Population Cells Demonstrate Stem Cell Properties in Recombination with Urogenital Sinus Mesenchyme

    PubMed Central

    Foster, Barbara A.; Gangavarapu, Kalyan J.; Mathew, Grinu; Azabdaftari, Gissou; Morrison, Carl D.; Miller, Austin; Huss, Wendy J.

    2013-01-01

    Stem cell enrichment provides a tool to examine prostate stem cells obtained from benign and malignant tissue. Functional assays can enrich stem cells based on common stem cell phenotypes, such as high ATP binding cassette (ABC) transporter mediated efflux of Hoechst substrates (side population assay). This functional assay is based upon mechanisms that protect cells from environmental insult thus contributing to the survival and protection of the stem cell population. We have isolated and analyzed cells digested from twelve clinical prostate specimens based on the side population assay. Prostate stem cell properties of the isolated cells were tested by serial recombination with rat urogenital mesenchyme. Recombinants with side population cells demonstrate an increase in the frequency of human ductal growth and the number of glands per recombinant when compared to recombinants with non-side population cells. Isolated cells were capable of prostatic growth for up to three generations in the recombination assay with as little as 125 sorted prostate cells. The ability to reproducibly use cells isolated by fluorescence activated cell sorting from human prostate tissue is an essential step to a better understanding of human prostate stem cell biology. ABC transporter G2 (ABCG2) was expressed in recombinants from side population cells indicating the side population cells have self-renewal properties. Epithelial cell differentiation of recombinants was determined by immunohistochemical analysis for expression of the basal, luminal, and neuroendocrine markers, p63, androgen receptor, prostate specific antigen, and chromogranin A, respectively. Thus, the ABCG2 expressing side population demonstrates multipotency and self-renewal properties indicating stem cells are within this population. PMID:23383057

  19. Prevention of human PC-346C prostate cancer growth in mice by a xenogeneic tissue vaccine.

    PubMed

    Suckow, Mark A; Rosen, Elliot D; Wolter, William R; Sailes, Valerie; Jeffrey, Randy; Tenniswood, Martin

    2007-08-01

    Vaccination, as an approach to prostate cancer, has largely focused on immunotherapy utilizing specific molecules or allogeneic cells. Such methods are limited by the focused antigenic menu presented to the immune system and by immunotolerance to antigens recognized as "self". To examine if a xenogeneic tissue vaccine could stimulate protective immunity in a human prostate cancer cell line, a vaccine was produced by glutaraldehyde fixation of harvested PAIII prostate cancer cells tumors (GFT cell vaccine) from Lobund-Wistar rats. Immunocompetent Ncr-Foxn1 mice were vaccinated with the GFT cell vaccine four times, 7 days apart. The control animals were either not vaccinated or vaccinated with media or glutaraldehyde-fixed PC346C human prostate cancer cells and adjuvant. About 8 days after the final boost, serum and spleens were harvested. The splenocytes were co-incubated with PC346C cells and then transplanted orthotopically into sygneneic immunodeficient nude mice. About 10 weeks later, the prostates were weighed and sampled for histolologic examination. The spleens were harvested from additional mice, and the splenocytes were cultured, either with or without pulsing by GFT cells, and the supernatants harvested 72 h later for cytokine analysis. Results showed that vaccination with GFT cells resulted in increased serum antibody to a PAIII cell lysate; reduced weight of the prostate/seminal vesicle complex and reduced incidence of prostate cancer in nude mice; increased splenocyte supernatant levels of TNF-alpha, IL-2, IFN-gamma and IL-12, cytokines associated with Th1 immunity; and increased splenocyte supernatant levels of IL-4 and IL-10, cytokines associated with Th2 immunity. In summary, the results suggest that use of a xenogeneic tissue vaccine can stimulate protective immunity against human prostate cancer cells.

  20. Activation of Polymine Catabolism as a Novel Strategy for Treating and/or Preventing Human Prostate Cancer

    DTIC Science & Technology

    2006-03-01

    based SSAT therapy of human prostate tumor xenografts to test therapeutic generality and (c) cross-breeding SSAT over-expressing transgenic mice (12...site (IRES) for GFP. Thus, both SSAT and GFP were under the control of a CMV promoter for maximum expression. The virus was prepared in human 293...D. Prostatic polyamines and polyamine targeting as a new approach to therapy of prostatic cancer. Cancer Surveys, 11: 217-238, 1991. 3. Porter, C

  1. DNA ploidy and proliferation heterogeneity in human prostate cancers

    SciTech Connect

    Shankey, T.V.; Graham, S. |; Dougherty, S.

    1995-09-01

    DNA ploidy determinations have been shown to have clinical application in predicting disease progression, survival, or response to anti-androgen therapies in prostate carcinomas. Since intra-tumor heterogeneity may have a profound effect on DNA measurements, we determined the frequency of DNA ploidy and proliferation (here S-phase fraction) heterogeneity in early prostatic carcinomas, and estimated the potential impact of heterogeneity on predicting disease course, survival, or response to therapy. Using image and flow cytometric analysis of archival, paraffin-embedded prostate tumors, we measured DNA ploidy in individual foci of prostatic carcinoma in stage T1a, T1b and T1c disease. Our results indicate that DNA aneuploid foci of prostate carcinoma are infrequently seen in stage T1a disease (13% of the individuals studied), and that the presence of both DNA diploid and aneuploid foci in the same sample is seen in less than 10% of these individuals. Stage T1b and T1c tumors containing only DNA diploid nuclei are seen, though these are likely most common in low volume, low Gleason grade tumors. By using flow cytometry to compare these results with those using image analysis of the same tumor foci, we demonstrated that the majority (>75%) of these aneuploid tumors are DNA tetraploid. Our data on prostate tumor S-phase fractions indicate that DNA diploid tumors generally have a lower S-phase than DNA aneuploid foci (including comparisons of DNA diploid and aneuploid foci in the same prostate tumor). These results support the model that early prostate tumors are DNA diploid and have a low S-phase, and that these tumors likely evolve to DNA tetraploid tumors with a similar low S-phase fraction. 25 refs., 4 figs., 4 tabs.

  2. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer.

    PubMed

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T; van der Horst, Geertje; Hemmer, Daniëlle M; Marijt, Koen A; Hwang, Ming S; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M; Meijer, Onno C; Culig, Zoran; van der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

  3. 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

  4. Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models.

    PubMed

    Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min; Shen, Michael M; Abate-Shen, Cory; Califano, Andrea

    2015-09-29

    Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.

  5. Prostate specific membrane antigen (PSM) is expressed in various human tissues: implication for the use of PSM reverse transcription polymerase chain reaction to detect hematogenous prostate cancer spread.

    PubMed

    Renneberg, H; Friedetzky, A; Konrad, L; Kurek, R; Weingärtner, K; Wennemuth, G; Tunn, U W; Aumüller, G

    1999-01-01

    Detection of prostate-specific membrane antigen (PSM)-mRNA expression in blood samples using reverse transcription polymerase chain reaction (RT-PCR) is discussed as a new diagnostic marker of circulating micrometastases in prostate cancer patients. We applied the RT-PCR technique to different human tissues and obtained positive signals for PSM transcripts in human genital and multiple extra-genital tissue sites. The cDNAs were prepared from different human tissues and prostatic cell lines. RT-PCR and nested RT-PCR for PSM was performed with primers derived from the published PSM cDNA. The RT-PCR fragments obtained were cloned and showed 100% sequence homology to PSM. Southern blot hybridization with labeled probes was used to confirm the specificity of the amplicons. In addition to the known PSM expression in the human brain, PSM-mRNA was detected in cDNA isolated from human testis, epididymis and seminal vesicles and in the PC-3 prostatic cancer cell line. Furthermore, we found PSM-mRNA in heart, liver, lung, kidney, spleen, and thyroid gland. The results indicate that PSM expression is not restricted to the prostate gland, but represents a more general component of genital and extra-genital human tissues. This must be considered when RT-PCR and nested RT-PCR screening for PSM expression is performed as a diagnostic measure in blood from prostate cancer patients.

  6. Are gastric hyperplastic polyps an additional manifestation in celiac disease?

    PubMed Central

    Dore, Maria Pina; Pes, Giovanni Mario; Rocchi, Chiara; Loria, Maria Francesca; Soro, Sara; Bassotti, Gabrio

    2017-01-01

    Abstract Gastric polyps are frequently reported in patients undergoing upper endoscopic procedures. In this retrospective study, the association between hyperplastic polyps and celiac disease in Northern Sardinia was estimated. Age, gender, body mass index, and medications taken in the 2 preceding months, including proton-pump inhibitors (PPIs), H2 receptor blockers (anti-H2), Helicobacter pylori status, endoscopic findings, and histology from charts of patients undergoing esophago-gastro-duodenoscopy were reviewed. Polyps were classified as hyperplastic, fundic gland, inflammatory, and adenomatous. 3.7% (423/11379) patients had celiac disease. Prevalence of gastric polyps was 4.2% (3.8% among celiac vs 4.2% nonceliac patients). Inflammatory polyp was the most common histotype (55.8% and 56.2%) followed by fundic gland polyps (31.4% and 43.7%), hyperplastic (8.7% and 0%), and adenomas, in celiac and nonceliac patients, respectively. Fundic gland polyps were more common in PPI users (odds ratio: 4.06) than in nonusers (2.65, P = 0.001) among celiac and nonceliac patients. Age older than 50, female gender, esophago-gastro-duodenoscopy year, and PPI use were associated with the presence of polyps, whereas active H pylori infection was not. Gastric polyps were common in Sardinian patients undergoing esophago-gastro-duodenoscopy. However, the previously reported association between hyperplastic polyps and celiac disease was not confirmed in our study. PMID:28151870

  7. Dendritic cells in hyperplastic thymuses from patients with myasthenia gravis.

    PubMed

    Nagane, Yuriko; Utsugisawa, Kimiaki; Obara, Daiji; Yamagata, Munehisa; Tohgi, Hideo

    2003-05-01

    To investigate the role of dendritic cells (DCs) in the hyperplastic myasthenia gravis (MG) thymus, we studied the frequency and distribution of three mature DC phenotypes (CD83(+)CD11c(+), CD86(+)CD11c(+), and HLA-DR(+)CD11c(+)) in samples from patients with MG whose symptoms dramatically improved following thymectomy and in non-MG control thymuses. In hyperplastic MG thymuses, mature DCs were much more numerous in nonmedullary areas, such as the subcapsular/outer cortex; around the germinal centers; and in extralobular connective tissue, particularly around blood vessels. Mature DCs strongly coexpressed CD44 and appeared to be components of a CD44-highly positive (CD44(high)) cell population migrating from the vascular system. Furthermore, in the hyperplastic MG thymus, the expression of secondary lymphoid-tissue chemokine (SLC) markedly increased especially around extralobular blood vessels, where the CD44(high) cell population accumulated. These findings suggest that DCs may migrate into the hyperplastic thymus from the vascular system via mechanisms that involve CD44 and SLC. DCs may present self-antigens, thereby promoting the priming and/or boosting of potentially autoreactive T cells against the acetylcholine receptor.

  8. Dual-modality probe intended for prostate cancer detection combining Raman spectroscopy and tactile resonance technology--discrimination of normal human prostate tissues ex vivo.

    PubMed

    Nyberg, M; Jalkanen, V; Ramser, K; Ljungberg, B; Bergh, A; Lindahl, O A

    2015-04-01

    Prostate cancer is the most common cancer for men in the western world. For the first time, a dual-modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for assessment of fresh human prostate tissue. The study investigates the potential of the dual-modality probe by testing its ability to differentiate prostate tissue types ex vivo. Measurements on four prostates show that the tactile resonance modality was able to discriminate soft epithelial tissue and stiff stroma (p < 0.05). The Raman spectra exhibited a strong fluorescent background at the current experimental settings. However, stroma could be discerned from epithelia by integrating the value of the spectral background. Combining both parameters by a stepwise analysis resulted in 100% sensitivity and 91% specificity. Although no cancer tissue was analysed, the results are promising for further development of the instrument and method for discriminating prostate tissues and cancer.

  9. Methylation of Integrin α4 and E-Cadherin Genes in Human Prostate Cancer.

    PubMed

    Mostafavi-Pour, Z; Kianpour, S; Dehghani, M; Mokarram, P; Torabinejad, S; Monabati, A

    2015-09-01

    Prostate cancer is the second most common malignancy in men worldwide. Abnormal epigenetic alterations such as DNA methylation and histone modification play an important role in tumor initiation, progression and regulation of cancer-related genes such as integrin α4 and E-cadherin. Expression of these genes was determined by semi-quantitative reverse transcriptase-PCR in prostate cancer cell lines, DU145 and PC3, before and after treatment with 5-aza-2-deoxycytidine and trichostatin A. Laser capture microdissection microscopy was used to obtain exclusively affected epithelial cells from prostate gland biopsies of 30 patients with prostate cancer and 40 with benign prostate hyperplasia. DNA bisulfite modifications followed by methylation-specific PCR were used to evaluate the promoter methylation status of E-cadherin and α4 integrin genes in extracted DNA from patients and aforementioned cell lines. The integrin α4 promoter in DU145 was fully methylated, whereas in PC3 cells, partial methylation was detected. E-cadherin was expressed in both cell lines; trichostatin A and 5-aza-2-deoxycytidine treatment had no effect on E-cadherin expression, however the combined treatment of both drugs or 5-aza-2-deoxycytidine alone increased integrin α4 expression. Integrin α4 and E-cadherin were hypermethylated in 66.6 % and 6.6 % of prostate cancer cases, respectively; no hypermethylation was observed in patients with benign prostate hyperplasia. These results together suggest that aberrant DNA methylation is one of the mechanisms involved in integrin α4 expression and may play an important role in human prostate carcinogenesis. In addition, the higher rate of integrin α4 gene methylation in prostate cancer patients elects it as a potential molecular tumor marker.

  10. Light penetration in the human prostate: a whole prostate clinical study at 763 nm

    NASA Astrophysics Data System (ADS)

    Moore, Caroline M.; Mosse, C. Alexander; Allen, Clare; Payne, Heather; Emberton, Mark; Bown, Stephen G.

    2011-01-01

    Photodynamic therapy (PDT) is being investigated as a treatment for localized prostate cancer. Photodynamic therapy uses a photosensitizing drug which is activated by a specific wavelength of light, in the presence of oxygen. The activated drug reacts with tissue oxygen to produce reactive oxygen species which are responsible for localized tissue necrosis. One of the determinants of the PDT effect is the penetration of light in the prostate. This study assesses the penetration depth of 763 nm light throughout the prostate. Eight men undergoing multiple hollow needle insertion for high dose rate brachytherapy were recruited. 763 nm light, produced by a diode laser, was delivered to the prostate using cylindrically diffusing optical fibers within the plastic needles. Light was detected at different distances from the source, using an isotropic detector within nearby needles. Penetration depth was calculated using the Boltzmann approximation to the diffusion equation. Delivery detector fiber separation was measured on computed tomography. The mean penetration depth was 0.57 cm, but there was within patient variation of a mean factor of 4.3. Further work is ongoing to assess the effect of such variability in light penetration, on the PDT effect.

  11. Acoustic radiation force impulse imaging of human prostates: initial in vivo demonstration.

    PubMed

    Zhai, Liang; Polascik, Thomas J; Foo, Wen-Chi; Rosenzweig, Stephen; Palmeri, Mark L; Madden, John; Nightingale, Kathryn R

    2012-01-01

    Reliably detecting prostate cancer (PCa) has been a challenge for current imaging modalities. Acoustic radiation force impulse (ARFI) imaging is an elasticity imaging method that uses remotely generated, focused acoustic beams to probe tissue stiffness. A previous study on excised human prostates demonstrated ARFI images portray various prostatic structures and has the potential to guide prostate needle biopsy with improved sampling accuracy. The goal of this study is to demonstrate the feasibility of ARFI imaging to portray internal structures and PCa in the human prostate in vivo. Custom ARFI imaging sequences were designed and implemented using a modified Siemens Antares™ scanner with a three-dimensional (3-D) wobbler, end-firing, trans-cavity transducer, EV9F4. Nineteen patients were consented and imaged immediately preceding surgical prostatectomy. Pathologies and anatomic structures were identified in histologic slides by a pathologist blinded to ARFI data and were then registered with structures found in ARFI images. The results demonstrated that when PCa is visible, it generally appears as bilaterally asymmetric stiff structures; benign prostatic hyperplasia (BPH) appears heterogeneous with a nodular texture; the verumontanum and ejaculatory ducts appears softer compared with surrounding tissue, which form a unique 'V' shape; and the boundary of the transitional zone (TZ) forms a stiff rim separating the TZ from the peripheral zone (PZ). These characteristic appearances of prostatic structures are consistent with those found in our previous study of prostate ARFI imaging on excised human prostates. Compared with the matched B-mode images, ARFI images, in general, portray prostate structures with higher contrast. With the end-firing transducer used for this study, ARFI depth penetration was limited to 22 mm. Image contrast and resolution were decreased as compared with the previous ex vivo study due to the small transducer aperture. Even with these

  12. Role of RUNX3 in suppressing metastasis and angiogenesis of human prostate cancer.

    PubMed

    Chen, Feifei; Wang, Meng; Bai, Jin; Liu, Qinghua; Xi, Yaguang; Li, Wang; Zheng, Junnian

    2014-01-01

    RUNX3 (runt-related transcription factor-3) has been reported to suppress tumor tumorigenesis and metastasis in different human cancers. In this study, we used tissue microarray (TMA) to determine the significance of RUNX3 in prostate cancer progession. Our results showed ectopic expression of RUNX3 in prostate cancer tissues when compared with tumor adjacent normal prostate tissues, and reduced RUNX3 staining was significantly correlated with TNM stage. Moreover, we demonstrated that RUNX3 overexpression inhibited prostate cancer cell migration and invasion resulting from the elevated upregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), which subsequently inhibited metalloproteinase-2 (MMP-2) expression and activity in vitro. Knock down of RUNX3 expression broke up the balance of TIMP-2/MMP-2, whereas silence of TIMP-2 resulted in the inhibition of MMP-2 expression in prostate cells. We also showed that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation. Strikingly, RUNX3 was demonstrated to inhibit tumor metastasis and angiogenesis in vivo. Altogether, our results support the tumor suppressive role of RUNX3 in human prostate cancer, and provide insights into development of targeted therapy for this disease.

  13. Defining phenotypes and cancer risk in hyperplastic polyposis syndrome.

    PubMed

    Kalady, Matthew F; Jarrar, Awad; Leach, Brandie; LaGuardia, Lisa; O'Malley, Margaret; Eng, Charis; Church, James M

    2011-02-01

    Hyperplastic polyposis syndrome is a rare syndrome of colorectal cancer predisposition. Patterns of inheritance of hyperplastic polyposis syndrome are not obvious and the clinical definition is relatively arbitrary. We hypothesize that there are multiple phenotypes included in what is currently called hyperplastic polyposis syndrome. We performed this review of a large series of patients who presented with multiple serrated polyps to look for clinical patterns that may confirm our hypothesis. Hereditary colorectal cancer, colonoscopy, and clinical databases from a single institution were queried for patients meeting the following criteria: 1) ≥ 20 serrated colorectal polyps; 2) ≥ 5 serrated polyps proximal to the sigmoid; 3) ≥ 2 serrated polyps ≥ 10 mm in size; 4) any serrated polyps in a person with at least one first-degree relative who has hyperplastic polyposis syndrome. Records were reviewed for demographics, polyp details, and personal or family history of colorectal extracolonic malignancy. One-hundred fifteen patients were included. Median age at diagnosis was 62 years and 56% were male. Ninety-seven percent were white. Twenty-five percent of patients had a personal history and 38% had a family history of colorectal cancer. Twenty-eight percent of patients had a personal history and 54% had a family history of extracolonic cancer. Phenotype analysis identified 3 patterns: relatively few large, right-sided polyps (n = 55), many small left-sided polyps (n = 18), and a combination of both left- and right-sided polyps (n = 42). The right-sided phenotype had more sessile serrated polyps and tended to develop colorectal cancer at a younger age. There are at least 3 different but overlapping clinical phenotypes within hyperplastic polyposis. Recognizing this clinical heterogeneity is important in defining underlying genetic causes.

  14. Preliminary report on the correlations among pineal concretions, prostatic calculi and age in human adult males.

    PubMed

    Mori, Ryoichi; Kodaka, Tetsuo; Sano, Tsuneyoshi

    2003-09-01

    By using quantitative image analysis of soft X-ray photographs on the bulk of extracted pineal glands and prostates, we made a preliminary investigation into the correlations among pineal concretions (% by mass), prostatic calculi (% by mass) and age (years) in 40 human adult males, ranging in age from 31 to 95 years (mean (+/-SD) 69.9 +/- 15.2 years), who died and underwent the routine dissection course. The mass concentrations of pineal concretions and prostatic calculi were 17.68 +/- 13.56% (range 0-51.34%) and 0.93 +/- 1.31% (range 0-5.82%), respectively. There was no correlation between the mass concentration of pineal concretions and aging (r = 0.03; P < 1.0). There was no correlation between mass concentration of prostatic calculi and aging (r = 0.28; P < 0.5). No pineal concretions and no prostatic calculi were observed in seven and 10 cases, respectively; in addition, in one case, neither-concretions nor calculi were seen. From such data and from the previously reported suggestion on the counteracting functions between the pineal gland and prostate, a negative correlation between the mass concentrations of pineal concretions and prostatic calculi was expected. This was certainly obtained, but the correlation was low (r = -0.39; P < 0.05). Such a low correlation and no correlations between the concentrations of pineal concretions and aging or between prostatic calculi and aging may have been caused by the examination of relatively older humans. Therefore, further investigations using a number of pair samples collected from males including younger age generations will be necessary.

  15. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    PubMed Central

    2012-01-01

    Background Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. Methods First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Results Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Conclusions Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer. PMID:23231703

  16. Analysis of XMRV integration sites from human prostate cancer tissues suggests PCR contamination rather than genuine human infection.

    PubMed

    Garson, Jeremy A; Kellam, Paul; Towers, Greg J

    2011-02-25

    XMRV is a gammaretrovirus associated in some studies with human prostate cancer and chronic fatigue syndrome. Central to the hypothesis of XMRV as a human pathogen is the description of integration sites in DNA from prostate tumour tissues. Here we demonstrate that 2 of 14 patient-derived sites are identical to sites cloned in the same laboratory from experimentally infected DU145 cells. Identical integration sites have never previously been described in any retrovirus infection. We propose that the patient-derived sites are the result of PCR contamination. This observation further undermines the notion that XMRV is a genuine human pathogen.

  17. Mitogenic activation of human prostate-derived fibromuscular stromal cells by bradykinin

    PubMed Central

    Walden, Paul D; Lefkowitz, Gary K; Ittmann, Michael; Lepor, Herbert; Monaco, Marie E

    1999-01-01

    Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, inflammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function. The objective of this study was to assess the consequences of kinin action on prostate cells.Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from human prostate tissue. Transcripts encoding both the human B1 and B2 bradykinin receptor subtypes were detected in human prostate transition-zone tissue and in cultured cells by RT–PCR. In receptor binding assays, the B1 subtype predominated on PE cell membranes and the B2 subtype predominated on PS cell membranes. In PS cells, but not in PE cells, BK induced significant inositol phosphate accumulation and [3H]-thymidine uptake. These responses were mediated through the B2 receptor subtype.The use of signal transduction inhibitors indicated that mitogenic activation by BK occurred through both protein kinase C (PKC) and protein tyrosine kinase dependent mechanisms. PMA (phorbol 12-myristate 13-acetate) produced maximal [3H]-thymidine uptake by PS cells, resulted in cell elongation and caused the α-actin fibres present in PS smooth muscle cells to became organized into parallel arrays along the length of the elongated cells.In summary, the prostate contains a functional kallikrein-kinin system, which could be significant in physiological and pathophysiological prostate function. PMID:10369476

  18. Melatonin as a negative mitogenic hormonal regulator of human prostate epithelial cell growth: potential mechanisms and clinical significance.

    PubMed

    Tam, Chun W; Chan, Kwok W; Liu, Vincent W S; Pang, Bo; Yao, Kwok-Ming; Shiu, Stephen Y W

    2008-11-01

    Circannual variation in the human serum levels of prostate-specific antigen, a growth marker of the prostate gland, has been reported recently. The present study was conducted to investigate the role of the photoperiodic hormone melatonin (MLT) and its membrane receptors in the modulation of human prostate growth. Expression of MT(1) and MT(2) receptors was detected in benign human prostatic epithelial tissues and RWPE-1 cells. MLT and 2-iodomelatonin inhibited RWPE-1 cell proliferation and up-regulated p27(Kip1) gene and protein expression in the cells. The effects of MLT were blocked by the nonselective MT(1)/MT(2) receptor antagonist luzindole, but were not affected by the selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetraline. Of note, the antiproliferative action of MLT on benign prostate epithelial RWPE-1 cells was effected via increased p27(Kip1) gene transcription through MT(1) receptor-mediated activation of protein kinase A (PKA) and protein kinase C (PKC) in parallel, a signaling process which has previously been demonstrated in 22Rv1 prostate cancer cells. Taken together, the demonstration of the MT(1)/PKA+PKC/p27(Kip1) antiproliferative pathway in benign and malignant prostate epithelial cell lines indicated the potential importance of this MLT receptor-mediated signaling mechanism in growth regulation of the human prostate gland in health and disease. Collectively, our data support the hypothesis that MLT may function as a negative mitogenic hormonal regulator of human prostate epithelial cell growth.

  19. Connexin expression in nonneoplastic human prostate epithelial cells.

    PubMed

    Saladino, Francesca; Carruba, Giuseppe; Quader, Salmaan T A; Amoroso, Maria; Di Cristina, Antoniette; Webber, Mukta M; Castagnetta, Luigi A M

    2002-06-01

    Expression of gap-junction proteins connexins (Cx), specifically Cx43, Cx32, and Cx26, in both nontumorigenic (RWPE-1) and tumorigenic (RWPE-2) human prostate epithelial cells as well as in two cell clones (WPEI-7 and WPEI-10) originating from the RWPE-1 cell line was investigated. The aim was to determine whether individual connexins are differentially expressed in cultured cells. Western blot analysis revealed striking differences in the expression of individual connexins in the cell lines studied. In particular, Cx43 is largely expressed in RWPE-1 and WPEI-10 cells, whereas Cx32 is expressed predominantly in RWPE-2 and WPEI-7 cells. In addition, both forskolin and estrone increase Cx43 expression levels in WPEI-10 cells, with no apparent effect on WPEI-7 cells. Conversely, forskolin and especially estrone induce a marked increase of Cx32 in WPEI-7 cells, whereas Cx32 expression is limitedly affected by both agents in WPEI-10 cells. Overall, expression levels of Cx43 and Cx32 appear to be inversely related, with RWPE-1 and WPEI-10 cells having a significantly higher Cx43 to Cx32 ratio than that observed in RWPE-2 and WPEI-7 cells. We recently reported that junctional communication could be rescued in RWPE-1 cells by either forskolin or estrone and that restoration of GJIC is associated with an increase of Cx43 or a decrease of Cx32, or both, eventually leading to a marked rise of the Cx43 to Cx32 ratio. Studies are currently ongoing in our laboratories to assess the potential effect of agents increasing the Cx43 to Cx32 ratio on GJIC activity in these systems.

  20. Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

    PubMed

    Kyprianou, N; Benning, C M

    2000-08-15

    Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both

  1. Breaking through a roadblock in prostate cancer research: an update on human model systems.

    PubMed

    Toivanen, R; Taylor, R A; Pook, D W; Ellem, S J; Risbridger, G P

    2012-09-01

    Prostate cancer is a prevalent disease that affects the aging male population. Whilst there have been significant advances of our biological understanding of the disease, clinical translation of promising agents continues to lag behind. In part, this is due to a paucity of relevant experimental and pre-clinical models required to further develop effective prevention and therapeutic strategies. Genetically modified cell lines fail to entirely represent the genetic and molecular diversity of primary human specimens, particularly from localised disease. Furthermore, primary prostate cancer tissues are extremely difficult to grow in the laboratory and virtually all human models, whether they grow as xenografts in immune-deficient animals or as cell cultures, are genetically modified by the investigator or derived from patients with advanced metastatic disease. In this review, we discuss the latest advances and improvements to current methods of xenografting human primary prostate cancer, and their potential application to translational research.

  2. Intracavitary birdcage resonator: applications to the human prostate.

    PubMed

    Merchant, T E; Schwartz, L H; Ballon, D; Koutcher, J A; Scher, H I; Minsky, B D

    1995-01-01

    Twenty-five patients with prostatic cancer were prospectively examined with a prototype endorectal surface coil featuring a birdcage resonator circuit design. The purpose was to determine the safety of an intracavitary probe for magnetic resonance (MR) imaging of the pelvis that incorporates the "inside-out" characteristics of a volume coil design and allows high-resolution MR imaging of the prostate and potentially serves as an alternative to single-loop intracavitary surface coils. Clinically useful images supplementing images obtained with the body or external surface coils were obtained with the prototype probe. It was tolerated by all patients enrolled in the study, and none experienced side effects. The cylindrically symmetric sensitivity profile of the probe allowed identification of prostate tumors and pelvic lymph node and bone metastases. Volume-type coils may improve endopelvic MR imaging when used alone or in combination with external coil systems.

  3. AR-Signaling in Human Malignancies: Prostate Cancer and Beyond

    PubMed Central

    Schweizer, Michael T.; Yu, Evan Y.

    2017-01-01

    In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types. PMID:28085048

  4. AR-Signaling in Human Malignancies: Prostate Cancer and Beyond.

    PubMed

    Schweizer, Michael T; Yu, Evan Y

    2017-01-11

    In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.

  5. Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer

    PubMed Central

    Luo, Wei; Karpf, Adam R.; Deeb, Kristin K.; Muindi, Josephia R.; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.

    2010-01-01

    Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. ChIP-qPCR reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of VDR to the CYP24A1 promoter. RT-PCR analysis of paired human prostate samples reveals that CYP24A1 expression is down-regulated in prostate malignant lesions compared to adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared to matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications. PMID:20587525

  6. Harvesting Human Prostate Tissue Material and Culturing Primary Prostate Epithelial Cells.

    PubMed

    Frame, Fiona M; Pellacani, Davide; Collins, Anne T; Maitland, Norman J

    2016-01-01

    In order to fully explore the biology of a complex solid tumor such as prostate cancer, it is desirable to work with patient tissue. Only by working with cells from a tissue can we take into account patient variability and tumor heterogeneity. Cell lines have long been regarded as the workhorse of cancer research and it could be argued that they are of most use when considered within a panel of cell lines, thus taking into account specified mutations and variations in phenotype between different cell lines. However, often very different results are obtained when comparing cell lines to primary cells cultured from tissue. It stands to reason that cells cultured from patient tissue represents a close-to-patient model that should and does produce clinically relevant data. This chapter aims to illustrate the methods of processing, storing and culturing cells from prostate tissue, with a description of potential uses.

  7. The molecular and cellular origin of human prostate cancer.

    PubMed

    Packer, John R; Maitland, Norman J

    2016-06-01

    Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs.

  8. Isolation and Growth of Prostate Stem Cells and Establishing Cancer Cell Lines from Human Prostate Tumors

    DTIC Science & Technology

    2009-05-01

    RU, Cheng D, and Witte ON. Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci U S A 2006; 29. Cunha GR...Hopkins School of Medicine Flow Sorting Facility) for their expert assistance and Jessica Hicks and Yuko Konishi (Johns Hopkins Department of...P. Mouse urogenital development: a practical approach. Differentiation 2003;71:402–13. 29. Xin L, Ide H, Kim Y, Dubey P, Witte ON. In vivo

  9. Colorectal Carcinomas Arising in the Hyperplastic Polyposis Syndrome Progress through the Chromosomal Instability Pathway

    PubMed Central

    Hawkins, Nicholas J.; Gorman, Patricia; Tomlinson, Ian P. M.; Bullpitt, Peter; Ward, Robyn L.

    2000-01-01

    The hyperplastic polyposis syndrome is characterized by the presence within the colon of multiple large hyperplastic polyps. We describe a case of hyperplastic polyposis syndrome associated with two synchronous carcinomas, one of which arises within a pre-existing hyperplastic lesion. Comparative genomic hybridization was used to determine genetic changes in both carcinomas and several associated hyperplastic lesions. Microsatellite analysis at five loci was performed on carcinomas and representative hyperplastic polyps, and p53 status was analyzed by immunohistochemistry. Both carcinomas showed multiple genetic aberrations, including high level gains of 8q and 13q, and loss of 5q. These changes were not seen in the hyperplastic polyps. Microsatellite instability was not seen in the carcinomas, four separate hyperplastic polyps, the hyperplastic polyp with mild adenomatous change associated with the carcinoma, or a separate serrated adenoma. Allelic imbalance in the cancers at D5S346 and D17S938 suggested allelic loss of both p53 and APC, as well as at the loci D13S263, D13S174, D13S159, and D18S49. An early invasive carcinoma in one hyperplastic polyp stained for p53 protein, but the associated hyperplastic polyp was negative. In this case, neoplastic progression followed the typical genetic pathway of common colorectal carcinoma and occurred synchronously with mutation of p53. PMID:10934143

  10. 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.

  11. Expression of connexins 26 and 43 in canine hyperplastic and neoplastic mammary glands.

    PubMed

    Torres, L N; Matera, J M; Vasconcellos, C H; Avanzo, J L; Hernandez-Blazquez, F J; Dagli, M L Z

    2005-09-01

    Gap junctions are the only communicating junctions found in animal tissues and are composed of proteins known as connexins. Alterations in connexin expression have been associated with oncogenesis; reported studies in rodent and human mammary glands, which normally express connexins 26 and 43, confirm these alterations in malignancies. Mammary neoplasms represent the second most frequent neoplasm in dogs, and since there are no reports on the study of connexins in canine mammary glands, the present study investigated the expression of connexins 26 and 43 in normal, hyperplastic, and neoplastic mammary glands of this species, to verify if altered patterns of connexin staining are related to higher cell proliferation and malignant phenotypes. A total of 4 normal, 8 hyperplastic mammary glands, 9 benign, and 51 malignant mammary gland neoplasms were submitted for the immunostaining of connexins 26 and 43, E-cadherin, and proliferating cell nuclear antigen (PCNA). Normal, hyperplastic, and benign neoplastic mammary glands showed a punctate pattern for connexin 26 and 43 staining and an intercellular E-cadherin staining. Malignant neoplasms, especially the most aggressive cases with high cell proliferation rates, presented either fewer gap junction spots on the cell membranes or increased cytoplasmic immunostaining. Malignant tumors also expressed a less intense immunostaining of E-cadherin; the expression of this adhesion molecule is important for the transportation of connexins to cell membranes and in forming communicating gap junctions. Deficient expression of E-cadherin could be related to the aberrant connexin localization and may contribute to the malignant phenotype. In conclusion, the expression and distribution of connexins and E-cadherin are inversely correlated to cell proliferation in malignant mammary neoplasms of dogs and may well be related to their more aggressive histologic type and biologic behavior.

  12. Androgen Receptor (AR) Suppresses Normal Human Prostate Epithelial Cell Proliferation via AR/β-catenin/TCF-4 Complex Inhibition of c-MYC Transcription

    PubMed Central

    Antony, Lizamma; van der Schoor, Freek; Dalrymple, Susan L.; Isaacs, John T.

    2016-01-01

    INTRODUCTION Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs). METHODS Lentiviral shRNA stable knock down of c-MYC, β-catenin, or TCF-4 completely inhibits normal (i.e., non-transformed) human PrECs growth. c-MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent β-catenin signaling either by blocking TCF-4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear β-catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor-I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor-I is overcome by constitutive c-MYC transcription. RESULTS In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c-MYC transcription, resulting in G0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen-induced formation of AR/β-catenin/TCF-4 complexes, which suppress c-MYC transcription. Such suppression does not occur when AR is mutated in its zinc-finger binding domain. DISCUSSION Proliferation of non-transformed human PrECs is dependent upon c-MYC transcription via formation/binding of β-catenin/TCF-4 complexes at both 5′ and 3′ c-MYC enhancers stimulated by Wnt-independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen-induced formation of AR/β-catenin/TCF-4 complexes, which retains binding to 3′ c-MYC enhancer, but now suppresses c-MYC transcription. PMID:24913829

  13. Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer

    PubMed Central

    Chen, Zhong; Lan, Xun; Thomas-Ahner, Jennifer M; Wu, Dayong; Liu, Xiangtao; Ye, Zhenqing; Wang, Liguo; Sunkel, Benjamin; Grenade, Cassandra; Chen, Junsheng; Zynger, Debra L; Yan, Pearlly S; Huang, Jiaoti; Nephew, Kenneth P; Huang, Tim H-M; Lin, Shili; Clinton, Steven K; Li, Wei; Jin, Victor X; Wang, Qianben

    2015-01-01

    Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand-specific induction of gene expression profiles. PMID:25535248

  14. Mouse Orthotopic Xenographs of Human Prostate Primary Tumors

    DTIC Science & Technology

    2006-11-01

    prostatic hyperplasia (BPH) and 4 from cancer) were isolated from multiple samples of 4 radical prostatectomy surgical specimens, two of which belonged...pellet (12.5 mg, 90 day- release) was implanted subcutaneously in all mice. 5 PI: Loda, Massimo b) Eight primary cell cultures (4 from benign

  15. The Cohesive Metastasis Phenotype in Human Prostate Cancer.

    PubMed

    Harryman, William L; Hinton, James P; Rubenstein, Cynthia P; Singh, Parminder; Nagle, Raymond B; Parker, Sarah J; Knudsen, Beatrice S; Cress, Anne E

    2016-12-01

    A critical barrier for the successful prevention and treatment of recurrent prostate cancer is detection and eradication of metastatic and therapy-resistant disease. Despite the fall in diagnoses and mortality, the reported incidence of metastatic disease has increased 72% since 2004. Prostate cancer arises in cohesive groups as intraepithelial neoplasia, migrates through muscle and leaves the gland via perineural invasion for hematogenous dissemination. Current technological advances have shown cohesive-clusters of tumor (also known as microemboli) within the circulation. Circulating tumor cell (CTC) profiles are indicative of disseminated prostate cancer, and disseminated tumor cells (DTC) are found in cohesive-clusters, a phenotypic characteristic of both radiation- and drug-resistant tumors. Recent reports in cell biology and informatics, coupled with mass spectrometry, indicate that the integrin adhesome network provides an explanation for the biophysical ability of cohesive-clusters of tumor cells to invade thorough muscle and nerve microenvironments while maintaining adhesion-dependent therapeutic resistance. Targeting cohesive-clusters takes advantage of the known ability of extracellular matrix (ECM) adhesion to promote tumor cell survival and represents an approach that has the potential to avoid the progression to drug- and radiotherapy-resistance. In the following review we will examine the evidence for development and dissemination of cohesive-clusters in metastatic prostate cancer.

  16. The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells

    PubMed Central

    Olokpa, Emuejevoke; Bolden, Adrienne

    2016-01-01

    The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand‐activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells. qRT‐PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARγ mRNA and protein within the castration‐resistant, AR‐positive C4‐2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARγ levels. In addition, siRNA mediated knockdown of AR increased PPARγ protein levels and ligand‐induced PPARγ transcriptional activity within the C4‐2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARγ and prevented the DHT‐mediated suppression of PPARγ. These data suggest that AR normally functions to suppress PPARγ expression within AR‐positive prostate cancer cells. To determine whether increases in AR protein would influence PPARγ expression and activity, we used lipofectamine‐based transfections to overexpress AR within the AR‐null PC‐3 cells. The addition of AR to PC‐3 cells did not significantly alter PPARγ protein levels. However, the ability of the PPARγ ligand rosiglitazone to induce activation of a PPARγ‐driven luciferase reporter and induce expression of FABP4 was suppressed in AR‐positive PC‐3 cells. Together, these data indicate AR serves as a key modulator of PPARγ expression and function within prostate tumors. J. Cell. Physiol. 231: 2664–2672, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:26945682

  17. Hyperspectral stimulated Raman scattering imaging facilitates accurate diagnosis of human prostate cancer

    NASA Astrophysics Data System (ADS)

    Cui, Sishan; Wang, Ping; Yue, Shuhua

    2017-02-01

    Due to the subject nature of histopathology, there is a significant inter-observer discordance for the differentiation between low-risk prostate cancer (Gleason score <= 6), which can be left without treatment, and high-risk prostate cancer (Gleason score >6), which requires active treatment. Our previous study using Raman spectromicroscopy reveals that cholesteryl ester accumulation underlies human prostate cancer aggressiveness. However, Raman spectromicroscopy could only provide compositional information of certain lipid droplets of interest, which overlooked cell-to-cell variation and hindered translation to accurate automated diagnosis. Here, we demonstrated quantitative mapping of cholesteryl ester molar percentage in human prostate cancer tissues using hyperspectral stimulated Raman scattering microscopy that renders compositional information for every pixel in the image. Specifically, hundreds of SRS images at Raman shift between 2800 3000 cm-1 were taken, and multivariate curve resolution algorism was used to retrieve concentration images of lipid, lipofuscin, and protein. We found that the height ratio between the prominent cholesterol band at 2870 cm-1 and the CH2 stretching band at 2850 cm-1 was proportional to the molar percentage of cholesteryl ester present in the total lipids. Based on the calibration curve, we were able to quantitatively map cholesteryl ester level in intact prostate cancer tissues. Our data showed that not only the amount of cholesteryl ester-rich lipid droplets, but also the CE molar percentage, was significantly greater in prostate cancer tissues with Gleason score > 6 compared to the ones with Gleason score <= 6. Our study offers an opportunity towards more accurate prostate cancer diagnosis.

  18. Positive correlation between PEDF expression levels and macrophage density in the human prostate

    PubMed Central

    Nelius, Thomas; Samathanam, Christina; Martinez-Marin, Dalia; Gaines, Natalie; Stevens, Jessica; Hickson, Johnny; de Riese, Werner; Filleur, Stéphanie

    2012-01-01

    BACKGROUND In this study, we investigated the capacity of PEDF to modulate the recruitment and the differentiation of monocytes/macrophages both in vitro and in human prostate. METHODS Using Boyden chambers, we assessed PEDF effect on the migration of monocytes and chemically-activated RAW264.7 macrophages. Normal, prostatitis and prostate cancer specimens were retrospectively selected and examined by immunohistochemistry for PEDF expression and infiltration of immune CD68+macrophagic cells. PEDF expression and macrophage density were then correlated with each other and clinicopathological parameters. M1 and M2 differentiation markers were quantified by qRT-PCR, western blotting and ELISA. RESULTS In chemotaxis, PEDF induced the migration of monocytes/macrophages. In immunohistochemistry, macrophages were markedly increased in prostatitis and malignant compared to normal tissues. PEDF was expressed at variable levels in the stroma and epithelium. PEDF mRNA was down-regulated in both prostate cancer and prostatitis compared to normal tissues. In correlation studies, macrophage density and PEDF expression were respectively positively and negatively associated with prostate size. Most importantly, PEDF expression positively correlated with macrophage density. Finally, PEDF stimulated the expression of iNOS, IL12 and TNFα; and inhibited IL10 and arginase 1 in mouse and human macrophages confirming a M1-type differentiation. CONCLUSIONS Our data demonstrate that PEDF acts directly on monocytes/macrophages by inducing their migration and differentiation into M1-type cells. These findings suggest a possible role of macrophages in PEDF anti-tumor properties and may support further development of PEDF-based anti-cancer therapy. PMID:23038613

  19. Differential effects of vitamin D on normal human prostate epithelial and stromal cells in primary culture.

    PubMed

    Krill, D; Stoner, J; Konety, B R; Becich, M J; Getzenberg, R H

    1999-07-01

    Because epidemiologic evidence has demonstrated that vitamin D may play a role in the etiology of prostate cancer, we tested the inhibitory effect of the biologically active form of vitamin D (1,25-D) on the cell proliferation of human prostate epithelial and stromal cells in a chemically defined situation in the presence and absence of dihydrotestosterone (DHT). We also tested the effect of 1,25-D in castrated rats in the presence and absence of flutamide, an androgen receptor blocker. Prostate stromal and epithelial cells were isolated from freshly collected human prostatectomy specimens, and cell proliferation was measured with the MTT assay. Immunohistochemistry was performed to detect the presence of 1,25-D receptors, androgen receptors, smooth muscle actin, and E-cadherin. For in vivo analysis of 1,25-D, male Sprague-Dawley rats were castrated, then treated with either 1,25-D, 1,25-D with flutamide, or vehicle control. Incubation of primary cultures of prostate epithelial cells with 1,25-D at a concentration of 10(-8) M reduced cell proliferation by 40% of controls. The inhibition of growth by 1,25-D was maintained in the presence of DHT. Conversely, the effect of a similar dose of 1,25-D on stromal cell exposure was increased proliferation. In vivo, 1,25-D increased the prostatic weight of castrated rats that had serum testosterone levels below the detectable limit. The addition of flutamide did not alter this effect. These results confirm that vitamin D may be an effective antiproliferative agent of epithelial cells in prostate cancer therapy and support in vivo studies performed in the normal rat prostate.

  20. Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death.

    PubMed

    Herrmann, Daniel; Schreiber, Andrea; Ciotkowska, Anna; Strittmatter, Frank; Waidelich, Raphaela; Stief, Christian G; Gratzke, Christian; Hennenberg, Martin

    2014-09-01

    Smooth muscle contraction and prostate growth are important targets for medical therapy of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Honokiol and Magnolol are lignan constituents of Magnolia species, which are used in traditional Asian medicine. Here, we examined effects of honokiol and magnolol on contraction of human prostate tissue and on growth of stromal cells. Prostate tissues were obtained from radical prostatectomy. Contraction of prostate strips was examined in organ bath studies. Effects in stromal cells were assessed in cultured immortalized human prostate stromal cells (WPMY-1). Ki-67 mRNA was assessed by reverse transcription-polymerase chain reaction, and proliferation by a fluorescence 5-ethynyl-2'-deoxyuridine assay. Honokiol (100μM) reduced noradrenaline-induced contractions, which was significant at 10 to 100μM noradrenaline. Honokiol reduced phenylephrine-induced contractions, which was significant at 3 to 100μM phenylephrine. Honokiol reduced electric field stimulation-induced contractions very slightly. In WPMY-1 cells, honokiol (24 hours) induced cell death. Magnolol (100μM) was without effects on contraction, and cellular viability. Honokiol inhibits smooth muscle contraction in the human prostate, and induces cell death in cultured stromal cells. Because prostate smooth muscle tone and prostate growth may cause LUTS, it appears possible that honokiol improves voiding symptoms.

  1. Role of hormonal and other factors in human prostate cancer.

    PubMed

    Wigle, Donald T; Turner, Michelle C; Gomes, James; Parent, Marie-Elise

    2008-03-01

    American men have a lifetime risk of about 18% for prostate cancer diagnosis. Large international variations in prostate cancer risks and increased risks among migrants from low- to high-risk countries indicate important roles for environmental factors. Major known risk factors include age, family history, and country/ethnicity. Type 2 diabetes appears to reduce risk, while high birth weight and adult height are linked to increased risk of aggressive prostate cancer. Limited evidence supports an association with a history of sexually transmitted infections. A previous meta-analysis of eight cohort studies indicated no associations with plasma androgen, estrogen, or sex hormone binding globulin (SHBG) levels. However, there were dose-response relationships with baseline plasma testosterone levels in two studies that adjusted for other serum hormones and obesity. Finasteride (a drug that blocks testosterone activation) reduced prostate cancer risk by 25%. Low-frequency genes linked to familial prostate cancer only explain a small fraction of all cases. Sporadic cases were linked to relatively common polymorphisms of genes involved in (1) androgen synthesis, activation, inactivation and excretion, (2) hormone and vitamin D receptors, (3) carcinogen metabolism, and (4) DNA repair. Epidemiologic evidence supports protective roles for dietary selenium, vitamin E, pulses, tomatoes/lycopene, and soy foods, and high plasma 1,25-dihydroxyvitamin D levels. There is inadequate evidence that vegetables, fruit, carotenoids, and vitamins A and C reduce risk and that animal fat, alpha-linoleic acid, meat, coffee, and tea increase risk. Two major cohort studies found dose-response relationships with dietary calcium intake. Total dietary energy intake may enhance risk. Limited evidence supports a protective role for physical activity and elevated risk for farmers and other men with occupational pesticide exposure, particularly to organochlorine compounds and phenoxy herbicides

  2. Role of connexin 43 in cadmium-induced proliferation of human prostate epithelial cells.

    PubMed

    Liu, Qingping; Ji, Xiaoli; Ge, Zehe; Diao, Haipeng; Chang, Xiuli; Wang, Lihua; Wu, Qing

    2017-02-08

    Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca(2+) and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27(Kip1) (p27) and p21(Waf1/Cip1) (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.

  3. Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution.

    PubMed

    Hu, Wen-Yang; Hu, Dan-Ping; Xie, Lishi; Li, Ye; Majumdar, Shyama; Nonn, Larisa; Hu, Hong; Shioda, Toshi; Prins, Gail S

    2017-08-01

    Using primary cultures of normal human prostate epithelial cells, we developed a novel prostasphere-based, label-retention assay that permits identification and isolation of stem cells at a single cell level. Their bona fide stem cell nature was corroborated using in vitro and in vivo regenerative assays and documentation of symmetric/asymmetric division. Robust WNT10B and KRT13 levels without E-cadherin or KRT14 staining distinguished individual stem cells from daughter progenitors in spheroids. Following FACS to isolate label-retaining stem cells from label-free progenitors, RNA-seq identified unique gene signatures for the separate populations which may serve as useful biomarkers. Knockdown of KRT13 or PRAC1 reduced sphere formation and symmetric self-renewal highlighting their role in stem cell maintenance. Pathways analysis identified ribosome biogenesis and membrane estrogen-receptor signaling enriched in stem cells with NF-ĸB signaling enriched in progenitors; activities that were biologically confirmed. Further, bioassays identified heightened autophagy flux and reduced metabolism in stem cells relative to progenitors. These approaches similarly identified stem-like cells from prostate cancer specimens and prostate, breast and colon cancer cell lines suggesting wide applicability. Together, the present studies isolate and identify unique characteristics of normal human prostate stem cells and uncover processes that maintain stem cell homeostasis in the prostate gland. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  4. Site of iodination in hyperplastic thyroid glands deduced from autoradiographs

    SciTech Connect

    Wollman, S.H.; Ekholm, R.

    1981-06-01

    We have tried to ascertain the site of iodination in the chronically stimulated, hyperplastic thyroid gland of rats. Rats were fed propylthiouracil in a commercial rat diet for 10 days. Then the diet was changed to a low iodine diet for 5 days. To label the gland, 10 mCi of 125I-iodide was injected into the left heart ventricle. Ten seconds later the animal was perfused through the left ventricle with a fixative solution containing a goitrogen to block further iodination, and stable iodide to help extract uncombined radioiodide. Electron microscopic autoradiographs prepared from the fixed thyroids show strong labeling over the lumen of the follicle and no consistent labeling of any other site or organelle. We conclude that the site of iodination in the chronically stimulated, hyperplastic thyroid is the follicular lumen, i.e. the same as that in the normal gland.

  5. Exploiting the Innate Antitumor Activity of Human gammadelta-TCells for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2006-04-01

    are representative of experiments performed at least 3 other times. Normal human keratinocytes (Ha- Cat cells) were labeled with 51Cr and incubated...cell experience " (R. Lopez) FINAL Report: DAMD17-03-1-0265 Principal Investigator: LOPEZ, Richard D. 15 CONCLUSIONS • As noted above, the findings...human prostate cell lines DU145, LNCaP and PC-3 (American Type Culture Collection, Manassas, Vir- ginia) and the normal human keratinocyte cell line

  6. Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

    PubMed Central

    Zemskova, Marina Y.; Song, Jin H.; Cen, Bo; Cerda-Infante, Javier; Montecinos, Viviana P.; Kraft, Andrew S.

    2014-01-01

    The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 overexpressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5’Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRβ mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs. PMID:25451079

  7. Frequency and Type Distribution of Human Papilloma Virus in Patients with Prostate Cancer, Kerman, Southeast of Iran.

    PubMed

    Atashafrooz, Fatemeh; Rokhbakhsh-Zamin, Farokh

    2016-01-01

    Prostatic cancer is the second cause of cancer-related death among men worldwide. The human papilloma viruses (HPVs) are a family of sexually transmitted viruses which have may have roles in the etiology of inflammation in the prostate leading to benign prostatic hyperplasia (BPH) and prostate cancer (PCa). In this study, we evaluated the frequency of different HPV types in prostatic cancer and benign prostatic hyperplasia (BPH) in Kerman province, southeast of Iran, using real-time PCR techniques. The aim of the present research was to clarify any association with prostatic carcinogenesis. Real Time PCR showed that HPV DNA was found in 20% of 200 PCa samples, 80 percent of these with high-risk HPV types, 40% with type-16,18, 30 % type-31,33 and 10% type 54. High risk HPV DNA was detected in only 2% of BPH samples. Values for low risk types were much higher. Our study provided support for a role of high risk HPV infection in prostatic disease in Iranian patients, and association between presence of HPV DNA and prostate carcinoma. In particular, HPV 16 and18 might have an important role in prostate cancer.

  8. Lycium barbarum polysaccharides induce apoptosis in human prostate cancer cells and inhibits prostate cancer growth in a xenograft mouse model of human prostate cancer.

    PubMed

    Luo, Qiong; Li, Zhuoneng; Yan, Jun; Zhu, Fan; Xu, Ruo-Jun; Cai, Yi-Zhong

    2009-08-01

    Lycium barbarum polysaccharides (LBPs) are important functional constituents in red-colored fruits of L. barbarum (Guo Qi Zi, a well-known traditional Chinese medicinal plant commonly known as Goji berry or wolfberry). The influence of LBP on human prostate cancer cells was systematically investigated in vitro and in vivo. The in vitro effects of LBP on two cell lines (PC-3 and DU-145) were examined by using trypan blue exclusion staining, single-cell gel electrophoresis, flow cytometry, terminal dUTP nick-end labeling assay, and immunohistochemical assay (assessment of Bcl-2 and Bax expression). The in vivo effect of LBP on PC-3 cells was assessed in the nude mouse xenograft tumor model. The in vitro results showed that LBP can dose- and time-dependently inhibit the growth of both PC-3 and DU-145 cells. LBP caused the breakage of DNA strands of PC-3 and DU-145 cells; the tail frequency and tail length were significantly higher than that of control cells. LBP also markedly induced PC-3 and DU-145 cell apoptosis, with the highest apoptosis rates at 41.5% and 35.5%, respectively. The ratio of Bcl-2/Bax protein expression following LBP treatments decreased significantly with a dose-effect relationship, which suggested that LBP can regulate the expression of Bcl-2 and Bax to induce apoptosis of PC-3 and DU-145 cells. The in vivo experimental results indicate that LBP might significantly inhibit PC-3 tumor growth in nude mice. Both the tumor volume and weight of the LBP treatment group were significantly lower than those of the control group.

  9. Coagulation of human prostate volumes with MRI-controlled transurethral ultrasound therapy: Results in gel phantoms

    PubMed Central

    N’Djin, William Apoutou; Burtnyk, Mathieu; Kobelevskiy, Ilya; Hadjis, Stefan; Bronskill, Michael; Chopra, Rajiv

    2012-01-01

    Purpose: The feasibility and safety of magnetic resonance imaging (MRI)-controlled transurethral ultrasound therapy were demonstrated recently in a preliminary human study in which a small subvolume of prostate tissue was treated prior to radical prostatectomy. Translation of this technology to full clinical use, however, requires the capability to generate thermal coagulation in a volume up to that of the prostate gland itself. The aim of this study was to investigate the parameters required to treat a full 3D human prostate accurately with a multi-element transurethral applicator and multiplanar MR temperature control. Methods: The approach was a combination of simulations (to select appropriate parameters) followed by experimental confirmation in tissue-mimicking phantoms. A ten-channel, MRI-compatible transurethral ultrasound therapy system was evaluated using six human prostate models (average volume: 36 cm3) obtained from the preliminary human feasibility study. Real-time multiplanar MR thermometry at 3 T was used to control the spatial heating pattern in up to nine planes simultaneously. Treatment strategies incorporated both single (4.6 or 8.1 MHz) and dual (4.6 and 14.4 MHz) frequencies, as well as maximum acoustic surface powers of 10 or 20 W cm−2. Results: Treatments at 4.6 MHz were capable of coagulating a volume equivalent to 97% of the prostate. Increasing power from 10 to 20 W cm−2 reduced treatment times by approximately 50% with full treatments taking 26 ± 3 min at a coagulation rate of 1.8 ± 0.4 cm3 min−1. A dual-frequency 4.6/14.4 MHz treatment strategy was shown to be the most effective configuration for achieving full human prostate treatment while maintaining good treatment accuracy for small treatment radii. The dual-frequency approach reduced overtreatment close to the prostate base and apex, confirming the simulations. Conclusions: This study reinforces the capability of MRI-controlled transurethral ultrasound therapy to treat

  10. Coagulation of human prostate volumes with MRI-controlled transurethral ultrasound therapy: Results in gel phantoms.

    PubMed

    N'Djin, William Apoutou; Burtnyk, Mathieu; Kobelevskiy, Ilya; Hadjis, Stefan; Bronskill, Michael; Chopra, Rajiv

    2012-07-01

    The feasibility and safety of magnetic resonance imaging (MRI)-controlled transurethral ultrasound therapy were demonstrated recently in a preliminary human study in which a small subvolume of prostate tissue was treated prior to radical prostatectomy. Translation of this technology to full clinical use, however, requires the capability to generate thermal coagulation in a volume up to that of the prostate gland itself. The aim of this study was to investigate the parameters required to treat a full 3D human prostate accurately with a multi-element transurethral applicator and multiplanar MR temperature control. The approach was a combination of simulations (to select appropriate parameters) followed by experimental confirmation in tissue-mimicking phantoms. A ten-channel, MRI-compatible transurethral ultrasound therapy system was evaluated using six human prostate models (average volume: 36 cm(3) ) obtained from the preliminary human feasibility study. Real-time multiplanar MR thermometry at 3 T was used to control the spatial heating pattern in up to nine planes simultaneously. Treatment strategies incorporated both single (4.6 or 8.1 MHz) and dual (4.6 and 14.4 MHz) frequencies, as well as maximum acoustic surface powers of 10 or 20 W cm(-2) . Treatments at 4.6 MHz were capable of coagulating a volume equivalent to 97% of the prostate. Increasing power from 10 to 20 W cm(-2) reduced treatment times by approximately 50% with full treatments taking 26 ± 3 min at a coagulation rate of 1.8 ± 0.4 cm(3)  min(-1) . A dual-frequency 4.6/14.4 MHz treatment strategy was shown to be the most effective configuration for achieving full human prostate treatment while maintaining good treatment accuracy for small treatment radii. The dual-frequency approach reduced overtreatment close to the prostate base and apex, confirming the simulations. This study reinforces the capability of MRI-controlled transurethral ultrasound therapy to treat full prostate volumes in a

  11. Coagulation of human prostate volumes with MRI-controlled transurethral ultrasound therapy: results in gel phantoms.

    PubMed

    N'djin, William Apoutou; Burtnyk, Mathieu; Kobelevskiy, Ilya; Hadjis, Stefan; Bronskill, Michael; Chopra, Rajiv

    2012-07-01

    The feasibility and safety of magnetic resonance imaging (MRI)-controlled transurethral ultrasound therapy were demonstrated recently in a preliminary human study in which a small subvolume of prostate tissue was treated prior to radical prostatectomy. Translation of this technology to full clinical use, however, requires the capability to generate thermal coagulation in a volume up to that of the prostate gland itself. The aim of this study was to investigate the parameters required to treat a full 3D human prostate accurately with a multi-element transurethral applicator and multiplanar MR temperature control. The approach was a combination of simulations (to select appropriate parameters) followed by experimental confirmation in tissue-mimicking phantoms. A ten-channel, MRI-compatible transurethral ultrasound therapy system was evaluated using six human prostate models (average volume: 36 cm(3)) obtained from the preliminary human feasibility study. Real-time multiplanar MR thermometry at 3 T was used to control the spatial heating pattern in up to nine planes simultaneously. Treatment strategies incorporated both single (4.6 or 8.1 MHz) and dual (4.6 and 14.4 MHz) frequencies, as well as maximum acoustic surface powers of 10 or 20 W cm(-2). Treatments at 4.6 MHz were capable of coagulating a volume equivalent to 97% of the prostate. Increasing power from 10 to 20 W cm(-2) reduced treatment times by approximately 50% with full treatments taking 26 ± 3 min at a coagulation rate of 1.8 ± 0.4 cm(3) min(-1). A dual-frequency 4.6∕14.4 MHz treatment strategy was shown to be the most effective configuration for achieving full human prostate treatment while maintaining good treatment accuracy for small treatment radii. The dual-frequency approach reduced overtreatment close to the prostate base and apex, confirming the simulations. This study reinforces the capability of MRI-controlled transurethral ultrasound therapy to treat full prostate volumes in a short

  12. Pathophysiological and clinical aspects of gastric hyperplastic polyps.

    PubMed

    Markowski, Adam Roman; Markowska, Agnieszka; Guzinska-Ustymowicz, Katarzyna

    2016-10-28

    Gastric polyps become a major clinical problem because of high prevalence and tendency to malignant transformation of some of them. The development of gastric hyperplastic polyps results from excessive proliferation of foveolar cells accompanied by their increased exfoliation, and they are macroscopically indistinguishable from other polyps with lower or higher malignant potential. Panendoscopy allows detection and differentiation of gastric polyps, usually after obtaining histopathological biopsy specimens. Unremoved gastric hyperplastic polyps may enlarge and sometimes spontaneously undergo a sequential progression to cancer. For this reason, gastric hyperplastic polyps larger than 5 mm in size should be removed in one piece. After excision of polyps with atypical focal lesion, endoscopic surveillance is suggested depending on histopathological diagnosis and possibility of confirming the completeness of endoscopic resection. Because of the risk of cancer development also in gastric mucosa outside the polyp, neighboring fragments of gastric mucosa should undergo microscopic investigations. This procedure allows for identification of patients who can benefit most from oncological endoscopic surveillance. If Helicobacter pylori (H. pylori) infection of the gastric mucosa is confirmed, treatment strategies should include eradication of bacteria, which may prevent progression of intestinal metaplasia. The efficacy of H. pylori eradication should be checked 3-6 mo later.

  13. Pathophysiological and clinical aspects of gastric hyperplastic polyps

    PubMed Central

    Markowski, Adam Roman; Markowska, Agnieszka; Guzinska-Ustymowicz, Katarzyna

    2016-01-01

    Gastric polyps become a major clinical problem because of high prevalence and tendency to malignant transformation of some of them. The development of gastric hyperplastic polyps results from excessive proliferation of foveolar cells accompanied by their increased exfoliation, and they are macroscopically indistinguishable from other polyps with lower or higher malignant potential. Panendoscopy allows detection and differentiation of gastric polyps, usually after obtaining histopathological biopsy specimens. Unremoved gastric hyperplastic polyps may enlarge and sometimes spontaneously undergo a sequential progression to cancer. For this reason, gastric hyperplastic polyps larger than 5 mm in size should be removed in one piece. After excision of polyps with atypical focal lesion, endoscopic surveillance is suggested depending on histopathological diagnosis and possibility of confirming the completeness of endoscopic resection. Because of the risk of cancer development also in gastric mucosa outside the polyp, neighboring fragments of gastric mucosa should undergo microscopic investigations. This procedure allows for identification of patients who can benefit most from oncological endoscopic surveillance. If Helicobacter pylori (H. pylori) infection of the gastric mucosa is confirmed, treatment strategies should include eradication of bacteria, which may prevent progression of intestinal metaplasia. The efficacy of H. pylori eradication should be checked 3-6 mo later. PMID:27833379

  14. Active Sonic Hedgehog Signaling between Androgen Independent Human Prostate Cancer Cells and Normal/Benign but Not Cancer-Associated Prostate Stromal Cells

    PubMed Central

    Shigemura, Katsumi; Huang, Wen-Chin; Li, Xiangyan; Zhau, Haiyen E.; Zhu, Guodong; Gotoh, Akinobu; Fujisawa, Masato; Xie, Jingwu; Marshall, Fray F.; Chung, Leland W. K.

    2012-01-01

    BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells. PMID:21520153

  15. Radiation inactivation of human prostate cancer cells: The role of apoptosis

    SciTech Connect

    Algan, O.; Stobbe, C.C.; Helt, A.M.

    1996-09-01

    Radiation induced apoptosis detected by gel electrophoresis was measured in cells of three human prostate carcinoma cell lines and compared to their intrinsic radiosensitivities as measured by clonogenic assays. The intrinsic radiosensitivities of each cell line were defined by their alpha and beta coefficients and their surviving fraction at 2 Gy, derived from complete survival curves.

  16. Proteolytic cleavage and truncation of NDRG1 in human prostate cancer cells, but not normal prostate epithelial cells

    PubMed Central

    Ghalayini, Mohammad K.; Dong, Qihan; Richardson, Des R.; Assinder, Stephen J.

    2013-01-01

    NDRG1 (N-myc downstream regulated gene-1) is a metastasis suppressor that is down-regulated in prostate cancer. NDRG1 phosphorylation is associated with inhibition of metastasis and Western blots indicate two bands at ~41 and ~46 kDa. Previous investigations by others suggest the higher band is due to NDRG1 phosphorylation. However, the current study using a dephosphorylation assay and the Phos-tag (phosphate-binding tag) SDS/PAGE assay, demonstrated that the 46 kDa NDRG1 protein band was not due to phosphorylation. Further experiments showed that the NDRG1 protein bands were not affected upon glycosidase treatment, despite marked effects of these enzymes on the glycosylated protein, fetuin. Analysis using RT–PCR (reverse transcriptase–PCR) demonstrated only a single amplicon, and thus, the two bands could not result from an alternatively spliced NDRG1 transcript. Western-blot analysis of prostate cancer cell lysates identified the 41 kDa band to be a truncated form of NDRG1, with MS confirming the full and truncated proteins to be NDRG1. Significantly, this truncated protein was not present in normal human PrECs (prostate epithelial cells). Western-blot analysis using anti-NDRG1 raised to its N-terminal sequence failed to detect the truncated protein, suggesting that it lacked N-terminus amino acids (residues 1–49). Sequence analysis predicted a pseudotrypsin protease cleavage site between Cys49–Gly50. Such cleavage of NDRG1 in cancer cells may result in loss of NDRG1 tumour suppressive activity. PMID:23634903

  17. Proteolytic cleavage and truncation of NDRG1 in human prostate cancer cells, but not normal prostate epithelial cells.

    PubMed

    Ghalayini, Mohammad K; Dong, Qihan; Richardson, Des R; Assinder, Stephen J

    2013-06-11

    NDRG1 (N-myc downstream regulated gene-1) is a metastasis suppressor that is down-regulated in prostate cancer. NDRG1 phosphorylation is associated with inhibition of metastasis and Western blots indicate two bands at ~41 and ~46 kDa. Previous investigations by others suggest the higher band is due to NDRG1 phosphorylation. However, the current study using a dephosphorylation assay and the Phos-tag (phosphate-binding tag) SDS/PAGE assay, demonstrated that the 46 kDa NDRG1 protein band was not due to phosphorylation. Further experiments showed that the NDRG1 protein bands were not affected upon glycosidase treatment, despite marked effects of these enzymes on the glycosylated protein, fetuin. Analysis using RT-PCR (reverse transcriptase-PCR) demonstrated only a single amplicon, and thus, the two bands could not result from an alternatively spliced NDRG1 transcript. Western-blot analysis of prostate cancer cell lysates identified the 41 kDa band to be a truncated form of NDRG1, with MS confirming the full and truncated proteins to be NDRG1. Significantly, this truncated protein was not present in normal human PrECs (prostate epithelial cells). Western-blot analysis using anti-NDRG1 raised to its N-terminal sequence failed to detect the truncated protein, suggesting that it lacked N-terminus amino acids (residues 1-49). Sequence analysis predicted a pseudotrypsin protease cleavage site between Cys49-Gly50. Such cleavage of NDRG1 in cancer cells may result in loss of NDRG1 tumour suppressive activity.

  18. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells

    SciTech Connect

    Pei, Yanxi; Wu, Bo; Cao, Qiuhui; Wu, Lingyun; Yang, Guangdong

    2011-12-15

    Hydrogen sulfide (H{sub 2}S) is a novel gasotransmitter that regulates cell proliferation and other cellular functions. Sulforaphane (SFN) is a sulfur-containing compound that exhibits anticancer properties, and young sprouts of broccoli are particularly rich in SFN. There is consistent epidemiological evidence that the consumption of sulfur-containing vegetables, such as garlic and cruciferous vegetables, may help reduce the occurrence of prostate cancer. Here we found that a large amount of H{sub 2}S is released when SFN is added into cell culture medium or mixed with mouse liver homogenates, respectively. Both SFN and NaHS (a H{sub 2}S donor) decreased the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner, and supplement of methemoglobin or oxidized glutathione (two H{sub 2}S scavengers) reversed SFN-reduced cell viability. We further found both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are expressed in PC-3 cells and mouse prostate tissues. H{sub 2}S production in prostate tissues from CSE knockout mice was only 20% of that from wild-type mice, suggesting CSE is a major H{sub 2}S-producing enzyme in prostate. CSE overexpression enhanced H{sub 2}S production and inhibited cell viability in PC-3 cells. In addition, both SFN and NaHS activated p38 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinase (JNK). Pre-treatment of PC-3 cells with methemoglobin decreased SFN-stimulated MAPK activities. Suppression of both p38 MAPK and JNK reversed H{sub 2}S- or SFN-reduced viability of PC-3 cells. Our results demonstrated that H{sub 2}S mediates the inhibitory effect of SFN on the proliferation of PC-3 cells, which suggests that H{sub 2}S-releasing diet or drug might be beneficial in the treatment of prostate cancer. Highlights: Black-Right-Pointing-Pointer A large amount of H{sub 2}S is released from sulforaphane. Black-Right-Pointing-Pointer H{sub 2}S mediates the anti-survival effect of

  19. Novel Fatty Acid Lipoxygenases in the Development of Human and Murine Prostate Cancer

    DTIC Science & Technology

    2000-10-01

    Shappell, S ., and Matusik, R. J. Regrowth of prostate tumor after castration in probasin-large T antigen transgenic mice - longitudinal study with MRI, J...21702-5012. The views, opinions and/or findings contained in this report are those of the author( s ) and should not be construed as an official...Novel Fatty Acid Lipoxygenases in the Development DAMD17-98-1-8637 of Human and Murine Prostate Cancer 6. AUTHOR( S ) Scott Shappell, M.D., Ph.D. 7

  20. Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer

    DTIC Science & Technology

    2005-01-01

    be generated by other pathways. LPA is produced from phosphatidic acid 4 ") (PA) in activated platelets and ovarian and prostate cancer cells by...material. Appendix 1 JCB in revision 2 ABSTRACT The bioactive phospholipids, lysophosphatidic acid (LPA) and phosphatidic acid (PA), regulate pivotal...glycerolipid synthesis, abundant evidence now indicates that bioactive LPA can also be generated by other pathways. LPA is produced from phosphatidic acid (PA

  1. NOTCH3 IS ACTIVATED BY CHRONIC HYPOXIA AND CONTRIBUTES TO THE PROGRESSION OF HUMAN PROSTATE CANCER

    PubMed Central

    Danza, Giovanna; Di Serio, Claudia; Ambrosio, Maria Raffaella; Sturli, Niccolò; Lonetto, Giuseppe; Rosati, Fabiana; Rocca, Bruno Jim; Ventimiglia, Giuseppina; del Vecchio, Maria Teresa; Prudovsky, Igor; Marchionni, Niccolò; Tarantini, Francesca

    2013-01-01

    Prostate cancer is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive prostate cancer cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition Notch3 migrated from the non-raft into the raft compartment where it co-localized with the γ-secretase complex. We also looked at human prostate cancer biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3 which, in turn, sustains proliferation of prostate cancer cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with prostate cancer. PMID:23729168

  2. The regulation of adiponectin receptors in human prostate cancer cell lines

    SciTech Connect

    Mistry, T.; Digby, J.E.; Chen, J.; Desai, K.M.; Randeva, H.S. . E-mail: H.Randeva@warwick.ac.uk

    2006-09-29

    Obesity is a risk factor for prostate cancer, and plasma levels of the adipokine, adiponectin, are low in the former but high in the latter. Adiponectin has been shown to modulate cell proliferation and apoptosis, suggesting that adiponectin and its receptors (Adipo-R1, Adipo-R2) may provide a molecular association between obesity and prostate carcinogenesis. We show for First time, the protein distribution of Adipo-R1 and Adipo-R2 in LNCaP and PC3 cells, and in human prostate tissue. Using real-time RT-PCR we provide novel data demonstrating the differential regulation of Adipo-R1 and Adipo-R2 mRNA expression by testosterone, 5-{alpha} dihydrotestosterone, {beta}-estradiol, tumour necrosis factor-{alpha}, leptin, and adiponectin in LNCaP and PC3 cells. Our findings suggest that adiponectin and its receptors may contribute to the molecular association between obesity and prostate cancer through a complex interaction with other hormones and cytokines that also play important roles in the pathophysiology of obesity and prostate cancer.

  3. 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.

  4. Characterization of alpha 1-adrenoceptor subtypes in tension response of human prostate to electrical field stimulation.

    PubMed Central

    Guh, J. H.; Chueh, S. C.; Ko, F. N.; Teng, C. M.

    1995-01-01

    1. The effects of various alpha 1-adrenoceptor antagonists and nifedipine on tension responses of human prostate to electrical field stimulation were evaluated in this study. 2. Prazosin (3 x 10(-10) to 10(-8) M) and 5-methyl-urapidil (10(-9) to 3 x 10(-8) M) blocked concentration-dependently the tension responses to electrical field stimulation and completely abolished them in the maximal concentrations (10(-8) M and 3 x 10(-8) M, respectively); in contrast, chloroethylclonidine (CEC), in the maximal concentration of 100 microM, blocked these effects by only 50%. 3. The contractile responses of rat vas deferens and spleen to exogenously-applied alpha 1-adrenoceptor agonists were competitively inhibited by prazosin and 5-methyl-urapidil; in addition, the pA2 values were calculated and the relative potencies with reference to prazosin were obtained. The relative potency of 5-methyl-urapidil in human prostate (0.105) was close to that in rat vas deferens (0.257), which contains primarily putative alpha 1A-adrenoceptors. However, it was much more than that in rat spleen (0.011), which contains primarily putative alpha 1B-adrenoceptors. 4. Nifedipine (10(-8) to 10(-6) M) inhibited concentration-dependently the contractile responses to electrical field stimulation in human prostate; in addition, the inhibition percentages were similar to those to exogenously-applied noradrenaline in rat vas deferens. In contrast, CEC (10 microM), which almost flattened the concentration-response curve of the rat spleen to phenylephrine, only partially inhibited (by 33.1%) the nerve-mediated contraction of human prostate. 5. The involvement of prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of human prostate was also examined.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7647968

  5. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

    PubMed Central

    2012-01-01

    Background Obesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer. Methods Supernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured. Results We show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration. Conclusions Our

  6. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer.

    PubMed

    Malik, Shazli N; Brattain, Michael; Ghosh, Paramita M; Troyer, Dean A; Prihoda, Thomas; Bedolla, Roble; Kreisberg, Jeffrey I

    2002-04-01

    Whereas the early stage of prostate cancer is marked by excessive proliferation, in advanced stages of the disease, a decreased apoptotic death rate (increased cell survival) also contributes to net tumor growth. Altered regulation of the mitogen-activated protein kinase (MAPK)-regulated cell proliferation and Akt-regulated cell survival pathways are suspected causes. In this study, we wanted to determine: (a) whether the degree of Akt activation can be assessed by immunohistochemical staining of paraffin- embedded human prostate cancer biopsies with an antibody to phospho-Akt (Ser473); and (b) whether phospho-MAPK/Erk1/2 and phospho-Akt expression are altered in prostate cancer. To examine the activation status of MAPK/Erk1/2 and Akt, archival paraffin-embedded sections from 74 cases of resected prostate cancer were immunostained with antibodies to phospho-MAPK/Erk1/2 (Thr202/ Tyr204) and phospho-Akt (Ser473). The staining intensity for phospho-Akt was significantly greater in Gleason grades 8-10 (92% of such cases staining strongly) compared with prostatic intraepithelial neoplasia and all other grades of prostate cancer (only 10% of these cases staining strongly; P < or = 0.001). The staining intensity for phospho-MAPK/Erk, on the other hand, was significantly greater for normal, hyperplastic, and prostatic intraepithelial neoplasia lesions but declined with disease progression, reaching its lowest level of expression in high Gleason grades 8-10 (P < 0.0001). The activation state of the cell survival protein Akt can be analyzed in human prostate cancer by immunohistochemical staining of paraffin-embedded tissue with a phospho-specific Akt (Ser473) antibody. Advanced disease is accompanied by activation of Akt and inactivation of Erk.

  7. Human coxsackie adenovirus receptor (CAR) expression in transgenic mouse prostate tumors enhances adenoviral delivery of genes.

    PubMed

    Bao, Yunhua; Peng, Weidan; Verbitsky, Amy; Chen, Jiping; Wu, Lily; Rauen, Katherine A; Sawicki, Janet A

    2005-09-01

    Transgenic mice that recapitulate the progression of human diseases are potentially useful models for testing the effectiveness of new therapeutic strategies. Their use in pre-clinical testing of adenovirally-delivered gene therapies, however, is limited because of restricted cell surface expression of Coxsackie adenovirus receptor (CAR) in mice. To develop a more suitable transgenic mouse model for testing adenoviral-based gene therapies for prostate cancer, we generated prostate specific antigen/human CAR (PSA/hCAR) transgenic mice in which a chimeric enhancer/promoter sequence of the human PSA gene drives expression of a functional hCAR coding sequence. Expression of an adenovirally-delivered luciferase reporter gene in prostate tumor cells in bigenic mice (PSA/hCAR + TRAMP) was enhanced compared to the level in tumor cells lacking the PSA/hCAR transgene. Breeding PSA/hCAR mice to existing transgenic mouse models for prostate cancer (e.g., TRAMP) results in improved mouse models for testing adenovirally-delivered therapeutic genes. Copyright 2005 Wiley-Liss, Inc.

  8. ChromSorter PC: A database of chromosomal regions associated with human prostate cancer

    PubMed Central

    Etim, Ann; Zhou, Guohui; Wen, Xinyu; Liu, Hang; Ruotti, Victor; Twigger, Simon; Jin, Weihong; Matysiak, Brian; Mathis, Jedidiah; Tonellato, Peter J; Datta, Milton W

    2004-01-01

    Background Our increasing use of genetic and genomic strategies to understand human prostate cancer means that we need access to simplified and integrated information present in the associated biomedical literature. In particular, microarray gene expression studies and associated genetic mapping studies in prostate cancer would benefit from a generalized understanding of the prior work associated with this disease. This would allow us to focus subsequent laboratory studies to genomic regions already related to prostate cancer by other scientific methods. We have developed a database of prostate cancer related chromosomal information from the existing biomedical literature. The input material was based on a broad literature search with subsequent hand annotation of information relevant to prostate cancer. Description The database was then analyzed for identifiable trends in the whole scale literature. We have used this database, named ChromSorter PC, to present graphical summaries of chromosomal regions associated with prostate cancer broken down by age, ethnicity and experimental method. In addition we have placed the database information on the human genome using the Generic Genome Browser tool that allows the visualization of the data with respect to user generated datasets. Conclusions We have used this database as an additional dataset for the filtering of genes identified through genetics and genomics studies as warranting follow-up validation studies. We would like to make this dataset publicly available for use by other groups. Using the Genome Browser allows for the graphical analysis of the associated data . Additional material from the database can be obtained by contacting the authors (mdatta@mcw.edu). PMID:15113398

  9. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells

    PubMed Central

    Chen, Congcong; Dienhart, Jason A.; Bolton, Eric C.

    2016-01-01

    Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that

  10. Frequency analysis of multispectral photoacoustic images for differentiating malignant region from normal region in excised human prostate

    NASA Astrophysics Data System (ADS)

    Sinha, Saugata; Rao, Navalgund A.; Valluru, Keerthi S.; Chinni, Bhargava K.; Dogra, Vikram S.; Helguera, Maria

    2014-03-01

    Frequency domain analysis of the photoacoustic (PA) radio frequency signals can potentially be used as a tool for characterizing microstructure of absorbers in tissue. This study investigates the feasibility of analyzing the spectrum of multiwavelength PA signals generated by excised human prostate tissue samples to differentiate between malignant and normal prostate regions. Photoacoustic imaging at five different wavelengths, corresponding to peak absorption coefficients of deoxyhemoglobin, whole blood, oxyhemoglobin, water and lipid in the near infrared (NIR) (700 nm - 1000 nm) region, was performed on freshly excised prostate specimens taken from patients undergoing prostatectomy for biopsy confirmed prostate cancer. The PA images were co-registered with the histopathology images of the prostate specimens to determine the region of interest (ROI) corresponding to malignant and normal tissue. The calibrated power spectrum of each PA signal from a selected ROI was fit to a linear model to extract the corresponding slope, midband fit and intercept parameters. The mean value of each parameter corresponding to malignant and adjacent normal prostate ROI was calculated for each of the five wavelengths. The results obtained for 9 different human prostate specimens, show that the mean values of midband fit and intercept are significantly different between malignant and normal regions. In addition, the average midband fit and intercept values show a decreasing trend with increasing wavelength. These preliminary results suggest that frequency analysis of multispectral PA signals can be used to differentiate malignant region from the adjacent normal region in human prostate tissue.

  11. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    SciTech Connect

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S. . E-mail: jrhim@cpdr.org

    2006-04-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

  12. Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer.

    PubMed

    Stewart, Paul A; Khamis, Zahraa I; Zhau, Haiyen E; Duan, Peng; Li, Quanlin; Chung, Leland W K; Sang, Qing-Xiang Amy

    2017-06-13

    Metastasis is often associated with epithelial-to-mesenchymal transition (EMT). To understand the molecular mechanisms of this process, we conducted proteomic analysis of androgen-repressed cancer of the prostate (ARCaP), an experimental model of metastatic human prostate cancer. The protein signatures of epithelial (ARCaPE) and mesenchymal (ARCaPM) cells were consistent with their phenotypes. Importantly, the expression of mini-chromosome maintenance 3 (MCM3) protein, a crucial subunit of DNA helicase, was significantly higher in ARCaPM cells than that of ARCaPE cells. This increased MCM3 protein expression level was verified using Western blot analysis of the ARCaP cell lineages. Furthermore, immunohistochemical analysis of MCM3 protein levels in human prostate tissue specimens showed elevated expression in bone metastasis and advanced human prostate cancer tissue samples. Subcutaneous injection experiments using ARCaPE and ARCaPM cells in a mouse model also revealed increased MCM3 protein levels in mesenchymal-derived tumors. This study identifies MCM3 as an upregulated molecule in mesenchymal phenotype of human prostate cancer cells and advanced human prostate cancer specimens, suggesting MCM3 may be a new potential drug target for prostate cancer treatment.

  13. Selenomethionine Induced Transcriptional Programs in Human Prostate Cancer Cells

    PubMed Central

    Zhao, Hongjuan; Brooks, James D.

    2009-01-01

    Purpose We determined the effects of selenomethionine, the major organic selenium containing compound found in the diet and the form of selenium being used in the Selenium and Vitamin E Cancer Prevention Trial, on prostate cancer cells. Materials and Methods We assessed global transcript profiles of selenomethionine treated LNCaP using cDNA microarrays and compared them to those of cells treated with methylselenic acid, a direct precursor of methylselenol, which is the active form of selenium in vivo. Results After treatment with selenomethionine 2,336 unique genes showed expression changes of at least 1.5-fold in at least 3 time points during 48 hours and 366 unique transcripts differed significantly between selenomethionine and methylselenic acid treated LNCaP. Approximately half of the 76 cell cycle regulated genes affected by selenomethionine were down-regulated and enriched for genes associated with the G2/M phase. Flow cytometry analysis showed that selenomethionine induced G2/M arrest in LNCaP at low concentrations. Selenomethionine also affected expression levels of 35 known androgen responsive genes and 18 of these transcripts showed changes that were the inverse of those seen after androgen stimulation. At high concentrations selenomethionine decreased prostate specific antigen promoter driven luciferase expression. Conclusions Selenomethionine modulates transcript levels of genes involved in a number of biological processes, including cell cycle/apoptosis androgen signaling, signal transduction and transcriptional regulation. Although the pathways affected paralleled in many ways those that are modulated by methylselenic acid, distinct differences in transcript patterns and effects on cell cycle regulation suggest that different selenium compounds could exert unique effects in prostate cells. PMID:17222674

  14. Selenomethionine induced transcriptional programs in human prostate cancer cells.

    PubMed

    Zhao, Hongjuan; Brooks, James D

    2007-02-01

    We determined the effects of selenomethionine, the major organic selenium containing compound found in the diet and the form of selenium being used in the Selenium and Vitamin E Cancer Prevention Trial, on prostate cancer cells. We assessed global transcript profiles of selenomethionine treated LNCaP using cDNA microarrays and compared them to those of cells treated with methylselenic acid, a direct precursor of methylselenol, which is the active form of selenium in vivo. After treatment with selenomethionine 2,336 unique genes showed expression changes of at least 1.5-fold in at least 3 time points during 48 hours and 366 unique transcripts differed significantly between selenomethionine and methylselenic acid treated LNCaP. Approximately half of the 76 cell cycle regulated genes affected by selenomethionine were down-regulated and enriched for genes associated with the G2/M phase. Flow cytometry analysis showed that selenomethionine induced G2/M arrest in LNCaP at low concentrations. Selenomethionine also affected expression levels of 35 known androgen responsive genes and 18 of these transcripts showed changes that were the inverse of those seen after androgen stimulation. At high concentrations selenomethionine decreased prostate specific antigen promoter driven luciferase expression. Selenomethionine modulates transcript levels of genes involved in a number of biological processes, including cell cycle/apoptosis androgen signaling, signal transduction and transcriptional regulation. Although the pathways affected paralleled in many ways those that are modulated by methylselenic acid, distinct differences in transcript patterns and effects on cell cycle regulation suggest that different selenium compounds could exert unique effects in prostate cells.

  15. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee.

    PubMed

    Shappell, Scott B; Thomas, George V; Roberts, Richard L; Herbert, Ron; Ittmann, Michael M; Rubin, Mark A; Humphrey, Peter A; Sundberg, John P; Rozengurt, Nora; Barrios, Roberto; Ward, Jerrold M; Cardiff, Robert D

    2004-03-15

    The Pathological Classification of Prostate Lesions in Genetically Engineered Mice (GEM) is the result of a directive from the National Cancer Institute Mouse Models of Human Cancer Consortium Prostate Steering Committee to provide a hierarchical taxonomy of disorders of the mouse prostate to facilitate classification of existing and newly created mouse models and the translation to human prostate pathology. The proposed Bar Harbor Classification system is the culmination of three meetings and workshops attended by various members of the Prostate Pathology Committee of the Mouse Models of Human Cancer Consortium. A 2-day Pathology Workshop was held at The Jackson Laboratory in Bar Harbor, Maine, in October 2001, in which study sets of 93 slides from 22 GEM models were provided to individual panel members. The comparison of mouse and human prostate anatomy and disease demonstrates significant differences and considerable similarities that bear on the interpretation of the origin and natural history of their diseases. The recommended classification of mouse prostate pathology is hierarchical, and includes developmental, inflammatory, benign proliferative, and neoplastic disorders. Among the neoplastic disorders, preinvasive, microinvasive, and poorly differentiated neoplasms received the most attention. Specific criteria were recommended and will be discussed. Transitions between neoplastic states were of particular concern. Preinvasive neoplasias of the mouse prostate were recognized as focal, atypical, and progressive lesions. These lesions were designated as mouse prostatic intraepithelial neoplasia (mPIN). Some atypical lesions were identified in mouse models without evidence of progression to malignancy. The panel recommended that mPIN lesions not be given histological grades, but that mPIN be further classified as to the absence or presence of documented associated progression to invasive carcinoma. Criteria for recognizing microinvasion, for classification of

  16. Transgenic mouse with human mutant p53 expression in the prostate epithelium.

    PubMed

    Elgavish, Ada; Wood, Philip A; Pinkert, Carl A; Eltoum, Isam-Eldin; Cartee, Todd; Wilbanks, John; Mentor-Marcel, Roycelynn; Tian, Liqun; Scroggins, Samuel E

    2004-09-15

    Apoptosis is disrupted in prostate tumor cells, conferring a survival advantage. p53 is a nuclear protein believed to regulate cancer progression, in part by inducing apoptosis. To test this possibility in future studies, the objective of the present study was to generate a transgenic mouse model expressing mutant p53 in the prostate (PR). Transgene incorporation was tested using Southern analysis. Expression of mutant p53 protein was examined using immunofluorescence microscopy. Apoptosis in the PR was evaluated using the Tunnel method. A construct, consisting of the rat probasin promoter and a mutant human p53 fragment, was prepared and used to generate transgenic mice. rPB-mutant p53 transgene incorporation, as well as nuclear accumulation of mutant human p53 protein, was demonstrated. Prostatic intraepithelial neoplasia (PIN) III and IV were found in PR of 52-week old transgenic mice, whereas no pathological changes were found in the other organs examined. PR ability to undergo apoptosis following castration was reduced in rPB-mutant p53 mice as compared to non transgenic littermates. Transgenic rPB-mutant p53 mice accumulate mutant p53 protein in PR, resulting in neoplastic lesions and reduced apoptotic potential in the PR. Breeding rPB-mutant p53 mice with mice expressing an oncogene in their PR will be useful in examining interactions of multiple genes that result in progression of slow growing prostate tumors expressing oncogenes alone to metastatic cancer. Copyright 2004 Wiley-Liss, Inc.

  17. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome.

    PubMed

    Silverman, Robert H; Nguyen, Carvell; Weight, Christopher J; Klein, Eric A

    2010-07-01

    Xenotropic murine leukemia virus-related virus (XMRV) is an authentic, newly recognized human retrovirus first identified in prostate cancer tissues from men with a deficiency in the innate immunity gene RNASEL. At present, studies have detected XMRV at widely different rates in prostate cancer cases (0-27%) and in patients with chronic fatigue syndrome (CFS; 0-67%). Indirect or direct modes of carcinogenesis by XMRV have been suggested depending on whether the virus was found in stroma or malignant epithelium. Viral replication in the prostate might be affected by androgens, which stimulate XMRV through a transcriptional enhancer site in viral DNA. By contrast, host restriction factors, such as APOBEC3 and tetherin, inhibit virus replication. Immune dysfunction mediated by XMRV has been suggested as a possible factor in CFS. Recent studies show that some existing antiretroviral drugs suppress XMRV infections and diagnostic assays are under development. Although other retroviruses of the same genus as XMRV (gammaretroviruses) cause cancer and neurological disease in animals, whether XMRV is a cause of either prostate cancer or CFS remains unknown. Emerging science surrounding XMRV is contributing to our knowledge of retroviral infections while focusing intense interest on two major human diseases.

  18. Complex formation between human prostate-specific antigen and protease inhibitors in mouse plasma.

    PubMed

    Hekim, Can; Riipi, Tero; Zhu, Lei; Laakkonen, Pirjo; Stenman, Ulf-Håkan; Koistinen, Hannu

    2010-04-01

    When secreted from the prostate, most of prostate-specific antigen (PSA) is free and enzymatically active. Upon reaching circulation, active PSA is inactivated by complex formation with protease inhibitors. To justify the use of mouse models for evaluation of the function of PSA and for studies on therapeutic modalities based on modulation of PSA activity, it is important to know whether PSA complexation is similar in mouse and man. To characterize the circulating forms of PSA in mouse, we used subcutaneous LNCaP and 22RV1 human prostate cancer cell xenograft tumor models. We also added PSA directly to mouse serum. Free and total PSA were measured by immunoassay, and PSA complexes were extracted by immunopurification followed by SDS-PAGE, in-gel trypsin digestion and identification of signature peptides by mass spectrometry. In mice bearing xenograft tumors, 68% of the immunoreactive PSA occurred in complex, and when added to mouse serum, over 70% of PSA forms complexes that comprises alpha(2)-macroglobulin and members of the alpha(1)-antitrypsin (AAT) family. In mouse plasma, PSA forms complexes similar to those in man, but the major immunoreactive complex contains AAT rather than alpha(1)-antichymotrypsin, which is the main complex forming serpin in man. The complex formation of PSA produced by xenograft tumor models in mice is similar to that of human prostate tumors with respect to the complexation of PSA. (c) 2009 Wiley-Liss, Inc.

  19. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells.

    PubMed

    Nam, Sangkil; Kim, Donghwa; Cheng, Jin Q; Zhang, Shumin; Lee, Ji-Hyun; Buettner, Ralf; Mirosevich, Janni; Lee, Francis Y; Jove, Richard

    2005-10-15

    Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl-dependent chronic myeloid leukemia xenografts in nude mice. Dasatinib also has been shown to have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which dasatinib acts on epithelial tumor cells remains unknown. In this study, we show that dasatinib blocks the kinase activities of the SFKs, Lyn, and Src, in human prostate cancer cells at low nanomolar concentrations. Moreover, focal adhesion kinase and Crk-associated substrate (p130(CAS)) signaling downstream of SFKs are also inhibited at similar concentrations of dasatinib. Consistent with inhibition of these signaling pathways, dasatinib suppresses cell adhesion, migration, and invasion of prostate cancer cells at low nanomolar concentrations. Therefore, dasatinib has potential as a therapeutic agent for metastatic prostate cancers harboring activated SFK and focal adhesion kinase signaling.

  20. FGFR1-WNT-TGF-β signaling in prostate cancer mouse models recapitulates human reactive stroma

    PubMed Central

    Carstens, Julienne L.; Shahi, Payam; Van Tsang, Susan; Smith, Billie; Creighton, Chad J.; Zhang, Yiqun; Seamans, Amber; Seethammagari, Mamatha; Vedula, Indira; Levitt, Jonathan M.; Ittmann, Michael M.; Rowley, David R.; Spencer, David M.

    2014-01-01

    The reactive stroma surrounding tumor lesions performs critical roles ranging from supporting tumor cell proliferation to inducing tumorigenesis and metastasis. Therefore, it is critical to understand the cellular components and signaling control mechanisms that underlay the etiology of reactive stroma. Previous studies have individually implicated fibroblast growth factor receptor 1 (FGFR1) and canonical WNT/β-catenin signaling in prostate cancer progression and the initiation and maintenance of a reactive stroma; however, both pathways are frequently found co-activated in cancer tissue. Using autochthonous transgenic mouse models for inducible FGFR1 (JOCK1) and prostate-specific and ubiquitously expressed inducible β-catenin (Pro-Cat and Ubi-Cat, respectively) and bigenic crosses between these lines (Pro-Cat × JOCK1 and Ubi-Cat × JOCK1), we describe WNT-induced synergistic acceleration of FGFR1-driven adenocarcinoma, associated with a pronounced fibroblastic reactive stroma activation surrounding prostatic intraepithelial neoplasia (mPIN) lesions found both in situ and reconstitution assays. Both mouse and human reactive stroma exhibited increased transforming growth factor-beta (TGF-β) signaling adjacent to pathologic lesions likely contributing to invasion. Furthermore, elevated stromal TGF-β signaling was associated with higher Gleason scores in archived human biopsies, mirroring murine patterns. Our findings establish the importance of the FGFR1-WNT-TGF-β signaling axes as driving forces behind reactive stroma in aggressive prostate adenocarcinomas, deepening their relevance as therapeutic targets. PMID:24305876

  1. A structural model for the prostate disease marker, human prostate-specific antigen.

    PubMed Central

    Villoutreix, B. O.; Getzoff, E. D.; Griffin, J. H.

    1994-01-01

    Prostate-specific antigen (PSA) provides an excellent serum marker for prostate cancer, the most frequent form of cancer in American males. PSA is a 237-residue protease based on sequence homology to kallikrein-like enzymes. To predict the 3-dimensional structure of PSA, homology modeling studies were performed based on sequence and structural alignments with tonin, pancreatic kallikrein, chymotrypsin, and trypsin. The structurally conserved regions of the 4 reference X-ray proteins provided the core structure of PSA, whereas the loop structures were modeled on the loops of tonin and kallikrein. The unique "kallikrein loop" insert, between Ser 95b and Pro 95k of kallikrein, was constructed using molecular mechanics, dynamics, and electrostatics calculations. In the resulting PSA structure, the catalytic triad, involving residues His 57, Asp 102, and Ser 195, and hydrophobic and electrostatic interactions typical of serine proteases were extremely well conserved. Similarly, the 5-disulfide bonds of kallikrein were also conserved in PSA. These results, together with the fact that no major steric clashes arose during the modeling process, provide strong evidence for the validity of the PSA model. Calculation of the electrostatic potential contours of kallikrein and PSA was carried out using the finite difference Poisson-Boltzmann method. The calculations revealed matching areas of negative potential near the catalytic triad, but differences in the positive potential surrounding the active site. The PSA glycosylation site, Asn 61, is fully accessible to the solvent and is enclosed in a positive region of the isopotential map. The bottom of the substrate specificity pocket, residue S1, is a serine (Ser 189) as in chymotrypsin, rather than aspartate (Asp 189) as in tonin, kallikrein, and trypsin. This fact, plus other features of the S1 binding-pocket region, suggest that PSA would prefer substrates with hydrophobic residues at the P1 position. The location of a

  2. Finasteride Inhibits Human Prostate Cancer Cell Invasion through MMP2 and MMP9 Downregulation

    PubMed Central

    Moroz, Andrei; Delella, Flávia K.; Almeida, Rodrigo; Lacorte, Lívia Maria; Fávaro, Wágner José; Deffune, Elenice; Felisbino, Sérgio L.

    2013-01-01

    Introduction The use of the 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride for prostate cancer prevention is still under debate. The FDA recently concluded that the increased prevalence of high-grade tumors among 5-ARI-treated patients must not be neglected, and they decided to disallow the use of 5-ARIs for prostate cancer prevention. This study was conducted to verify the effects of finasteride on prostate cell migration and invasion and the related enzymes/proteins in normal human and tumoral prostatic cell lines. Materials and Methods RWPE-1, LNCaP, PC3 and DU145 cells were cultivated to 60% confluence and exposed for different periods to either 10 µM or 50 µM finasteride that was diluted in culture medium. The conditioned media were collected and concentrated, and MMP2 and MMP9 activities and TIMP-1 and TIMP-2 protein expression were determined. Cell viability, migration and invasion were analyzed, and the remaining cell extracts were submitted to androgen receptor (AR) detection by western blotting techniques. Experiments were carried out in triplicate. Results Cell viability was not significantly affected by finasteride exposure. Finasteride significantly downregulated MMP2 and MMP9 activities in RWPE-1 and PC3 cells and MMP2 in DU145 cells. TIMP-2 expression in RWPE-1 cells was upregulated after exposure. The cell invasion of all four tested cell lines was inhibited by exposure to 50 µM of finasteride, and migration inhibition only occurred for RWPE-1 and LNCaP cells. AR was expressed by LNCaP, RWPE-1 and PC3 cells. Conclusions Although the debate on the higher incidence of high-grade prostate cancer among 5-ARI-treated patients remains, our findings indicate that finasteride may attenuate tumor aggressiveness and invasion, which could vary depending on the androgen responsiveness of a patient’s prostate cells. PMID:24386413

  3. Finasteride inhibits human prostate cancer cell invasion through MMP2 and MMP9 downregulation.

    PubMed

    Moroz, Andrei; Delella, Flávia K; Almeida, Rodrigo; Lacorte, Lívia Maria; Fávaro, Wágner José; Deffune, Elenice; Felisbino, Sérgio L

    2013-01-01

    The use of the 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride for prostate cancer prevention is still under debate. The FDA recently concluded that the increased prevalence of high-grade tumors among 5-ARI-treated patients must not be neglected, and they decided to disallow the use of 5-ARIs for prostate cancer prevention. This study was conducted to verify the effects of finasteride on prostate cell migration and invasion and the related enzymes/proteins in normal human and tumoral prostatic cell lines. RWPE-1, LNCaP, PC3 and DU145 cells were cultivated to 60% confluence and exposed for different periods to either 10 µM or 50 µM finasteride that was diluted in culture medium. The conditioned media were collected and concentrated, and MMP2 and MMP9 activities and TIMP-1 and TIMP-2 protein expression were determined. Cell viability, migration and invasion were analyzed, and the remaining cell extracts were submitted to androgen receptor (AR) detection by western blotting techniques. Experiments were carried out in triplicate. Cell viability was not significantly affected by finasteride exposure. Finasteride significantly downregulated MMP2 and MMP9 activities in RWPE-1 and PC3 cells and MMP2 in DU145 cells. TIMP-2 expression in RWPE-1 cells was upregulated after exposure. The cell invasion of all four tested cell lines was inhibited by exposure to 50 µM of finasteride, and migration inhibition only occurred for RWPE-1 and LNCaP cells. AR was expressed by LNCaP, RWPE-1 and PC3 cells. Although the debate on the higher incidence of high-grade prostate cancer among 5-ARI-treated patients remains, our findings indicate that finasteride may attenuate tumor aggressiveness and invasion, which could vary depending on the androgen responsiveness of a patient's prostate cells.

  4. Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation

    PubMed Central

    Gao, Xian-Shu; Li, Yi; Yu, Hongliang; Xiong, Wei; Yu, Hao; Wang, Wen; Li, Yingbo; Teng, Yingqi; Zhou, Demin

    2016-01-01

    Aldo-keto reductase 1C3(AKR1C3) is an enzyme involved in prostaglandins metabolism. Studies suggest that AKR1C3 has a pivotal role in the radioresistance of esophageal cancer and non-small-cell lung cancer, yet the role of AKR1C3 in prostate cancer cells radiation resistance has not yet been clarified. In our study, we established a stable overexpressing AKR1C3 cell line (AKR1C3-over) derived from the prostate cell line DU145 and its control cell line (Control). We conducted colony formation assay to determine the role of AKR1C3 in radioresistance and we used its chemical inhibitor to detect whether it can restored the sensitivity of the acquired tumor cells. Flow cytometry assay was carried out to detect IR-induced ROS accumulation. Elisa was adopted to dedect the concentration of PGF2α in the suspension of the cells after 6GY radiation. Western blotting was used to dedect the MAPK and PPAR γ. The results demonstrated that overexpression of AKR1C3 in prostate cancer can result in radioresistance and suppression of AKR1C3 via its chemical inhibitor indocin restored the sensitivity of the acquired tumor cells. According to the flow cytometry assay, ROS was decreased by 80% in DU145-over cells. Also overexpression of AKR1C3 could result in the accumulation of prostaglandin F2α (PGF2α), which can not only promote prostate cancer cell 's proliferation but also could enhance prostate cancer cells resistance to radiation and activated the MAPK pathway and inhibited the expression of PPARγ. In conclusion, we found that overexpression of AKR1C3 significantly enhanced human prostate cancer cells resistance to radiation through activation of MAPK pathway. PMID:27385003

  5. Combined effects of atorvastatin and aspirin on growth and apoptosis in human prostate cancer cells.

    PubMed

    He, Yan; Huang, Huarong; Farischon, Chelsea; Li, Dongli; Du, Zhiyun; Zhang, Kun; Zheng, Xi; Goodin, Susan

    2017-02-01

    Epidemiologic studies indicate the use of either statins or aspirin have beneficial effects in prostate cancer patients. The present study was undertaken to evaluate the effects and mechanisms of atorvastatin and aspirin alone or in combination in human prostate cancer cells cultured in vitro and grown as xenograft tumors in severe combined immune-deficient (SCID) mice. The growth and apoptosis in prostate cancer cells were determined by the trypan blue exclusion and propidium iodide staining assays. Activation of the nuclear factor κB (NF-κB) was measured by luciferase reporter assay, and the levels of phospho-signal transducer and activator of transcription (Stat)3 and phospho-extracellular signal-regulated kinase (Erk)1/2 were determined by western blot analysis. Mice were injected subcutaneously with PC-3 cells in Matrigel. After 4-6 weeks, mice with PC-3 tumors received i.p. injections of vehicle, atorvastatin (5 mg/kg), aspirin (80 mg/kg), or atorvastatin (5 mg/kg) + aspirin (80 mg/kg) three times a week for 30 days. Our results demonstrated the combination of atorvastatin and aspirin had more potent effects on growth inhibition and apoptosis stimulation in prostate cancer cells than either drug alone. Mechanistic studies indicated the induction of apoptosis in PC-3 cells was associated with strong inhibition of NF-κB and decreases in the levels of phospho-Stat3 and phospho-Erk1/2. Results of the present study demonstrated a strong combined effect of atorvastatin and aspirin on inhibiting the growth of prostate cancer cells in vitro and in vivo. The findings provide a strong rationale for clinical evaluation of the combination of atorvastatin and aspirin in patients with prostate cancer.

  6. Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors.

    PubMed

    Lai, Ching-Shu; Li, Shiming; Miyauchi, Yutaka; Suzawa, Michiko; Ho, Chi-Tang; Pan, Min-Hsiung

    2013-06-01

    Prostate cancer is one of the most prevalent malignancies and is the second leading cause of cancer-related deaths in men. Fruit and vegetable consumption is a novel, non-toxic therapeutic approach that can be used to prevent and treat prostate cancer. Citrus peels and their extracts have been reported to have potent pharmacological activities and health benefits due to the abundance of flavonoids in citrus fruits, particularly in the peels. Our previous studies demonstrated that oral administration of Gold Lotion (GL), an extract of multiple varieties of citrus peels containing abundant flavonoids, including a large percentage of polymethoxyflavones (PMFs), effectively suppressed azoxymethane (AOM)-induced colonic tumorigenesis. However, the efficacy of GL against prostate cancer has not yet been investigated. Here, we explored the anti-tumor effects of GL using a human prostate tumor xenograft mouse model. Our data demonstrated that treatment with GL by both intraperitoneal (i.p.) injection and oral administration dramatically reduced both the weights (57%-100% inhibition) and volumes (78%-94% inhibition) of the tumors without any observed toxicity. These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), metastasis (matrix metallopeptidase-2, MMP-2 and MMP-9), angiogenesis (vascular endothelial growth factor, VEGF), and proliferative molecules, as well as by the induction of apoptosis in prostate tumors. Our findings suggest that GL is an effective anti-cancer agent that may potentially serve as a novel therapeutic option for prostate cancer treatment.

  7. Quantification of Mesenchymal Stem Cells (MSCs) at sites of human prostate cancer.

    PubMed

    Brennen, W Nathaniel; Chen, Shuangling; Denmeade, Samuel R; Isaacs, John T

    2013-01-01

    Circulating bone marrow-derived Mesenchymal Stem Cells (BM-MSCs) have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. The prostate is bombarded by numerous infectious and inflammatory insults over a lifetime. Chronic inflammation is associated with CXCL12, CCL5, and CCL2, which are highly overexpressed in prostate cancer. Among other cell types, these chemoattractant stimuli recruit BM-MSCs to the tumor. MSCs are minimally defined as plastic-adhering cells characterized by the expression of CD90, CD73, and CD105 in the absence of hematopoietic markers, which can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs are immunoprivileged and have been implicated in tumorigenesis through multiple mechanisms, including promoting proliferation, angiogenesis, and metastasis, in addition to the generation of an immunosuppressive microenvironment. We have demonstrated that MSCs represent 0.01-1.1% of the total cells present in core biopsies from primary human prostatectomies. Importantly, these analyses were performed on samples prior to expansion in tissue culture. MSCs in these prostatectomy samples are FAP-, CD90-, CD73-, and CD105-positive, and CD14-, CD20-, CD34-, CD45-, and HLA-DR-negative. Additionally, like BM-MSCs, these prostate cancer-derived stromal cells (PrCSCs) were shown to differentiate into osteoblasts, adipocytes and chondrocytes. In contrast to primary prostate cancer-derived epithelial cells, fluorescently-labeled PrCSCs and BM-MSCs were both shown to home to CWR22RH prostate cancer xenografts following IV injection. These studies demonstrate that not only are MSCs present in sites of prostate cancer where they may contribute to carcinogenesis, but these cells may also potentially be used to deliver cytotoxic or imaging agents for therapeutic and/or diagnostic purposes.

  8. Cellular distribution of Glut-1 and Glut-5 in benign and malignant human prostate tissue.

    PubMed

    Reinicke, Karin; Sotomayor, Paula; Cisterna, Pedro; Delgado, Carolina; Nualart, Francisco; Godoy, Alejandro

    2012-02-01

    Over-expression of hexose transporters (Gluts), specifically Glut-1, is a common event in human malignancies. In prostate cancer (CaP), however, expression of Gluts has been characterized poorly. In this study, expression and distribution of Glut-1 and Glut-5 proteins were characterized using immunohistochemistry in 76 specimens of benign prostate, 10 specimens of high-grade intraepithelial neoplasia (HGPIN), and 28 specimens of CaP. In addition, mRNA expression of Glut-2, Glut-7, Glut-9, and Glut-11 was analyzed in a set of five specimens of benign prostate and CaP. In benign prostate, Glut-1 localized to the basal cells and to the basolateral membrane of secretory/luminal epithelial cells. Glut-5, however, localized to the apical membrane of secretory/luminal epithelial cells. In HGPIN, Glut-1 was immunohistochemically undetectable. Glut-5, however, localized to the apical membrane of the neoplastic epithelial cells. In CaP, Glut-1 and Glut-5, were immunohistochemically undetectable. However, over-expression of GLUT1 was observed in some specimens of highly proliferative intraductal CaP. Glut-7, Glut-9, and Glut-11 mRNAs were detected in benign prostate and CaP, however, only Glut-11 mRNA was consistently up-regulated in CaP compared to benign prostate. Low levels of expression of Glut-1 protein in the majority of CaP could explain, at least in part, the limited clinical applicability of positron emission tomography using 2-[18F]-fluoro-2-deoxy-D-glucose for imaging CaP. Moreover, expression of Glut-5 in HGPIN suggested that fructose could be utilized as potential metabolic substrate in HGPIN. Understanding the molecular mechanisms involved in regulation/dysregulation of Gluts in CaP could provide insight in the understanding of hexose metabolism in CaP.

  9. Thymidine phosphorylase expression in normal and hyperplastic endometrium

    PubMed Central

    Sivridis, E.; Giatromanolaki, A.; Koukourakis, M.; Bicknell, R.; Harris, A.; Gatter, K.

    2000-01-01

    Aims—To investigate the expression of thymidine phosphorylase (TP), a known angiogenic factor for endothelial cells, in normally cycling endometrium and various forms of endometrial hyperplasia. Methods—TP expression was assessed with the P-GF.44C monoclonal antibody, using the alkaline phosphatase anti-alkaline phosphatase method. Ninety two normal and hyperplastic endometria were studied. Results—In normal proliferative endometrium, TP is found exclusively in the basal layer and the inner third of the functionalis; expression is cytoplasmic in glandular epithelium and nuclear in stromal cells. It is invariably patchy. This immunohistochemical picture remains almost unaltered during the early and mid secretory phase of the normal menstrual cycle but, most impressively, TP is expressed uniformly in the epithelium of all endometrial glands towards the end of the cycle. At this stage, expression is mixed nuclear/cytoplasmic and there is very little stromal nuclear staining. In simple endometrial hyperplasia, the staining pattern for TP is identical to normal proliferative endometrium, with a distribution that is usually limited to a few rather weakly proliferating glands and to the adjacent periglandular stroma of the deep endometrium. The distribution is more extensive in complex and atypical endometrial hyperplasias, where a mixed nuclear/cytoplasmic pattern usually prevails over the pure cytoplasmic reaction. Conclusions—TP is expressed consistently in normal and hyperplastic endometrium, suggesting a role in physiological and pathological angiogenesis. In normal endometrium, TP has a definite pattern of distribution, which is dependent on the phase of the menstrual cycle, whereas in all forms of endometrial hyperplasia the enzyme is randomly distributed and lacks an orderly pattern. Key Words: thymidine phosphorylase • normal endometrium • hyperplastic endometrium PMID:11041061

  10. Relationship between electrical admittivity and quantitative histopathology in human prostate

    NASA Astrophysics Data System (ADS)

    Halter, Ryan; Milone, Michael; Schned, Alan; Heaney, John

    2010-04-01

    Passive bioelectrical properties have been demonstrated to provide sufficient contrast for use in differentiating benign from malignant tissue in a number of different organs including breast, prostate, cervix, bladder, and skin. The underlying microscopic anatomy responsible for these measured differences has been primarily speculative in the past. In this study we recorded electrical conductivity and permittivity spectra (100 Hz - 100 kHz) from 464 three mm diameter circular prostate samples. Each of these tissue specimens were stained with hematoxylin and eosin, processed onto microscopy slides, and digitized using optical microscopy. We used digital imaging processing tools to extract quantitative morphological features including total number of glands, average and total glandular lumen size, shape characteristics of the luminal spaces, and average and total glandular perimeter lengths. Correlative analysis was performed to assess the relationships between the tissue architectural features and the precisely co-registered electrical properties. We report on the findings from this analysis. This statistical assessment aims to provide a valuable piece of new information to help formulate a better understanding of the precise influence morphological architecture has on the flow of current through tissue.

  11. Hypericum perforatum methanolic extract inhibits growth of human prostatic carcinoma cell line orthotopically implanted in nude mice.

    PubMed

    Martarelli, D; Martarelli, B; Pediconi, D; Nabissi, M I; Perfumi, M; Pompei, P

    2004-07-08

    The antiproliferative effect of serotonin-reuptake inhibitors (SSRI) and serotonin antagonists has been demonstrated in prostate tumors. Since Hypericum perforatum components act as serotonin-reuptake inhibitors and exert cytotoxic effects on several human cancer cell lines, in this work we analyzed the effect of a treatment with Hypericum perforatum extract (HPE) on the growth of human prostate cancer cells in vitro and in vivo. This study highlighted a significant reduction of tumor growth and number of metastasis suggesting that this natural compound may be useful in the treatment of prostate cancer. Copyright 2004 Elsevier Ireland Ltd.

  12. Isolated diffuse hyperplastic gastric polyposis presenting with severe anemia

    PubMed Central

    Jayawardena, Suriya; Anandacoomaraswamy, Dharshan; Burzyantseva, Olga; Abdullah, Muhammad

    2008-01-01

    Introduction Gastric polyps exist in a wide variety of types, most of which are small and often benign. Discovery of gastric polyps during Endoscopy necessitates biopsies. Case presentation We present a case report of an isolated diffuse hyperplastic gastric polyposis in a 26 years old Hispanic female when she was investigated for profound anemia. The Esophagogastroduodenoscopy revealed numerous gastric polyps filling the entire stomach. She was treated with near-total gastrectomy and her anemia resolved Conclusion Isolated diffuse hyperplasic gastric polyposis with normal gastrin level is a rare entity and can present with severe anemia. PMID:18755016

  13. An unusual expression of hyperplastic gastropathy (Menetrier type) in twins.

    PubMed

    Ibarrola, Carolina; Rodriguez-Pinilla, Maria; Valiño, Cristina; Gomez-Casado, Eduardo; Garcia de la Torre, Juan Pablo; Rodriguez-Cuellar, E; Abad, Alfredo; Colina, Francisco

    2003-04-01

    Menetrier's disease is an uncommon condition of unknown aetiology. We describe two cases of male identical twins with haematemesis aged 29 and 35 years that exhibited a similar and particular form of this hyperplastic gastropathy. Their stomachs showed confluent polypoid mucosal projections affecting mainly the gastric fundus and the antrum. To the best of our knowledge, only four previous cases have been reported in a familial setting, and this is the first documented example of an occurrence in twins. These two cases suggest the possibility of a genetic predisposition for this condition.

  14. Therapy of Prostate Cancer Using a Human Antibody Targeting the Type 1 Insulin-Like Growth Factor Receptor (IGF-IR)

    DTIC Science & Technology

    2009-09-01

    inhibit prostate cancer growth and metastasis . Further, in the Preliminary data presented in this study, we show that the IGF-IR remains as a viable...7 8 This study is to determine the role of genes co-stimulated by IGF-1 and the androgen receptor in prostate cancer metastasis Paul Lange, MD...Ozen M, Pathak S, Chung LW. 2000. LNCaP progression model of human prostate cancer: Androgen-indepen- dence and osseous metastasis . Prostate 44 (2):91

  15. Robust HPLC-MS/MS method for levofloxacin and ciprofloxacin determination in human prostate tissue.

    PubMed

    Szerkus, O; Jacyna, J; Gibas, A; Sieczkowski, M; Siluk, D; Matuszewski, M; Kaliszan, R; Markuszewski, M J

    2017-01-05

    Fluoroquinolones are the drugs of choice in the prevention of bacterial infections after transrectal ultrasound guided prostate biopsy. In order to improve assessment of antibacterial efficacy in the target tissue a simple, selective, rapid and robust HPLC-ESI-MS/MS method for the determination of levofloxacin and ciprofloxacin concentrations in human prostate bioptates was developed and validated. Preparation procedure for prostate samples (10mg) was carried out using homogenization and filtration steps. Analyses were performed within 3.5min using RP C18 column in the isocratic elution mode with mobile phase composed of a mixture of 0.1% formic acid aqueous solution and 0.1% formic acid methanol solution (v/v; 79:21). The method was linear between 0.3μg/g and 15μg/g for levofloxacin and ciprofloxacin with coefficient of correlation (r) ≥0.999. The limit of detection and the limit of quantification for levofloxacin were 0.06μg/g and 0.2μg/g and for ciprofloxacin were 0.04μg/g and 0.13μg/g, respectively. Average concentrations (±SD) of levofloxacin and ciprofloxacin obtained from patients tissue were 5.4±2.2μg/g and 3.9±1.5μg/g, respectively. Additionally, during validation procedure a novel, experimental design approach was applied for the robustness study. For evaluation of analytical method robustness, Plackett-Burman design was employed and for sample preparation method robustness Fractional Factorial design was used. The developed and validated method was successfully applied to examine prostate tissue samples obtained from patients enrolled into a clinical study. Up to now, there has been no other HPLC-ESI-MS/MS method reported for the simultaneous determination of levofloxacin and ciprofloxacin in human prostatic tissue. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Clinical and Experimental Progression of a New Model of Human Prostate Cancer and Therapeutic Approach

    PubMed Central

    de Pinieux, Gonzague; Legrier, Marie-Emmanuelle; Poirson-Bichat, Florence; Courty, Yves; Bras-Gonçalves, Rui; Dutrillaux, Anne-Marie; Némati, Fariba; Oudard, Stéphane; Lidereau, Rosette; Broqua, Pierre; Junien, Jean-Louis; Dutrillaux, Bernard; Poupon, Marie-France

    2001-01-01

    We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient’s tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp6-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp6-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism. PMID:11485933

  17. Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

    PubMed

    Kobayashi, Ikuo; Ikawa, Kazuro; Nakamura, Kogenta; Nishikawa, Genya; Kajikawa, Keishi; Yoshizawa, Takahiko; Watanabe, Masahito; Kato, Yoshiharu; Zennami, Kenji; Kanao, Kent; Tobiume, Motoi; Yamada, Yoshiaki; Mitsui, Kenji; Narushima, Masahiro; Morikawa, Norifumi; Sumitomo, Makoto

    2015-08-01

    This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective. Copyright © 2015. Published by Elsevier Ltd.

  18. Intestinal trefoil factor (TFF 3) and pS2 (TFF 1), but not spasmolytic polypeptide (TFF 2) mRNAs are co-expressed in normal, hyperplastic, and neoplastic human breast epithelium.

    PubMed

    Poulsom, R; Hanby, A M; Lalani, E N; Hauser, F; Hoffmann, W; Stamp, G W

    1997-09-01

    pS2-TFF 1 is expressed in breast cancers and has been investigated as a potential prognostic factor reflecting oestrogen dependence. The relationship to the expression of other trefoil peptides, human spasmolytic polypeptide (hSP-TFF 2) and intestinal trefoil factor (hITF/hPI.B-TFF 3) is documented here. Fifty-seven breast specimens were selected from surgical pathology archives and included five normal breasts (two lactating), seven benign proliferative lesions, 11 ductal carcinomas in situ (DCIS), three lobular carcinomas in situ (LCIS), 24 invasive ductal carcinomas (IDC), and seven invasive lobular carcinomas (ILC). The comparative distribution of trefoil mRNAs was assessed by in situ hybridization using 35S-labelled riboprobes and immunohistochemical staining for pS2-TFF 1 and hSP-TFF 2. pS2-TFF 1 and hITF/hPI.B-TFF 3 mRNA were focally present at low signal intensity in normal and benign breast. Both pS2-TFF 1 and hITF/hPI.B-TFF 3 were expressed in all DCIS, LCIS and ILC, and 21/24 IDC. Overall, expression patterns of pS2-TFF 1 and hITF/hPI.B-TFF 3 coincided, but hITF/hPI.B-TFF 3 mRNA was usually found in a greater proportion of cells. Expression of hSP-TFF 2 peptide or mRNA was not detected in any of these cases. MCF 7 breast carcinoma cells also expressed hITF/hPI.B-TFF 3 and pS2-TFF 1 mRNAs but not hSP-TFF 2. hITF/hPI.B-TFF 3 co-expression with pS2-TFF 1 may act as a prognostic factor, but also raises questions about the regulatory pathway for pS2-TFF 1 hITF/hPI.B-TFF 3. Trefoil factors have effects on cell motility and spreading in vitro, and co-expression of hITF/hPI.B-TFF 3 with pS2-TFF 1 could be functionally significant if they form a heterodimer or compete for receptor binding. Absence of hSP-TFF 2 expression may be of equal relevance to tumour cell biology.

  19. Allelic loss of chromosomes 16q and 10q in human prostate cancer

    SciTech Connect

    Carter, B.S.; Ewing, C.M.; Ward, W.S.; Treiger, B.F.; Isaacs, W.B.; Epstein, J.I. ); Aalders, T.W.; Schalken, J.A. )

    1990-11-01

    Recent advances in understanding the molecular genetics of common adult tumors have indicated that multiple genetic alterations including the activation of oncogenes and the inactivation of tumor suppressor genes are important in the pathogenesis of these tumors. Loss of heterozygosity is a hallmark of tumor suppressor gene inactivation and has been used to identify chromosomal regions that contain these genes. The authors have examines allelic loss in the most common tumor in men, prostate cancer. Twenty-eight prostate cancer specimens have been examined for loss of heterozygosity at 11 different chromosomal arms including 3p, 7q, 9q, 10p, 10q, 11p, 13q, 16p, 17p, and 18q. Fifty-four percent (13/24) of clinically localized tumors and 4 of 4 metastatic tumors showed loss of heterozygosity on at least one chromosome. Chromosomes 16q and 10q exhibited the highest frequency of loss of heterozygosity with 30% of tumors showing loss at these chromosomes. These data demonstrate that allelic loss is a common event in prostate cancer and suggest that chromosomes 16q and 10q may contain the sites of tumor suppressor genes important in the pathogenesis of human prostate cancer.

  20. Resveratrol and propolis as necrosis or apoptosis inducers in human prostate carcinoma cells.

    PubMed

    Scifo, Christian; Cardile, Venera; Russo, Alessandra; Consoli, Rosanna; Vancheri, Carlo; Capasso, Francesco; Vanella, Angelo; Renis, Marcella

    2004-01-01

    Vegetables and fruit help the prevention and the therapy of several kinds of cancer because they contain micronutrients, a class of substances that have been shown to exhibit chemopreventive and chemotherapeutic activities. In the present study the effects of resveratrol (100 and 200 microM), a phytoalexin found in grapes, and of the ethanolic extract of propolis (50 and 100 microg/ml), a natural honeybee hive product, were tested in androgen-resistant prostate cancer cells (DU145), a cell line resembling the last stage of prostate carcinoma. A comparison between the activity of these micronutrients and vinorelbine bitartrate (Navelbine), a semi-synthetic drug normally used in the therapy of prostate cancer, was conducted. Several biochemical parameters were tested, such as cell viability (MTT assay), cell membrane integrity (lactate dehydrogenase release), cell redox status (nitric oxide formation, reactive oxygen species production, reduced glutathione levels), genomic DNA fragmentation (COMET assay) with special attention on the presence of apoptotic DNA damage (TUNEL test), and possible mitochondrial transmembrane potential alteration (deltapsi). Our results point out the anticancer activity of resveratrol and propolis extract in human prostate cancer, exerting their cytotoxicity through two different types of cell death: necrosis and apoptosis, respectively. The data obtained suggest the possible use of these micronutrients both in alternative to classic chemotherapy, and in combination with very low dosage of vinorelbine (5 microM).

  1. Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer

    PubMed Central

    Provero, Paolo; Fusco, Carlo; Delorenzi, Mauro; Stehle, Jean-Christophe; Stamenkovic, Ivan

    2011-01-01

    Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value. PMID:21611158

  2. Fine structure and mineral components of primary calculi in some human prostates.

    PubMed

    Kodaka, Tetsuo; Hirayama, Akihiko; Sano, Tsuneyoshi; Debari, Kazuhiro; Mayahara, Mitsuori; Nakamura, Masanori

    2008-08-01

    The fine structure of prostatic calculi has not been elucidated yet, although the chemical components were reported in detail. We studied the primary or endogenous calculi removed from eight human prostates by secondary scanning electron microscopy, backscattered electron imaging, energy-dispersive X-ray microanalysis and X-ray diffraction. The primary calculi containing Mg, Zn and S, besides Ca and P were basically classified into four stone groups (I-IV) by fine structure and mineral components. Stone I had the core deposits of calcospherites showing concentric rings and the laminated deposits concentrically around the core. Their deposits were identified as apatite. Stone II was occupied with the calcospherite deposits of apatite although the stone growth showed a rough concentric formation. Stone III contained the core of calcospherites and concentric laminated structures, similar to a smaller type of group I, whereas the wider peripheral region was deposited with needle-like structures, identified as calcium oxalates. Stone IV had the core deposits containing small hexahedral structures, identified as whitlockite, which were surrounded with several incompletely concentric laminated bands of apatite. Whitlockite crystals were also found between the fused large calculi. The initial and formative calculi were basically observed as the deposition of mineralizing spherical structures suggesting variously sized corpora amylaceous bodies. Thus, the primary prostatic calculi of stones I-III will begin from the mineralization of amylaceous bodies as a core, while the organic substances, which form stone IV, might be derived from the simple precipitation of prostatic secretion.

  3. Inhibitors of Vacuolar ATPase Proton Pumps Inhibit Human Prostate Cancer Cell Invasion and Prostate-Specific Antigen Expression and Secretion

    PubMed Central

    Michel, Vera; Licon-Munoz, Yamhilette; Trujillo, Kristina; Bisoffi, Marco; Parra, Karlett J.

    2012-01-01

    Vacuolar ATPases (V-ATPases) comprise specialized and ubiquitously distributed pumps that acidify intracellular compartments and energize membranes. To gain new insights into the roles of V-ATPases in prostate cancer (PCa) we studied the effects of inhibiting V-ATPase pumps in androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells of a human PCa progression model. Treatment with nanomolar concentrations of the V-ATPase inhibitors bafilomycin A or concanamycin A reduced the in vitro invasion in both cell types by 80%, regardless that V-ATPase was prominent at the plasma membrane of C4-2B cells and only traces were detected in the low-metastatic LNCaP parental cells. In both cell types intracellular V-ATPase was excessive and co-localized with prostate-specific antigen (PSA) in the Golgi compartment. V-ATPase inhibitors reversibly excluded PSA from the Golgi and led to the accumulation of largely dispersed PSA-loaded vesicles of lysosomal composition. Inhibition of acridine orange staining and transferrin receptor recycling suggested defective endosomal and lysosomal acidification. The inhibitors, additionally, interfered with the AR-PSA axis under conditions that reduced invasion. Bafilomycin A significantly reduced steady-state and R1881-induced PSA mRNA expression and secretion in the LNCaP cells which are androgen-dependent, but not in the C4-2B cells which are androgen ablation-resistant. In the C4-2B cells, an increased susceptibility to V-ATPase inhibitors was detected after longer treatments, as proliferation was reduced and reversibility of bafilomycin-induced responses impaired. These findings make V-ATPases attractive targets against early and advanced PCa tumors. PMID:22945374

  4. Animal models relevant to human prostate carcinogenesis underlining the critical implication of prostatic stem/progenitor cells

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K.

    2012-01-01

    Recent development of animal models relevant to human prostate cancer (PC) etiopathogenesis has provided important information on the specific functions provided by key gene products altered during disease initiation and progression to locally invasive, metastatic and hormone-refractory stages. Especially, the characterization of transgenic mouse models has indicated that the inactivation of distinct tumor suppressor proteins such as phosphatase tensin homolog deleted on chromosome 10 (PTEN), Nkx3.1, p27KIP1 and p53 and retinoblastoma (pRb) may cooperate for the malignant transformation of prostatic stem/progenitor cells into PC stem/progenitor cells and tumor development and metastases. Moreover, the sustained activation of diverse oncogenic signaling elements, including epidermal growth factor receptor (EGFR), sonic hedgehog, Wnt/β-catenin, c-Myc, Akt and nuclear factor-kappaB (NF-κB) also may contribute to the acquisition of more aggressive and hormone-refractory phenotypes by PC stem/progenitor cells and their progenies during disease progression. Importantly, it has also been shown that an enrichment of PC stem/progenitor cells expressing stem cell-like markers may occur after androgen deprivation therapy and docetaxel treatment in the transgenic mouse models of PC suggesting the critical implication of these immature PC cells in treatment resistance, tumor re-growth and disease recurrence. Of clinical interest, the molecular targeting of distinct gene products altered in PC cells by using different dietary compounds has also been shown to counteract PC initiation and progression in animal models supporting their potential use as chemopreventive or chemotherapeutic agents for eradicating the total tumor cell mass, improving current anti-hormonal and chemotherapies and preventing disease relapse. PMID:21396984

  5. EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression

    PubMed Central

    Xie, Chongwei; Wu, Zhiyuan; Kang, Zhihua; Fang, Zujun; Su, Bing; Guan, Ming

    2015-01-01

    Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo. EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6-regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP. PMID:26041887

  6. Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model.

    PubMed

    Dzojic, H; Cheng, W-S; Essand, M

    2007-03-01

    The recombinant prostate-specific PPT sequence comprises a prostate-specific antigen enhancer, a PSMA enhancer and a TARP promoter. It is transcriptionally active in human prostate cancer cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer, it has no detectable transcriptional activity. Herein, we describe that the PPT sequence in combination with a two-step transcriptional amplification (TSTA) system becomes active also in murine prostate cancer cells. An adenovirus with TSTA-amplified PPT-controlled expression of the luciferase reporter gene, Ad[PPT/TSTA-Luc], has up to 100-fold higher prostate-specific transcriptional activity than a non-amplified PPT-based adenovirus, Ad[PPT-Luc], in human cells. In addition, Ad[PPT/TSTA-Luc] confers prostate-specific transgene expression in murine cells, with an activity that is approximately 23% of Ad[CMV-Luc] in the transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2 cells. Moreover, to visualize luciferase expression in living mice a charge-coupled device camera was used. Ad[PPT/TSTA-Luc] yielded approximately 30-fold higher transgene expression than Ad[PPT-Luc] in LNCaP tumor xenografts. Importantly, Ad[PPT/TSTA-Luc] also showed activity in murine TRAMP-C2 tumors, whereas Ad[PPT-Luc] activity was undetectable. These results highlight that the recombinant PPT sequence is active in murine prostate cancer cells when augmented by a TSTA system. This finding opens up for preclinical studies with prostate-specific therapeutic gene expression in immunocompetent mice.

  7. Hyperplasticity effect under magnetic pulse straightening of dual phase steel

    NASA Astrophysics Data System (ADS)

    Falaleev, AP; Meshkov, VV; Shymchenko, A.

    2016-10-01

    An investigation of the behaviour of dual phase steel parts during straightening operations, by means of magnetic pulse treatment, is presented. The mechanical analysis of magnetic-pulse treatment for the straightening of thin-walled sheet metal parts produced from dual phase steel was performed, taking into account the effect of hyperplasticity under the influence of the magnetic field. Taking account of the causes of the hyperplasticity and thus the increase of material plasticity, it has been shown that the magnetic impulse gravity can be adjusted by controlling the operation modes. The dependence of the generated magnetic impulse gravity force on the electrical current strength inducted in this part was explored and used for analysis of the magnetic pulse straightening of dual phase steel part. Experimental results were obtained for thin-walled sheet metal part produced from dual phase steel DP 780. The results are used to demonstrate the material deformation under the influence of magnetic impulse gravity force considering the increase of material plasticity. The dependence of relative material deformation on the generated magnetic impulse gravity as well as on the current strength induced in this material was obtained and analyzed

  8. Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

    PubMed

    Wilkinson, Ray; Woods, Katherine; D'Rozario, Rachael; Prue, Rebecca; Vari, Frank; Hardy, Melinda Y; Dong, Ying; Clements, Judith A; Hart, Derek N J; Radford, Kristen J

    2012-02-01

    Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.

  9. Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice.

    PubMed

    DeMiguel, Fernando; Lee, Soo Ok; Lou, Wei; Xiao, Xiao; Pflug, Beth R; Nelson, Joel B; Gao, Allen C

    2002-07-01

    Prostate cancer frequently progresses from an initial androgen dependence to androgen independence, rendering the only effective androgen ablation therapy useless. The mechanism underlying the androgen-independent progression is unknown. Stat3, a member of the family of signal transducers and activators of transcription, is activated in numerous cancers, including prostate. This study is to investigate the role of Stat3 activation in the growth of prostate cancer cells. A constitutively active Stat3 was ectopically expressed in androgen-sensitive LNCaP prostate cancer cells and resulting stable clones expressing activated Stat3 were isolated. The effect of Stat3 activation on LNCaP cell growth in response to androgen in vitro and in vivo was examined. We show that the levels of activated Stat3 are associated with the progression of androgen-independent prostate cancer. Activation of Stat3 in androgen-sensitive LNCaP prostate cancer cells results in enhancement of tumor growth in both intact and castrated male nude mice and enhances androgen receptor-mediated prostate specific antigen expression. These findings demonstrate that intracellular signaling mediated by Stat3 can enhance the growth of androgen-sensitive human LNCaP prostate cancer cells in both intact and castrated male nude mice. Copyright 2002 Wiley-Liss, Inc.

  10. Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

    PubMed Central

    2010-01-01

    Background The serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. In mouse models, Pim1 is known to cooperate with c-Myc to promote tumorigenicity. However, there has been limited analysis of the tumorigenic potential of Pim1 overexpression in benign and malignant human prostate cancer cells in vivo. Methods We overexpressed Pim1 in three human prostate cell lines representing different disease stages including benign (RWPE1), androgen-dependent cancer (LNCaP) and androgen-independent cancer (DU145). We then analyzed in vitro and in vivo tumorigenicity as well as the effect of Pim1 overexpression on c-MYC transcriptional activity by reporter assays and gene expression profiling using an inducible MYC-ER system. To validate that Pim1 induces tumorigenicity and target gene expression by modulating c-MYC transcriptional activity, we inhibited c-MYC using a small molecule inhibitor (10058-F4) or RNA interference. Results Overexpression of Pim1 alone was not sufficient to convert the benign RWPE1 cell to malignancy although it enhanced their proliferation rates when grown as xenografts in vivo. However, Pim1 expression enhanced the in vitro and in vivo tumorigenic potentials of the human prostate cancer cell lines LNCaP and DU145. Reporter assays revealed increased c-MYC transcriptional activity in Pim1-expressing cells and mRNA expression profiling demonstrated that a large fraction of c-MYC target genes were also regulated by Pim1 expression. The c-MYC inhibitor 10058-F4 suppressed the tumorigenicity of Pim1-expressing prostate cancer cells. Interestingly, 10058-F4 treatment also led to a reduction of Pim1 protein but not mRNA. Knocking-down c-MYC using short hairpin RNA reversed the effects of Pim1 on Pim1/MYC target genes. Conclusion Our results suggest an in vivo role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities

  11. Role of Bax in quercetin-induced apoptosis in human prostate cancer cells

    PubMed Central

    Lee, Dae-Hee; Szczepanski, Miroslaw; Lee, Yong J.

    2012-01-01

    The aim of this study was to investigate the effect of quercetin, a flavonoid, on the apoptotic pathway in a human prostate cell line (LNCaP). We observed that treatment of cells for 24 h with quercetin induced cell death in a dose-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in quercetin-treated cells. Treatment of LNCaP cells with an apoptosis inducing concentration of quercetin (100 μM) resulted in a rapid decrease in the inhibitory Ser(473) phosphorylation of Akt leading to inhibition of its kinase activity. Quercetin treatment (100 μM) also caused a decrease in Ser(136) phosphorylation of Bad, which is a downstream target of Akt. Protein interaction assay revealed that during treatment with quercetin, Bcl-xL dissociated from Bax and then associated with Bad. Our results also show that quercetin decreases the Bcl-xL:Bax ratio and increases translocation and multimerization of Bax to the mitochondrial membrane. The translocation is accompanied by cytochrome c release, and procaspases-3, -8 and -9 cleavage and increased poly (ADP-ribose) polymerase (PARP) cleavage. Similar results were observed in human colon cancer HCT116Bax+/+ cell line, but not HCT116Bax−/− cell line. Interestingly, at similar concentrations (100 μM), quercetin treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cell line (PrEC) and rat prostate epithelial cell line (YPEN-1). Our results indicate that the apoptotic processes caused by quercetin are mediated by the dissociation of Bax from Bcl-xL and the activation of caspase families in human prostate cancer cells. PMID:18455702

  12. Effect of resveratrol and zinc on intracellular zinc status in normal human prostate epithelial cells

    USDA-ARS?s Scientific Manuscript database

    To evaluate the influence of resveratrol on cellular zinc status, normal human prostate epithelial (NHPrE) cells were treated with 6 levels of resveratrol (0, 0.5, 1, 2.5, 5 and 10 microM) and 4 levels of zinc [0, 4, 16, and 32 microM for zinc-deficient (ZD), zinc-normal (ZN), zinc-adequate (ZA), an...

  13. Aberrant hypomethylation-mediated CD147 overexpression promotes aggressive tumor progression in human prostate cancer.

    PubMed

    Liang, Yu-Xiang; Mo, Ru-Jun; He, Hui-Chan; Chen, Jia-Hong; Zou, Jun; Han, Zhao-Dong; Lu, Jian-Ming; Cai, Chao; Zeng, Yan-Ru; Zhong, Wei-De; Wu, Chin-Lee

    2015-05-01

    Our previous study revealed the potential role of CD147 in human prostate cancer (PCa). Here, we investigated the CD147 promoter methylation status and the correlation with tumorigenicity in human PCa. CD147 mRNA and protein expression levels were both significantly higher in the 4 PCa cell lines, than in the 2 non-tumorigenic benign human prostatic epithelial cell lines (all P<0.01). We showed hypomethylation of promoter regions of CD147 in PCa cell lines with significant CD147 expression as compared to non-tumorigenic benign human prostatic epithelial cell lines slowly expressing CD147. Additionally, the treatment of methylated cell lines with 5-aza-2'-deoxycytidine increased CD147 expression significantly in low-expressing cell lines and also activated the expression of matrix metalloproteinase (MMP)-2, which may be one of the most important downstream targets of CD147. Furthermore, PCa tissues displayed decreased DNA methylation in the promoter region of CD147 compared to the corresponding non-cancerous prostate tissues, and methylation intensity correlated inversely with the CD147 mRNA levels. There was a significant negative correlation between CD147 mRNA levels and the number of methylated sites in PCa tissues (r=-0.467, P<0.01). In conclusion, our data offer convincing evidence for the first time that the DNA promoter hypomethylation of CD147 may be one of the regulatory mechanisms involved in the cancer-related overexpression of CD147 and may play a crucial role in the tumorigenesis of PCa.

  14. Advancing the Capabilities of an Authentic Ex Vivo Model of Primary Human Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    which slices of human PCa are embedded under the renal capsules of immune-deficient mice (21, 22). The TSG model will benefit from extending the...performed sub- renal implantation of benign TSCs that have been cultured for 3 days, combining the in vitro TSC and in vivo TSG models . Future work...characterization of in vivo tumorgraft models for primary prostate cancer in which thin, precision-cut slices of tissue are implanted under the renal

  15. Prostate Diseases

    MedlinePlus

    ... The Most Common Types of Prostate Diseases Benign prostatic hyperplasia (BPH) Prostatitis Prostate cancer For men over the ... the prostate disease most often encountered is benign prostatic hyperplasia (BPH). If you have BPH, your prostate has ...

  16. Antioxidant Prophylaxis in the Prevention of Prostatic Epithelial Neoplasia

    DTIC Science & Technology

    2009-02-01

    addition to increased variability in nuclear shape, chromasia, nucleolar spacing, cell crowding and cytoplasmic eosinophilia which sharply contrasted...contain protein with increased eosinophilia ; acinar walls are thickened with reactive hyperplastic epithelial cells. Low power magnification of prostate...cell infiltration into the stroma. The acini variably contain protein with increased eosinophilia ; acinar walls are thickened with reactive

  17. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer

    PubMed Central

    Watkins, Stephanie K.; Zhu, Ziqiang; Riboldi, Elena; Shafer-Weaver, Kim A.; Stagliano, Katherine E.R.; Sklavos, Martha M.; Ambs, Stefan; Yagita, Hideo; Hurwitz, Arthur A.

    2011-01-01

    The limited success of cancer immunotherapy is often attributed to the loss of antigen-specific T cell function in situ. However, the mechanism for this loss of function is unknown. In this study, we describe a population of tumor-associated DCs (TADCs) in both human and mouse prostate cancer that tolerizes and induces suppressive activity in tumor-specific T cells. In tumors from human prostate cancer patients and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, TADCs expressed elevated levels of FOXO3 and Foxo3, respectively, which correlated with expression of suppressive genes that negatively regulate T cell function. Silencing FOXO3 and Foxo3 with siRNAs abrogated the ability of human and mouse TADCs, respectively, to tolerize and induce suppressive activity by T cells. Silencing Foxo3 in mouse TADCs was also associated with diminished expression of tolerogenic mediators, such as indoleamine-2,3-dioxygenase, arginase, and TGF-β, and upregulated expression of costimulatory molecules and proinflammatory cytokines. Importantly, transfer of tumor-specific CD4+ Th cells into TRAMP mice abrogated TADC tolerogenicity, which was associated with reduced Foxo3 expression. These findings demonstrate that FOXO3 may play a critical role in mediating TADC-induced immune suppression. Moreover, our results identify what we believe to be a novel target for preventing CTL tolerance and enhancing immune responses to cancer by modulating the immunosuppressive activity of TADCs found in the tumor microenvironment. PMID:21436588

  18. Variations in activin receptor, inhibin/activin subunit and follistatin mRNAs in human prostate tumour tissues

    PubMed Central

    Schaik, R H N van; Wierikx, C D J; Timmerman, M A; Oomen, M H; Weerden, W M van; Kwast, T H van der; Steenbrugge, G J van; Jong, F H de

    1999-01-01

    The possible role of activin in the regulation of malignant prostatic growth was studied using RNAase protection assays of activin receptors, inhibin/activin subunits and follistatin mRNAs in the human prostatic carcinoma cell lines LNCaP-FGC, -R and -LNO, in human prostatic carcinoma xenografts and in human prostatic tissue. Activin receptor types IA (ActRIA), IB (ActRIB), IIA (ActRIIA) and IIB (ActRIIB) mRNAs were generally expressed in prostate pithelial cells, with significantly lower levels of ActRIB mRNA in prostate tumour aterial when compared to non-malignant tissue (P< 0.05; Mann–Whitney U -test). Inhibin/activin βA- and βB-subunit mRNA expression was also found in prostate tissue. Androgen-independent xenografts expressed significantly lower amounts of βB-subunit mRNA when compared to androgen-dependent xenografts (P< 0.05). While βB-subunit mRNA was expressed by LNCaP-FGC and -LNO cells, virtually no expression was found in the androgen-independent LNCaP-R line. Inhibin α-subunit mRNA levels were low or undetectable in all samples investigated. Follistatin mRNA was undetectable in LNCaP-sublines, while low levels were found in prostatic tissues. In androgen-independent LNCaP-R cells, activin inhibited cell growth in a dose-dependent manner. These results suggest that prostate tumour progression is accompanied by a decrease of the inhibitory effect of locally produced activin by either a decrease in the expression of activin βB-subunit mRNA or by a decrease of ActRIB mRNA levels. © 2000 Cancer Research Campaign PMID:10638976

  19. Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.

    PubMed

    González-Chavarría, Iván; Cerro, Rita P; Parra, Natalie P; Sandoval, Felipe A; Zuñiga, Felipe A; Omazábal, Valeska A; Lamperti, Liliana I; Jiménez, Silvana P; Fernandez, Edelmira A; Gutiérrez, Nicolas A; Rodriguez, Federico S; Onate, Sergio A; Sánchez, Oliberto; Vera, Juan C; Toledo, Jorge R

    2014-01-01

    Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

  20. Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells

    PubMed Central

    González-Chavarría, Iván; Cerro, Rita P.; Parra, Natalie P.; Sandoval, Felipe A.; Zuñiga, Felipe A.; Omazábal, Valeska A.; Lamperti, Liliana I.; Jiménez, Silvana P.; Fernandez, Edelmira A.; Gutiérrez, Nicolas A.; Rodriguez, Federico S.; Onate, Sergio A.; Sánchez, Oliberto; Vera, Juan C.; Toledo, Jorge R.

    2014-01-01

    Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells. PMID:25170920

  1. Mapping MRI/MRS Parameters with Genetic Over-expression Profiles In Human Prostate Cancer: Demonstrating the Potential

    PubMed Central

    Lenkinski, Robert E.; Bloch, B. Nicholas; Liu, Fangbing; Frangioni, John V.; Perner, Sven; Rubin, Mark A.; Genega, Elizabeth; Rofsky, Neil M.; Gaston, Sandra M.

    2009-01-01

    Magnetic resonance imaging (MRI) and MR spectroscopy can probe a variety of physiological (e.g. blood vessel permeability) and metabolic characteristics of prostate cancer. However, little is known about the changes in gene expression that underlie the spectral and imaging features observed in prostate cancer. Tumor induced changes in vascular permeability and angiogenesis are thought to contribute to patterns of dynamic contrast enhanced (DCE) MRI images of prostate cancer even though the genetic basis of tumor vasculogenesis is complex and the specific mechanisms underlying these DCEMRI features have not yet been determined. In order to identify the changes in gene expression that correspond to MRS and DCEMRI patterns in human prostate cancers, we have utilized tissue print micropeel techniques to generate “whole mount” molecular maps of radical prostatectomy specimens that correspond to pre-surgical MRI/MRS studies. These molecular maps include RNA expression profiles from both Affymetrix GeneChip microarrays and quantitative reverse transcriptase PCR (qrt-PCR) analysis, as well as immunohistochemical studies. Using these methods on patients with prostate cancer, we found robust over-expression of choline kinase a in the majority of primary tumors. We also observed overexpression of neuropeptide Y (NPY), a newly identified angiogenic factor, in a subset of DCEMRI positive prostate cancers. These studies set the stage for establishing MRI/MRS parameters as validated biomarkers for human prostate cancer. PMID:18752015

  2. A human GRPr-transfected Ace-1 canine prostate cancer model in mice.

    PubMed

    Ding, Haiming; Kothandaraman, Shankaran; Gong, Li; Williams, Michelle M; Dirksen, Wessel P; Rosol, Thomas J; Tweedle, Michael F

    2016-06-01

    A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer. We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs. Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13 nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ∼0.5 cm diameter in 1 week. In vivo imaging of the mice at 800 nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24 h post IV administration of 10 nmol of the imaging agents. Blood retention (4-8% ID at 1 h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4 h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay. The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic

  3. 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

  4. Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer

    PubMed Central

    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

    2016-01-01

    Abstract 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. PMID:27749584

  5. 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.

  6. Cadmium induces p53-dependent apoptosis in human prostate epithelial cells.

    PubMed

    Aimola, Pierpaolo; Carmignani, Marco; Volpe, Anna Rita; Di Benedetto, Altomare; Claudio, Luigi; Waalkes, Michael P; van Bokhoven, Adrie; Tokar, Erik J; Claudio, Pier Paolo

    2012-01-01

    Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl(2) and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl(2) concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis.

  7. Cadmium Induces p53-Dependent Apoptosis in Human Prostate Epithelial Cells

    PubMed Central

    Aimola, Pierpaolo; Carmignani, Marco; Volpe, Anna Rita; Di Benedetto, Altomare; Claudio, Luigi; Waalkes, Michael P.; van Bokhoven, Adrie; Tokar, Erik J.; Claudio, Pier Paolo

    2012-01-01

    Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis. PMID:22448262

  8. [Ocular ultrasonography in pediatrics: persistence of hyperplastic primary vitreous].

    PubMed

    Pieroni, G; Russo, M; Bolli, V; Abbasciano, V; Fabrizzi, G

    2001-04-01

    To assess the diagnostic viability of ultrasound and color Doppler ultrasound in a particular segment of paediatric ophthalmology-persistent primary hyperplastic vitreous, in the presence of leucocoria, retrospectively evaluated in patients observed over the last two years. We re-evaluated four patients (two new-born, one unweaned and one nine-years-old) who at ophthalmoscopic examination were suspected having persistent primitive hyperplastic vitreous. The follow-up included an ultrasound examination, basic color-Doppler ultrasound and re-evaluation during sedation both using an operative microscope and ultrasound. The examinations were performed with linear 7.5 Mhz probes and a Doppler frequency of 3.7 Mhz, while the sedation examination was performed with an anular 13 Mhz probe. The scans were sagittal and axial to correctly localize the lesion with respect to the lens, to ciliary bodies and to the optic nerve head. In the first patient ultrasound revealed a hyperechogenic inhomogeneous structure bilaterally in the vitreous structure; this extended from the posterior wall of the lens to the optic nerve head and retina, and was found to be highly vascolarized at the subsequent color-Doppler ultrasound. In the second patient there was an echogenic band extending from the posterior wall of the lens to the optic nerve head and to the retina, as the fourth patient showed a series of echogenic bands extending from the temporal ciliar of bodies to the temporal retina; in both cases no significant vascolarization was found by color Doppler ultrasound. In the third patient ultrasound showed a lesion involving nearly all of the vitreous body, with inhomogeneous structure with small calcifications and intense vascolarization. Ultrasound supplies essential information for the diagnosis of persistent hyperplastic primary vitreous as it determines the presence of the lesion, its extension and retinal and optic nerve head involvement. As confirmed by operative microscopy the

  9. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma.

    PubMed

    Diamandis, Eleftherios P; Okui, Akira; Mitsui, Shinichii; Luo, Liu-Ying; Soosaipillai, Antoninus; Grass, Linda; Nakamura, Terukazu; Howarth, David J C; Yamaguchi, Nozomi

    2002-01-01

    Human kallikrein 11 (hK11) is a putative serine protease of the human kallikrein gene family. Currently, no methods are available for measuring hK11 in biological fluids and tissues. Our aim was to develop immunological reagents and assays for measuring hK11 and examine if the concentration of this kallikrein is altered in disease states. We produced recombinant hK11 protein in a baculovirus system and used it to develop monoclonal and polyclonal antibodies against hK11. We then developed an immunofluorometric procedure for measuring hK11 in biological fluids and tissue extracts with high sensitivity and specificity. We further quantified hK11 in various biological fluids and in serum of patients with various cancers. The hK11 immunofluorometric assay is highly sensitive (detection limit, 0.1 microg/l) and specific (no detectable cross-reactivity for other homologous kallikreins). We established the tissue expression pattern of hK11 at the protein level and found the highest levels in the prostate, followed by stomach, trachea, skin, and colon. We have immunohistochemically localized hK11 in epithelial cells of various organs. We further detected hK11 in amniotic fluid, milk of lactating women, cerebrospinal fluid, follicular fluid, and breast cancer cytosols. However, highest levels were seen in prostatic tissue extracts and seminal plasma. hK11 in seminal plasma and prostatic extracts is present at approximately 300-fold lower levels than prostate-specific antigen and at approximately the same levels as hK2. hK11 expression in breast cancer cell lines is up-regulated by estradiol. Elevated serum levels of hK11 were found in 70% of women with ovarian cancer and in 60% of men with prostate cancer. This is the first reported immunological assay for hK11. Analysis of this biomarker in serum may aid in the diagnosis and monitoring of ovarian and prostatic carcinoma.

  10. Serial lectin affinity chromatography with concavalin A and wheat germ agglutinin demonstrates altered asparagine-linked sugar-chain structures of prostatic acid phosphatase in human prostate carcinoma.

    PubMed

    Yoshida, K I; Honda, M; Arai, K; Hosoya, Y; Moriguchi, H; Sumi, S; Ueda, Y; Kitahara, S

    1997-08-01

    Differences between human prostate carcinoma (PCA, five cases) and benign prostatic hyperplasia (BPH, five cases) in asparagine-linked (Asn) sugar-chain structure of prostatic acid phosphatase (PAP) were investigated using lectin affinity chromatography with concanavalin A (Con A) and wheat germ agglutinin (WGA). PAP activities were significantly decreased in PCA-derived PAP, while no significant differences between the two PAP preparations were observed in the enzymatic properties (Michaelis-Menten value, optimal pH, thermal stability, and inhibition study). In these PAP preparations, all activities were found only in the fractions which bound strongly to the Con A column and were undetectable in the Con A unbound fractions and in the fractions which bound weakly to the Con A column. The relative amounts of PAP which bound strongly to the Con A column but passed through the WGA column, were significantly greater in BPH-derived PAP than in PCA-derived PAP. In contrast, the relative amounts of PAP which bound strongly to the Con A column and bound to the WGA column, were significantly greater in PCA-derived PAP than in BPH-derived PAP. The findings suggest that Asn-linked sugar-chain structures are altered during oncogenesis in human prostate and also suggest that studies of qualitative differences of sugar-chain structures of PAP might lead to a useful diagnostic tool for PCA.

  11. Expression analysis onto microarrays of randomly selected cDNA clones highlights HOXB13 as a marker of human prostate cancer

    PubMed Central

    Edwards, S; Campbell, C; Flohr, P; Shipley, J; Giddings, I; te-Poele, R; Dodson, A; Foster, C; Clark, J; Jhavar, S; Kovacs, G; Cooper, C S

    2004-01-01

    In a strategy aimed at identifying novel markers of human prostate cancer, we performed expression analysis using microarrays of clones randomly selected from a cDNA library prepared from the LNCaP prostate cancer cell line. Comparisons of expression profiles in primary human prostate cancer, adjacent normal prostate tissue, and a selection of other (nonprostate) normal human tissues, led to the identification of a set of clones that were judged as the best candidate markers of normal and/or malignant prostate tissue. DNA sequencing of the selected clones revealed that they included 10 genes that had previously been established as prostate markers: NKX3.1, KLK2, KLK3 (PSA), FOLH1 (PSMA), STEAP2, PSGR, PRAC, RDH11, Prostein and FASN. Following analysis of the expression patterns of all selected and sequenced genes through interrogation of SAGE databases, a further three genes from our clone set, HOXB13, SPON2 and NCAM2, emerged as additional candidate markers of human prostate cancer. Quantitative RT–PCR demonstrated the specificity of expression of HOXB13 in prostate tissue and revealed its ubiquitous expression in a series of 37 primary prostate cancers and 20 normal prostates. These results demonstrate the utility of this expression-microarray approach in hunting for new markers of individual human cancer types. PMID:15583692

  12. Expression analysis onto microarrays of randomly selected cDNA clones highlights HOXB13 as a marker of human prostate cancer.

    PubMed

    Edwards, S; Campbell, C; Flohr, P; Shipley, J; Giddings, I; Te-Poele, R; Dodson, A; Foster, C; Clark, J; Jhavar, S; Kovacs, G; Cooper, C S

    2005-01-31

    In a strategy aimed at identifying novel markers of human prostate cancer, we performed expression analysis using microarrays of clones randomly selected from a cDNA library prepared from the LNCaP prostate cancer cell line. Comparisons of expression profiles in primary human prostate cancer, adjacent normal prostate tissue, and a selection of other (nonprostate) normal human tissues, led to the identification of a set of clones that were judged as the best candidate markers of normal and/or malignant prostate tissue. DNA sequencing of the selected clones revealed that they included 10 genes that had previously been established as prostate markers: NKX3.1, KLK2, KLK3 (PSA), FOLH1 (PSMA), STEAP2, PSGR, PRAC, RDH11, Prostein and FASN. Following analysis of the expression patterns of all selected and sequenced genes through interrogation of SAGE databases, a further three genes from our clone set, HOXB13, SPON2 and NCAM2, emerged as additional candidate markers of human prostate cancer. Quantitative RT-PCR demonstrated the specificity of expression of HOXB13 in prostate tissue and revealed its ubiquitous expression in a series of 37 primary prostate cancers and 20 normal prostates. These results demonstrate the utility of this expression-microarray approach in hunting for new markers of individual human cancer types.

  13. Vanadate monomers and dimers both inhibit the human prostatic acid phosphatase.

    PubMed

    Crans, D C; Simone, C M; Saha, A K; Glew, R H

    1989-11-30

    A combination of enzyme kinetics and 51V NMR spectroscopy was used to identify the species of vanadate that inhibits acid phosphatases. Monomeric vanadate was shown to inhibit wheat germ and potato acid phosphatases. At pH 5.5, the vanadate dimer inhibits the human prostatic acid phosphatase whereas at pH 7.0 it is the vanadate monomer that inhibits this enzyme. The pH-dependent shift in the affinity of the prostatic phosphatase for vanadate is presumably due to deprotonation of an amino acid side chain in or near the binding site resulting in a conformational change in the protein. pH may be a subtle effector of the insulin-like vanadate activity in biological systems and may explain some of the differences in selectivity observed with the protein phosphatases.

  14. Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor

    PubMed Central

    Xu, Weisheng; Ngo, Lang; Perez, Gisela; Dokmanovic, Milos; Marks, Paul A.

    2006-01-01

    There is a great need to develop better mechanism-based therapies for prostate cancer. In this investigation, we studied four human prostate cancer cell lines, LNCaP, DU145, LAPC4, and PC3, which differ in response to the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (vorinostat), a new anticancer drug. Examining the role of intrinsic mitochondrial caspase-dependent apoptosis and caspase-independent, reactive oxygen species (ROS) facilitated cell death, has provided an understanding of mechanisms that may determine the varied response to the histone deacetylase inhibitor. We found striking differences among these cancer cells in constitutive expression and response to suberoylanilide hydroxamic acid in levels of antiapoptotic and proapoptotic proteins, mitochondria membrane integrity, activation of caspases, ROS accumulation, and expression of thioredoxin, the major scavenger of ROS. Identifying these differences can have predictive value in assessing therapeutic response and identifying targets to enhance therapeutic efficacy. PMID:17030815

  15. Magnetic resonance spectroscopy: A promising tool for the diagnostics of human prostate cancer?☆

    PubMed Central

    Kurth, Johannes; DeFeo, Elita; Cheng, Leo L.

    2013-01-01

    Background Prostate Cancer (CaP) is one of the topmost diagnosed malignant diseases worldwide. In developed countries, early cancer detection methods have led to an increase of incidence rates over the last decades; however, with great variance of the prognosis. There is no diagnostic tool for an exact prediction of tumor aggressiveness, thus there is a lack of adequate and optimal treatment planning. Methods Electronic databases (Medline, PubMed) were scanned for scientific literature. Basic concepts of magnetic resonance spectroscopy (MRS), important results and its clinical applications were extracted and reviewed in this article. Conclusions MRS provides crucial information about the metabolic status of human prostate samples while preserving the specimens for further investigations. Single metabolites and metabolomic profiles can be quantified to distinguish benign from malignant tissue and to predict aggressiveness, such as the recurrence rates of CaP. Studies are also anticipating that MRS might be beneficially applicable for in vivo investigations in the future. PMID:21930088

  16. Vasoactive intestinal peptide (VIP) induces malignant transformation of the human prostate epithelial cell line RWPE-1.

    PubMed

    Fernández-Martínez, Ana B; Bajo, Ana M; Isabel Arenas, M; Sánchez-Chapado, Manuel; Prieto, Juan C; Carmena, María J

    2010-12-18

    The carcinogenic potential of vasoactive intestinal peptide (VIP) was analyzed in non-tumor human prostate epithelial cells (RWPE-1) and in vivo xenografts. VIP induced morphological changes and a migratory phenotype consistent with stimulation of expression/activity of metalloproteinases MMP-2 and MMP-9, decreased E-cadherin-mediated cell-cell adhesion, and increased cell motility. VIP increased cyclin D1 expression and cell proliferation that was blocked after VPAC(1)-receptor siRNA transfection. Similar effects were seen in RWPE-1 tumors developed by subcutaneous injection of VIP-treated cells in athymic nude mice. VIP acts as a cytokine in RWPE-1 cell transformation conceivably through epithelial-mesenchymal transition (EMT), reinforcing VIP role in prostate tumorigenesis.

  17. Basal epithelial cells of human prostate gland are not myoepithelial cells. A comparative immunohistochemical and ultrastructural study with the human salivary gland.

    PubMed Central

    Srigley, J. R.; Dardick, I.; Hartwick, R. W.; Klotz, L.

    1990-01-01

    The hypothesis that basal epithelial cells of the human prostate are of myoepithelial origin was investigated using immunohistochemical and ultrastructural methodologies. The immunohistologic analyses show significant phenotypic differences between prostatic basal cells and myoepithelial cells of the salivary gland. Although both cell types stain intensely with the 312C8-1 monoclonal antibody, only true myoepithelial cells demonstrated significant amounts of muscle-specific actin as decorated by the HHF35 monoclonal antibody. Furthermore, using double-labeling experiments, the prostatic basal cells were strongly decorated with a fluorescein-tagged basal cell-specific keratin but were negative with the rhodamine-tagged phalloidin, a chemical that binds specifically to actin microfilaments. Ultrastructural studies also showed an absence of thin microfilament bundles, dense bodies, and micropinocytotic vesicles in the prostatic basal cells. The current investigations show that the prostatic acini do not have a basal myoepithelium. Although some authors have suggested a stem cell role for prostatic basal cells, the weight of experimental work argues against this hypothesis. The exact role of the basal epithelial cells of the prostate is not known, although they may serve endocrine, paracrine, or other regulatory functions and may be involved in modulating signals between prostatic stroma and epithelium. Images Figure 3 Figure 1 Figure 2 Figure 4 PMID:1691595

  18. Diagnosis of prostate cancer by analyzing oxidative stress in human seminal plasma: developing unsophisticated tools for noninvasive prostate cancer diagnosis.

    PubMed

    Barrio-Muñoz, Miriam; Abad-Gairín, Carlos; Amengual-Guedán, José M; Prats-López, Joan

    2016-11-01

    Prostate-specific antigen blood testing has improved early detection of prostate cancer (PCa); however, PCa mortality has not decreased accordingly and a prostate biopsy is still required for a definitive diagnosis. Proteomic biomarker screening in easily available body fluids such as seminal plasma is now increasingly being proposed as a solution to improve PCa detection and prognosis. PCa cells typically produce high levels of reactive oxygen species (ROS). In this study, we therefore investigated ROS levels in semen samples from patients with a negative or a positive prostate biopsy to predict PCa diagnosis. Multiple clinicopathological parameters (digital rectal examination, prostate-specific antigen scoring, prostate biopsy, and ROS levels) of patients examined for PCa were measured. No significant differences in ROS levels were detected in relation to PCa diagnosis. Although seminal plasma is a well-suited medium for prostate-related biomarkers, no significant differences in ROS levels were observed between the patient groups. Comparison with ROS levels encountered in semen of larger patient groups is the next logical step.

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

    PubMed

    Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona; Pavone, Luigi Michele; Campese, Roberto; Monaco, Roberto; Iachetta, Giuseppina; Assisi, Loredana; Mirabella, Nicola; Forte, Maurizio; Costagliola, Anna; Vittoria, Alfredo

    2015-09-04

    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 in 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.

  20. Effect of topical application of phenylephrine hydrochloride on hyperplastic gingivitis.

    PubMed

    Pernsteiner, C L; Ash, M M

    1977-08-01

    A double blind study was conducted to evaluate the effectiveness of Phenodent Type A (brand of phenylephrine hydrochloride) on decongesting hyperplastic gingivitis. Three solutions were used: a 0.5% a placebo, and a 0.25% concentration of phenylephrine hydrochloride. The periodontal disease index was used to score variables which might have an effect on gingival response to local irritants. Impressions were taken and casts were made on 45 subjects at 0, 1, 3, and 6-week intervals. An instrument with accuracy of 0.001 inch was constructed to measure the changes in the interdental papillae of the stone casts. No significant reduction of gingival volume was established for any of the three solutions.

  1. Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; Chen, Y.; Tjandrawinata, R. R.

    2001-01-01

    It has been proposed that the omega-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE(2) stimulate tumor growth while oleic acid (OA) and the omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE(2) via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE(2) synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake.

  2. Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; Chen, Y.; Tjandrawinata, R. R.

    2001-01-01

    It has been proposed that the omega-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE(2) stimulate tumor growth while oleic acid (OA) and the omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE(2) via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE(2) synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake.

  3. Molecular profiling of indolent human prostate cancer: tackling technical challenges to achieve high-fidelity genome-wide data.

    PubMed

    Dunn, Thomas A; Fedor, Helen L; De Marzo, Angelo M; Luo, Jun

    2012-05-01

    The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men, and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases. Since progressive acquisition and accumulation of genomic alterations, both genetic and epigenetic, is a defining feature of all human cancers at different stages of disease progression, it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer. Approaches capable of detecting such alterations on a genome-wide level are the most promising. Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression, and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment. However, defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge, particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded (FFPE) tissue specimens. Here, we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies, identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues, and highlight recent progresses in efforts to address these technical challenges.

  4. Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells.

    PubMed Central

    Shen, Chuanlu; Nathan, Carl

    2002-01-01

    BACKGROUND: Peroxiredoxins (Prxs) are antioxidant enzymes expressed by most free-living organisms, often in multiple isoforms. Because mammalian Prxs have not been experimentally deleted or inhibited, it is not known how much they contribute to antioxidant defense, nor whether the multiple isoforms afford redundant or additive protection. MATERIALS AND METHODS: Expression of the four members of the 2-Cys family of human Prxs was tested in human tumor cell lines. Monospecific antibodies were developed and used to monitor the extent and specificity of inhibition of expression of each isoform in prostate cancer cells stably transfected with antisense constructs. RESULTS: Seventeen tumor lines transcribed genes for all four human Prxs. Prostate cancer cells coexpressed each isoform at the protein level. Stable transfection with antisense allowed partial, selective suppression of Prx 1, 2, 3, or 4. Prostate cancer cells were rendered more sensitive to hydrogen peroxide or an organic hydroperoxide when Prx 1, 2, or 3 but not 4 was partially suppressed, bringing them into the range of sensitivity of mouse cells. The effect of partially suppressing a single Prx was comparable to that of depleting glutathione. In contrast, sensitization to adriamycin, an antitumor agent with a redox-active quinone, followed the partial suppression of Prxs 1, 2, or 4 but not 3. Individual suppression of Prxs 1-4 had no effect on sensitivity of the cells to reactive nitrogen intermediates, tumor necrosis factor (TNF), paclitaxel (Taxol), or etoposide. CONCLUSIONS: The 2-Cys Prxs act in a mutually nonredundant and sometimes stress-specific fashion to protect human cells from oxidant injury. The substantial resistance of human cells to hydroperoxides may result in part from the additive action of multiple Prxs. PMID:12080185

  5. Increased Expression of CYR61, an Extracellular Matrix Signaling Protein, in Human Benign Prostatic Hyperplasia and Its Regulation by Lysophosphatidic Acid

    PubMed Central

    SAKAMOTO, SHINJI; YOKOYAMA, MASAHIRO; ZHANG, XIANGHUA; PRAKASH, KULKARNI; NAGAO, KAORI; HATANAKA, TAKASHI; GETZENBERG, ROBERT H.; KAKEHI, YOSHIYUKI

    2012-01-01

    Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G protein-coupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease. (Endocrinology 145: 2929–2940, 2004) PMID:14988385

  6. Enhanced detection of metastatic prostate cancer cells in human plasma with lipid bodies staining.

    PubMed

    Mitra, Ranjana; Goodman, Oscar B; Le, Thuc T

    2014-02-15

    non-transformed prostate epithelial cells using fluorescent glucose or lipid uptake kinetics. However, metastatic prostate cancer cells in plasma could be clearly distinguished from blood nucleated cells due to the presence of intracellular lipid bodies. Fluorescent labeling of lipid bodies permitted a simple and sensitive means for high throughput detection of metastatic prostate cancer cells in human plasma.

  7. Gastric neuroendocrine cell hyperplasia and type 1 tumours occurring within gastric hyperplastic polyps.

    PubMed

    Chetty, Runjan; Gill, Pelvender; Mugon, Parassar; Shrimankar, Jyotsna; Hughes, Caroline

    2012-11-01

    We wish to highlight the unusual occurrence of gastric neuroendocrine cell hyperplasia and type I neuroendocrine tumours within three hyperplastic polyps. In all cases, the neuroendocrine component was present within and between the hyperplastic foveolar glands of the polyps and overall formed the minor part of the polyps. Two of the patients presented with epigastric pain and the other with fatigue from anaemia, and on endoscopy, all three were found to have superficially ulcerated gastric polyps in the body (cases 1 and 2) and fundus (case 3). Two of the cases had serologically proven autoimmune atrophic gastritis, while the third case had histological evidence of an atrophic gastritis, most likely also autoimmune in aetiology. Cases 1 and 3 had single hyperplastic polyps, while case 2 had three polyps. All polyps showed linear neuroendocrine cell hyperplasia within hyperplastic foveolar epithelium both at the surface and within deeper-situated glands. Neuroendocrine immunohistochemistry highlighted the neuroendocrine cell hyperplasia. The bulk of the neuroendocrine component was restricted to hyperplastic mucosa forming the polyps. Non-hyperplastic adjacent mucosa showed less prominent neuroendocrine cell hyperplasia. It is unclear whether the two pathologies occurred simultaneously or independently. The common feature and causal link is atrophic gastritis, which predisposed the gastric mucosa to the development of both neuroendocrine cell hyperplasia and tumours, and hyperplastic polyps.

  8. p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines.

    PubMed

    Wong, Lilian I L; Labrecque, Mark P; Ibuki, Naokazu; Cox, Michael E; Elliott, John E; Beischlag, Timothy V

    2015-03-25

    Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additionally, we used the fully automated COBAS PSA detection system to determine that extracellular PSA levels were also significantly repressed. These chemicals achieve this by blocking the recruitment of AR to the PSA promoter region at 10 μM, as demonstrated by the chromatin immunoprecipitation (ChIP) in LNCaP cells. Both p,p'-DDT and p,p'-DDE repressed R1881-inducible AR protein accumulation at 10 μM. Thus, we conclude that men who have been exposed to either DDT or DDE may produce a false-negative PSA test when screening for prostate cancer, resulting in an inaccurate clinical diagnosis. More importantly, prolonged exposure to these anti-androgens may mimic androgen ablation therapy in individuals with prostate cancer, thus exacerbating the condition by inadvertently forcing adaptation to this stress early in the disease.

  9. Human α(2)β(1)(HI) CD133(+VE) epithelial prostate stem cells express low levels of active androgen receptor.

    PubMed

    Williamson, Stuart C; Hepburn, Anastasia C; Wilson, Laura; Coffey, Kelly; Ryan-Munden, Claudia A; Pal, Deepali; Leung, Hing Y; Robson, Craig N; Heer, Rakesh

    2012-01-01

    Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.

  10. Genetic deletion of osteopontin in TRAMP mice skews prostate carcinogenesis from adenocarcinoma to aggressive human-like neuroendocrine cancers

    PubMed Central

    Mauri, Giorgio; Jachetti, Elena; Comuzzi, Barbara; Dugo, Matteo; Arioli, Ivano; Miotti, Silvia; Sangaletti, Sabina; Di Carlo, Emma; Tripodo, Claudio; Colombo, Mario P.

    2016-01-01

    Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN−/−) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN−/− TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors. PMID:26700622

  11. Biological effect of human serum collected before and after oral intake of Pygeum africanum on various benign prostate cell cultures

    PubMed Central

    Larré, Stéphane; Camparo, Philippe; Comperat, Eva; Boulbés, Delphine; Haddoum, Mohammed; Baulande, Sylvain; Soularue, Pascal; Costa, Pierre; Cussenot, Olivier

    2012-01-01

    Pygeum africanum (Tadenan) is a popular phytotherapeutic agent used in the treatment of symptomatic benign prostatic hyperplasia. The active compounds of the drug have not been identified, and determining the plasma concentration of the drug is, therefore, not possible. Because there are conflicting results on the efficacy of this drug, we aimed to investigate its effect on prostate cell growth in vitro using human serum collected before and after Pygeum africanum intake. We used primary and organotypic cultures of human prostatic stromal myofibroblast cell line WPMY and prostatic epithelial cell line PNT2. We also used fresh benign prostatic tissue. The serum of a treated man induced decreases in the proliferation of primary cells, organotypic cells and WPMY cells but not PNT2 cells. We also analysed the effect of treated serum on the gene expression profile of WPMY cells. The transcriptome analysis revealed an upregulation of genes involved in multiple tumour suppression pathways and a downregulation of genes involved in inflammation and oxidative-stress pathways. The oral intake of Pygeum africanum resulted in serum levels of active substances that were sufficient to inhibit the proliferation of cultured myofibroblasts prostatic cells. This inhibition was associated with changes in the transcriptome. PMID:22198631

  12. Tocopherols and saponins derived from Argania spinosa exert, an antiproliferative effect on human prostate cancer.

    PubMed

    Drissi, A; Bennani, H; Giton, F; Charrouf, Z; Fiet, J; Adlouni, A

    2006-10-01

    The aim of our study is to evaluate the antiproliferative effect of tocopherols obtained from alimentary virgin argan oil extracted from the endemic argan tree of Morocco and of saponins extracted from argan press cake on three human prostatic cell lines (DU145, LNCaP, and PC3). The results were compared to 2-methoxyestradiol as antiproliferative drug candidates. Cytotoxicity and antiproliferative effects were investigated after cells' treatment with tocopherols and saponins compared to 2-Methoxyoestradiol as the positive control. Tocopherols and saponins extracted from argan tree and 2-methoxyestradiol exhibit a dose-response cytotoxic effect and an antiproliferative action on the tested cell lines. The best antiproliferative effect of tocopherols is obtained with DU145 and LNCaP cell lines (28 microg/ml and 32 microg/ml, respectively, as GI50). The saponins fraction displayed the best antiproliferative effect on the PC3 cell line with 18 microg/ml as GI50. Our results confirm the antiproliferative effect of 2-methoxyestradiol and show for the first time the antiproliferative effect of tocopherols and saponins extracted from the argan tree on hormone-dependent and hormone-independent prostate cancer cell lines. These data suggest that argan oil is of potential interest in developing new strategies for prostate cancer prevention.

  13. Proapoptotic effects of new pentabromobenzylisothiouronium salts in a human prostate adenocarcinoma cell line.

    PubMed

    Koronkiewicz, Mirosława; Kazimierczuk, Zygmunt; Szarpak, Kinga; Chilmonczyk, Zdzisław

    2012-01-01

    Prostate cancer is the second most common cancer in elderly men worldwide and its incidence rate is rising continuously. Agents capable of inducing apoptosis in prostate cancer cells seem a promising approach to treat this malignancy. In this study we describe the synthesis of a number of novel N- and N,N'-substituted S-2,3,4,5,6-pentabromobenzylisothiouronium bromides and their activity against the human prostate adenocarcinoma PC3 cell line. All the compounds produced changes in mitochondrial transmembrane potential and cell cycle progression, showed a cytostatic effect and induced apoptosis in the tested cancer line in a concentration- and time-dependent manner. The most effective compounds ZKK-3, ZKK-9 and ZKK-13 produced, at 20 microM concentration, apoptosis in 42, 46, and 66% of the cells, respectively, after 48 h incubation. Two selected S-2,3,4,5,6-pentabromobenzylisothiouronium bromides (ZKK-3, ZKK-9) showed also a synergic proapoptotic effect with the new casein kinase II inhibitor 2-(4-methylpiperazin-1-yl)-4,5,6,7-tetrabromo-1H-benzimidazole (TBIPIP) in the PC3 cell line.

  14. Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer

    PubMed Central

    Attard, G; Clark, J; Ambroisine, L; Mills, I G; Fisher, G; Flohr, P; Reid, A; Edwards, S; Kovacs, G; Berney, D; Foster, C; Massie, C E; Fletcher, A; De Bono, J S; Scardino, P; Cuzick, J; Cooper, C S

    2008-01-01

    A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5′-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5′-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer. PMID:18594527

  15. Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer.

    PubMed

    Attard, G; Clark, J; Ambroisine, L; Mills, I G; Fisher, G; Flohr, P; Reid, A; Edwards, S; Kovacs, G; Berney, D; Foster, C; Massie, C E; Fletcher, A; De Bono, J S; Scardino, P; Cuzick, J; Cooper, C S

    2008-07-22

    A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

  16. Suppression of β-catenin Signaling Pathway in Human Prostate Cancer PC3 Cells by Delphinidin

    PubMed Central

    Lee, Wooje; Yun, Jung-Mi

    2016-01-01

    Delphinidin possesses strong anti-oxidant, anti-inflammatory, and anti-cancer properties. Suppression of the Wnt/β-catenin signaling pathway is a potential strategy for chemoprevention and therapy. As aberrant activation of the β-catenin signaling pathway contributes to prostate cancer progression, we evaluated the effect of delphinidin on this pathway in human PC3 prostate cancer cells. An MTT assay showed that treatment with delphinidin (15–180 μM, 72 hours) resulted in a dose-dependent growth inhibition of cells. Treatment with delphinidin increased the phosphorylation of serine or threonine residues on β-catenin and decreased the levels of cytoplasmic β-catenin. Moreover, treatment with delphinidin inhibited the nuclear translocation of β-catenin and the expression of β-catenin target genes such as cyclin D1, c-myc, Axin-2, and T cell factor-1. Delphinidin also induced the phosphorylation of glycogen synthase kinase 3β and the expression of adenomatous polyposis coli and Axin proteins. Our results indicate that inhibition of cell growth by delphinidin is mediated, at least in part, through modulation of the β-catenin signaling pathway. We suggest that delphinidin is a potent inhibitor of Wnt/β-catenin signaling in prostate cancer cells. PMID:27390740

  17. Sulforaphane, a cruciferous vegetable-derived isothiocyanate, inhibits protein synthesis in human prostate cancer cells.

    PubMed

    Wiczk, Aleksandra; Hofman, Dagmara; Konopa, Grażyna; Herman-Antosiewicz, Anna

    2012-08-01

    Sulforaphane (SFN) is a compound derived from cruciferous plants. Its anticancer properties have been demonstrated both, in cancer cell lines as well as tumors in animal models. It has been shown that SFN inhibits cell proliferation, induces apoptosis, autophagy, and sensitizes cancer cells to therapies. As induction of catabolic processes is often related to perturbation in protein synthesis we aimed to investigate the impact of SFN on this process in PC-3 human prostate cancer cells. In the present study we show that SFN inhibits protein synthesis in PC-3 cells in a dose- and time-dependent manner which is accompanied by a decreased phosphorylation of mTOR substrates. Translation inhibition is independent of mitochondria-derived ROS as it is observed in PC-3 derivatives devoid of functional mitochondrial respiratory chain (Rho0 cells). Although SFN affects mitochondria and slightly decreases glycolysis, the ATP level is maintained on the level characteristic for control cells. Inhibition of protein synthesis might be a protective response of prostate cancer cells to save energy. However, translation inhibition contributes to the death of PC-3 cells due to decreased level of a short-lived protein, survivin. Overexpression of this anti-apoptotic factor protects PC-3 cells against SFN cytotoxicity. Protein synthesis inhibition by SFN is not restricted to prostate cancer cells as we observed similar effect in SKBR-3 breast cancer cell line. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

    PubMed Central

    Misra, Uma Kant; Pizzo, Salvatore Vincent

    2015-01-01

    Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2–3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2–3-fold increase in lipogenesis as determined by 6-[14C]glucose or 1-[14C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [14CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy. PMID:25720493

  19. Characterization of PacMetUT1, a recently isolated human prostate cancer cell line.

    PubMed

    Troyer, D A; Tang, Y; Bedolla, R; Adhvaryu, S G; Thompson, I M; Abboud-Werner, S; Sun, L-Z; Friedrichs, W E; deGraffenried, L A

    2008-06-01

    Existing prostate cancer cell lines have limitations. Cells were characterized using Western blotting, immunohistochemistry, invasion into Matrigel, and by studying xenograft tumors. We describe a cell line (PacMetUT1) isolated from a lymph node of a 57-year-old male with prostate cancer. Compared to existing prostate cancer cell lines, the growth rate of PacMetUT1 xenograft tumors is slower with tumors occurring at injection sites and with metastases to lung and liver. Androgen receptor (AR) was detected in vivo by Western blotting and the cells responded to methyltrienolone (R1881). PacMetUT1 cells are more invasive in Matrigel than DU-145, PC-3, and LNCaP cells, and showed greater anchorage-independent growth in soft agar. The cells do not express prostate specific antigen (PSA) in vitro or in xenografts. However, the green fluorescent protein (GFP) gene was introduced and stably expressed in PacMetUT1 cells, allowing tumor imaging in vivo. Xenograft tumors show epithelial features and are positive for keratin, epithelial membrane antigen, EGF receptor, and E cadherin. In contrast, fibroblast markers vimentin, desmin, and Factor VIII, were negative. Karyotyping showed losses of 6p, 7q, 8p, 18q, and 22q, and gains of 8q and 9q; additional genetic material was observed at 2q and 12p. The PacMetUT1 cell line allows metastases to be assessed using a single animal model. Because of its slower growth, PacMetUT1 more closely mimics the human disease. Studies of tumor progression or metastasis can be conducted over a longer period of time. (c) 2008 Wiley-Liss, Inc.

  20. Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells.

    PubMed

    Shigemura, Katsumi; Arbiser, Jack L; Sun, Shi-Yong; Zayzafoon, Majd; Johnstone, Peter A S; Fujisawa, Masato; Gotoh, Akinobu; Weksler, Babette; Zhau, Haiyen E; Chung, Leland W K

    2007-04-01

    Honokiol, a soluble nontoxic natural product derived from Magnolia spp., has been shown to induce apoptosis in malignant cells. The effect of honokiol and the combined therapy with docetaxel on prostate cancer (PCa) growth and bone metastasis was investigated in experimental models. The in vitro proapoptotic effects of honokiol on human androgen-dependent and -independent PCa, bone marrow, bone marrow-derived endothelial, and prostate stroma cells were investigated. Honokiol-induced activation of caspases was evaluated by Western blot and FACS analysis. To confirm the cytotoxicity of honokiol, mice bone was inoculated in vivo with androgen-independent PCa, C4-2 cells and the effects of honokiol and/or docetaxel on PCa growth in bone were evaluated. Daily honokiol (100 mg/kg) and/or weekly docetaxel (5 mg/kg) were injected intraperitoneally for 6 weeks. PCa growth in mouse bone was evaluated by radiography, serum prostate-specific antigen (PSA) and tissue immunohistochemistry. Honokiol induced apoptosis in all cell lines tested. In PCa cells honokiol induced apoptosis via the activation of caspases 3, 8, and 9 and the cleavage of poly-adenosine diphosphate ribose polymerase in a dose- and time-dependent manner. Honokiol was shown to inhibit the growth and depress serum PSA in mice harboring C4-2 xenografts in the skeleton and the combination with docetaxel showed additive effects that inhibited further growth without evidence of systemic toxicity. Immunohistochemical staining confirmed honokiol exhibited growth-inhibitory, apoptotic, and antiangiogenic effects on PCa xenografts. The combination of honokiol and low-dose docetaxel may be used to improve patient outcome in androgen-independent prostate cancer with bone metastasis. (c) 2007 American Cancer Society.

  1. Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.

    PubMed

    Misra, Uma Kant; Pizzo, Salvatore Vincent

    2015-04-10

    Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2-3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2-3-fold increase in lipogenesis as determined by 6-[(14)C]glucose or 1-[(14)C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [(14)CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Investigation of scattering coefficients and anisotropy factors of human cancerous and normal prostate tissues using Mie theory

    NASA Astrophysics Data System (ADS)

    Pu, Yang; Chen, Jun; Wang, Wubao

    2014-02-01

    The scattering coefficient, μs, the anisotropy factor, g, the scattering phase function, p(θ), and the angular dependence of scattering intensity distributions of human cancerous and normal prostate tissues were systematically investigated as a function of wavelength, scattering angle and scattering particle size using Mie theory and experimental parameters. The Matlab-based codes using Mie theory for both spherical and cylindrical models were developed and applied for studying the light propagation and the key scattering properties of the prostate tissues. The optical and structural parameters of tissue such as the index of refraction of cytoplasm, size of nuclei, and the diameter of the nucleoli for cancerous and normal human prostate tissues obtained from the previous biological, biomedical and bio-optic studies were used for Mie theory simulation and calculation. The wavelength dependence of scattering coefficient and anisotropy factor were investigated in the wide spectral range from 300 nm to 1200 nm. The scattering particle size dependence of μs, g, and scattering angular distributions were studied for cancerous and normal prostate tissues. The results show that cancerous prostate tissue containing larger size scattering particles has more contribution to the forward scattering in comparison with the normal prostate tissue. In addition to the conventional simulation model that approximately considers the scattering particle as sphere, the cylinder model which is more suitable for fiber-like tissue frame components such as collagen and elastin was used for developing a computation code to study angular dependence of scattering in prostate tissues. To the best of our knowledge, this is the first study to deal with both spherical and cylindrical scattering particles in prostate tissues.

  3. 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.

  4. Selenite Treatment Inhibits LAPC-4 Tumor Growth and Prostate-Specific Antigen Secretion in a Xenograft Model of Human Prostate Cancer

    SciTech Connect

    Bhattacharyya, Rumi S.; Husbeck, Bryan; Feldman, David; Knox, Susan J.

    2008-11-01

    Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an inorganic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-specific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-independent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle-treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer.

  5. Variations of Human DNA Polymerase Genes as Biomarkers of Prostate Cancer Progression

    DTIC Science & Technology

    2013-07-01

    heterogeneity at the androgen receptor locus in prostate tumors, Mutation Detection 2011 meeting, Human Genetics Society of Australasia, Santorini, Greece...Thermo Scientific). Blots were blocked by 5% non-fat dry milk in Tris-buffered saline-Tween 20 (0.1% Tween) and incubated with anti-His Tag...to create a single nucleotide gap. The mixture was incubated at 95 °C for 5 min, slow cooled to 50 °C over 30 min, and incubated at 50 °C for 20 min

  6. Assessment of Tumor Stiffness With Shear Wave Elastography in a Human Prostate Cancer Xenograft Implantation Model.

    PubMed

    Wang, Yiru; Yao, Binwei; Li, Hongfei; Zhang, Yan; Gao, Hanjing; Gao, Yabin; Peng, Ruiyun; Tang, Jie

    2017-05-01

    To investigate the stiffness of human prostate cancer in a xenograft implantation model using shear wave elastography and compare the pathologic features of tumors with varying elasticity. Human prostate cancer DU-145 cells were injected into 24 nude male mice. The mice were divided into 3 groups according to the time of transplantation (6, 8, and 10 weeks). The volume, elasticity, and Young modulus of tumors were recorded by 2-dimensional sonography and shear wave elastography. The tumors were collected for pathologic analyses: hematoxylin-eosin staining, Ponceau S, and aniline staining were used to stain collagen and elastic fibers, and picric acid-sirius red staining was used to indicate type I and III collagen. The area ratios of collagen I/III were calculated. The correlation between the Young modulus of the tumor and area ratio of collagen I/III were evaluated. Immunohistochemistry of vimentin and α-smooth muscle actin was performed. Nineteen tumors in 3 groups were collected. The volume and mean Young modulus increased with the time of transplantation. There were more collagen fibers in the stiff tumors, and there were significant differences in the area ratios of collagen I/III between groups 1 (mean ± SD, 0.50 ± 0.17) and 3 (1.97 ± 0.56; P < .01). The Young modulus of the tumors showed a very significant correlation with the area ratios of collagen I/III (r = 0.968; P < .05). The expression level of α-smooth muscle actin protein was higher in group 3 than in the other groups, but differences in vimentin expression were barely seen. Shear wave elastography is a novel useful technology for showing the elasticity of human prostate cancer xenograft implantation tumors. Collagen fibers, especially collagen type I, play a crucial role in the elasticity in the human prostate cancer xenograft implantation model. © 2017 by the American Institute of Ultrasound in Medicine.

  7. Echinophora platyloba DC (Apiaceae) crude extract induces apoptosis in human prostate adenocarcinoma cells (PC 3).

    PubMed

    Shahneh, Fatemeh Zare; Baradaran, Behzad; Majidi, Jafar; Babaloo, Zohreh

    2014-01-01

    Prostate cancer is the second leading malignancy worldwide and the second prominent cause of cancer-related deaths among men. Therefore, there is a serious necessity for finding advanced alternative therapeutic measures against this lethal malignancy. In this article, we report the cytotoxicity and the mechanism of cell death of the methanolic extract prepared from Echinophora platyloba DC plant against human prostate adenocarcinoma PC 3 cell line and Human Umbilical Vein Endothelial Cells HUVEC cell line. Cytotoxicity and viability of the methanolic extract were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and dye exclusion assay. Cell death enzyme-linked immunosorbent assay (ELISA) was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis and determine whether the mechanism involves induction of apoptosis or necrosis. The cell death was identified as apoptosis using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and DNA fragmentation gel electrophoresis. E. platyloba could decrease cell viability in malignant cells in a dose- and time-dependent manner. The IC50 values against PC 3 were determined as 236.136 ± 12.4, 143.400 ± 7.2, and 69.383 ± 1.29 μg/ml after 24, 36, and 48 h, respectively, but there was no significant activity in HUVEC normal cell (IC50 > 800 μg/ml). Morphological characterizations and DNA laddering assay showed that the methanolic extract treated cells displayed marked apoptotic characteristics such as nuclear fragmentation, appearance of apoptotic bodies, and DNA laddering fragment. Increase in an early apoptotic population was observed in a dose-dependent manner. PC 3 cell death elicited by the extract was found to be apoptotic in nature based a clear indication of TUNEL assay and gel electrophoresis DNA fragmentation, which is a hallmark of apoptosis. In summary, the E. platyloba extract attenuated the

  8. The Role of XMRV, a Novel Xenotropic Murine Retrovirus, in Human Prostate Cancers

    DTIC Science & Technology

    2011-05-01

    antiviral pathway from human prostate tumors. Proc Natl Acad Sci U S A 104:1655-60. 2. Dunn, G.P., K.C. Sheehan , L.J. Old, and R.D. Schreiber. 2005. IFN...sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A 5. Lombardi, V.C., F.W. Ruscetti...The views, opinions and/or findings contained in this report are those of the author( s ) and should not be construed as an official Department of

  9. HIV-1 enhancing effect of prostatic acid phosphatase peptides is reduced in human seminal plasma.

    PubMed

    Martellini, Julie A; Cole, Amy L; Svoboda, Pavel; Stuchlik, Olga; Chen, Li-Mei; Chai, Karl X; Gangrade, Bhushan K; Sørensen, Ole E; Pohl, Jan; Cole, Alexander M

    2011-01-20

    We recently reported that HIV-1 infection can be inhibited by innate antimicrobial components of human seminal plasma (SP). Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called "SEVI" and enhance HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP-derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1:200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity.

  10. Erythropoietin receptor expression in the human urogenital tract: immunolocalization in the prostate, neurovascular bundle and penis.

    PubMed

    Liu, Tongyun; Allaf, Mohamad E; Lagoda, Gwen; Burnett, Arthur L

    2007-11-01

    To investigate whether the erythropoietin (EPO) receptor is expressed in human periprostatic (including the neurovascular bundles) and penile tissues, and define its distribution in these tissues, as the administration of exogenous EPO in cavernous nerve injury promoted the recovery of erectile function in a rat model. Human prostate (six samples) and penile (two) tissue were collected and paraffin-embedded. Tissue was sectioned and processed for immunohistochemical studies using an antibody for the EPO receptor; immunolocalization was assessed using light microscopy. There was prominent staining for the EPO receptor in neuronal cell bodies of the periprostatic neurovascular bundles, and in the axons emanating from these ganglia. The glandular epithelium of the prostate also had weak staining. There was EPO receptor immunoreactivity in the penile specimens in the penile dorsal nerves, sinusoidal endothelium of the corpus cavernosum, and endothelial cells lining the dorsal veins and arteries. All slides processed with no primary antibody or blocking peptide showed no staining. EPO receptor expression was identified and localized in human penile tissues and in the periprostatic neurovascular bundles responsible for erectile function. This suggests a likely role for endogenous EPO within these tissues, and provides the rationale for its clinical use as a protective agent locally.

  11. Propionibacterium acnes inhibits FOXM1 and induces cell cycle alterations in human primary prostate cells.

    PubMed

    Sayanjali, Behnam; Christensen, Gitte J M; Al-Zeer, Munir A; Mollenkopf, Hans-Joachim; Meyer, Thomas F; Brüggemann, Holger

    2016-11-01

    Propionibacterium acnes has been detected in diseased human prostate tissue, and cell culture experiments suggest that the bacterium can establish a low-grade inflammation. Here, we investigated its impact on human primary prostate epithelial cells. Microarray analysis confirmed the inflammation-inducing capability of P. acnes but also showed deregulation of genes involved in the cell cycle. qPCR experiments showed that viable P. acnes downregulates a master regulator of cell cycle progression, FOXM1. Flow cytometry experiments revealed that P. acnes increases the number of cells in S-phase. We tested the hypothesis that a P. acnes-produced berninamycin-like thiopeptide is responsible for this effect, since it is related to the FOXM1 inhibitor siomycin. The thiopeptide biosynthesis gene cluster was strongly expressed; it is present in subtype IB of P. acnes, but absent from type IA, which is most abundant on human skin. A knock-out mutant lacking the gene encoding the berninamycin-like peptide precursor was unable to downregulate FOXM1 and to halt the cell cycle. Our study reveals a novel host cell-interacting activity of P. acnes.

  12. HIV-1 Enhancing Effect of Prostatic Acid Phosphatase Peptides Is Reduced in Human Seminal Plasma

    PubMed Central

    Martellini, Julie A.; Cole, Amy L.; Svoboda, Pavel; Stuchlik, Olga; Chen, Li-Mei; Chai, Karl X.; Gangrade, Bhushan K.; Sørensen, Ole E.; Pohl, Jan; Cole, Alexander M.

    2011-01-01

    We recently reported that HIV-1 infection can be inhibited by innate antimicrobial components of human seminal plasma (SP). Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called “SEVI” and enhance HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP-derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1∶200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity. PMID:21283773

  13. [Hyperplastic polyposis syndrome: phenotypic diversity and association to colorectal cancer].

    PubMed

    Navarro, Matilde; González, Sara; Iglesias, Silvia; Capellá, Gabriel; Rodríguez-Moranta, Francisco; Blanco, Ignacio

    2013-07-21

    Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorectal cáncer (CRC) and a family history. Its genetic basis is unknow. We describe individuals with HPS criteria from a series of families assessed in our Unit of Genetic Advice for colonic polyposis. Our objective is to identify the clinical characteristics of this syndrome. Retrospective study of 197 families with colonic polyposis (1998-2011), identifying patients with HPS criteria. To know the number of polyps, we took into account polypectomies and/or the histologic study of surgical samples. Polyps were classified into adenomas, serrated lesiones (HP and SA) and MP. Genetic studies revealed: microsatellite instability (MSI), MUTYH gene variants (p.Tyr165Cys, p.Gly382Asp and p.Glu396GlyfsX43) and APC gene. Eighteen individuals, with a median age of 51.1 years, had criteria of HPS (11M/7F). Number of HP varied between 14 and 100 coexisting with classical adenomas, SA and MP in 14 individuals (77.8%). Localization of polyps: ascending and descending colon in 13 individuals (72.2%) and only descending colon in 5 (27.8%). A CRC was detected in 10/18 (55.6%) patients, and 3 of them had a double CRC, a family history in 3 patients (16.7%) and a history of HPS in one. IMS was not detected in 8 CRC nor in 3 adenomas studied; we detected 2/13 heterozygous mutations in the MUTYH gene (p.Gly382Asp) and one variant with an unknown biological significance in the APC gene (p.Ser926Pro). The phenotypic variability of HPS difficults its identification, hence it is important to adhere to the clinical criteria established for its classification as well as to establish screening guidelines for CRC on the basis of its high incidence. Copyright © 2012 Elsevier Espa

  14. Contouring variability of human- and deformable-generated contours in radiotherapy for prostate cancer

    NASA Astrophysics Data System (ADS)

    Gardner, Stephen J.; Wen, Ning; Kim, Jinkoo; Liu, Chang; Pradhan, Deepak; Aref, Ibrahim; Cattaneo, Richard, II; Vance, Sean; Movsas, Benjamin; Chetty, Indrin J.; Elshaikh, Mohamed A.

    2015-06-01

    This study was designed to evaluate contouring variability of human-and deformable-generated contours on planning CT (PCT) and CBCT for ten patients with low-or intermediate-risk prostate cancer. For each patient in this study, five radiation oncologists contoured the prostate, bladder, and rectum, on one PCT dataset and five CBCT datasets. Consensus contours were generated using the STAPLE method in the CERR software package. Observer contours were compared to consensus contour, and contour metrics (Dice coefficient, Hausdorff distance, Contour Distance, Center-of-Mass [COM] Deviation) were calculated. In addition, the first day CBCT was registered to subsequent CBCT fractions (CBCTn: CBCT2-CBCT5) via B-spline Deformable Image Registration (DIR). Contours were transferred from CBCT1 to CBCTn via the deformation field, and contour metrics were calculated through comparison with consensus contours generated from human contour set. The average contour metrics for prostate contours on PCT and CBCT were as follows: Dice coefficient—0.892 (PCT), 0.872 (CBCT-Human), 0.824 (CBCT-Deformed); Hausdorff distance—4.75 mm (PCT), 5.22 mm (CBCT-Human), 5.94 mm (CBCT-Deformed); Contour Distance (overall contour)—1.41 mm (PCT), 1.66 mm (CBCT-Human), 2.30 mm (CBCT-Deformed); COM Deviation—2.01 mm (PCT), 2.78 mm (CBCT-Human), 3.45 mm (CBCT-Deformed). For human contours on PCT and CBCT, the difference in average Dice coefficient between PCT and CBCT (approx. 2%) and Hausdorff distance (approx. 0.5 mm) was small compared to the variation between observers for each patient (standard deviation in Dice coefficient of 5% and Hausdorff distance of 2.0 mm). However, additional contouring variation was found for the deformable-generated contours (approximately 5.0% decrease in Dice coefficient and 0.7 mm increase in Hausdorff distance relative to human-generated contours on CBCT). Though deformable contours provide a reasonable starting point for contouring on

  15. Animal models of human prostate cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee

    PubMed Central

    Ittmann, Michael; Huang, Jiaoti; Radaelli, Enrico; Martin, Philip; Signoretti, Sabina; Sullivan, Ruth; Simons, Brian W.; Ward, Jerrold M.; Robinson, Brian D.; Chu, Gerald C.; Loda, Massimo; Thomas, George; Borowsky, Alexander; Cardiff, Robert D.

    2013-01-01

    Animal models, particularly mouse models, play a central role in the study of the etiology, prevention and treatment of human prostate cancer (PCa). While tissue culture models are extremely useful in understanding the biology of PCa, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The NCI Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of PCa and make recommendations regarding the pathological analysis of these models. Over 40 different models with 439 samples were reviewed including genetically engineered mouse models, xenograft, rat and canine models. Numerous relevant models have been developed over the last 15 years and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histological manifestation of epithelial-mesenchymal transition. The significant progress in development of improved models of PCa has already accelerated our understanding the complex biology of PCa and promises to enhance development of new approaches to prevention, detection and treatment of this common malignancy. PMID:23610450

  16. Effects of dexamethasone on proliferation of and fibronectin synthesis by human primary prostatic stromal cells in vitro.

    PubMed

    Albrecht, M; Janssen, M; Konrad, L; Renneberg, H; Aumüller, G

    2002-02-01

    Glucocorticoids are anti inflammatory stress hormones and have been suggested to be involved in a large number of pathological processes. To test the effects of glucocorticoids on stromal prostatic cell growth and proliferation in vitro, the influence of a synthetic glucocorticoid (dexamethasone, dex) on recently established human primary cells from prostatic stroma (hPCPs) was analysed. The localization and distribution of the glucocorticoid receptor (GR) was investigated by immunohistochemistry. In addition, expression of the active isoform of the receptor (alpha-GR) was examined by reverse transcription PCR, and the effect of different doses of dex on proliferation of the stromal cells evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and amido black assays. alpha-GR mRNA was expressed by the hPCPs, and the GR protein was detected in the cytoplasm and nucleus of these cells. Incubating the cells with dex resulted in an enhanced cell proliferation that was mainly restricted to the fibroblasts. Moreover, fibronectin (FN) gene expression and secretion of the protein was increased by high doses of dex (> or = 10(-8) M), whereas low doses of dex (10(-10)M) showed no effect. Human prostatic stromal cells show sensitivity to dex in vitro, resulting in an increase in cell proliferation and FN synthesis. The authors assume that locally accumulating glucocorticoids can also influence the regulation of cell growth and extracellular matrix synthesis in the human prostate in vivo and may play a role in the pathologically altered prostate.

  17. First Evidence that Sika Deer (Cervus nippon) Velvet Antler Extract Suppresses Migration of Human Prostate Cancer Cells

    PubMed Central

    Tang, YuJiao; Jeon, Byong-Tae; Wang, Yanmei; Choi, Eun-Ju; Kim, Yon-Suk; Hwang, Jin-Woo; Park, Pyo-Jam; Moon, Sang Ho; Kim, Eun-Kyung

    2015-01-01

    Deer velvet antler (DVA) is one of the most popular medicines in China. Numerous studies have demonstrated that velvet antler possess biological effects. However, data regarding its anti-migration activity on prostate cancer is scarce. In this study, we investigated the inhibitory effect of top DVA (T-DVA) on the expression of prostate-specific antigen (PSA) and migration-related genes in the human prostate cancer cell, LNCaP. The T-DVA down-regulated the expression of PSA. In addition, the RadiusTM assay revealed that T-DVA inhibited the migration behavior of prostate cancer cells. Furthermore, the expression of matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) was also decreased with T-DVA. On the contrary, T-DVA increased the tissue inhibition of metalloproteinase (TIMP)-1 and (TIMP)-2. Taken together, our findings indicate that the T-DVA possesses anti-migration activity on prostate cancer cells. This is the first study of DVA to report the anti-migration activity on prostate cancer. PMID:26761873

  18. First Evidence that Sika Deer (Cervus nippon) Velvet Antler Extract Suppresses Migration of Human Prostate Cancer Cells.

    PubMed

    Tang, YuJiao; Jeon, Byong-Tae; Wang, Yanmei; Choi, Eun-Ju; Kim, Yon-Suk; Hwang, Jin-Woo; Park, Pyo-Jam; Moon, Sang Ho; Kim, Eun-Kyung

    2015-01-01

    Deer velvet antler (DVA) is one of the most popular medicines in China. Numerous studies have demonstrated that velvet antler possess biological effects. However, data regarding its anti-migration activity on prostate cancer is scarce. In this study, we investigated the inhibitory effect of top DVA (T-DVA) on the expression of prostate-specific antigen (PSA) and migration-related genes in the human prostate cancer cell, LNCaP. The T-DVA down-regulated the expression of PSA. In addition, the Radius(TM) assay revealed that T-DVA inhibited the migration behavior of prostate cancer cells. Furthermore, the expression of matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) was also decreased with T-DVA. On the contrary, T-DVA increased the tissue inhibition of metalloproteinase (TIMP)-1 and (TIMP)-2. Taken together, our findings indicate that the T-DVA possesses anti-migration activity on prostate cancer cells. This is the first study of DVA to report the anti-migration activity on prostate cancer.

  19. Expression of the human relaxin gene in the corpus luteum of the menstrual cycle and in the prostate.

    PubMed

    Ivell, R; Hunt, N; Khan-Dawood, F; Dawood, M Y

    1989-10-01

    DNA-RNA hybridization has been used to assess the presence of relaxin gene transcripts in human luteal tissues of pregnancy and the menstrual cycle, as well as in the human testis and prostate. The results imply a substantial capacity for hormone biosynthesis in the mid to late luteal phase of the ovary in non-pregnant women. In men the prostate has been shown also to express relaxin gene transcripts, though levels are low. The testis appears negative. The results suggest that functions for relaxin must be sought also outside pregnancy.

  20. Local steroid application for hyperplastic dystrophy of the vulva. Clinical and pathologic evaluation.

    PubMed

    Bergman, A; Karram, M; Bhatia, N N

    1988-06-01

    Fifteen women complaining of vulvar pruritus of at least three months' duration were evaluated clinically and noted to have white lesions of the vulva consistent with hyperplastic dystrophy. Histologic evaluation confirmed the diagnosis, and all the patients were treated with local application of halocidine cream and crotamiton cream. After six weeks of therapy a repeat clinical and histologic evaluation revealed 13 of the 15 patients to be completely relieved of the vulvar pruritus, and 12 of the 13 were histologically demonstrated to have complete reversal of the hyperplastic process to normal skin. The other two denied any improvement in their pruritus and were histologically noted to have persistence of the hyperplastic process. A good clinical and histologic correlation was noted following local steroid application in patients with histologically proven hyperplastic dystrophy.

  1. Evaluation of the chemopreventive potential of retinoids using a novel in vitro human prostate carcinogenesis model.

    PubMed

    Quader, S T; Bello-DeOcampo, D; Williams, D E; Kleinman, H K; Webber, M M

    2001-09-20

    The prevalence of prostatic intraepithelial neoplasia (PIN) and latent prostatic carcinoma, representing multiple steps in carcinogenesis and progression to invasive carcinoma, makes them relevant targets for prevention. A unique family of human prostate epithelial cell lines, which mimic steps in prostate carcinogenesis and progression, were used to evaluate the chemopreventive potential of all-trans-retinoic acid (RA) and N-(4-hydroxyphenyl)retinamide (4-HPR). The effects of RA and 4-HPR on anchorage-dependent growth of an immortalized, non-tumorigenic cell line RWPE-1 and two tumorigenic cell lines, WPE1-NB14 and WPE1-NB11, derived from RWPE-1 by exposure to N-methyl-N-nitrosourea (MNU), were examined. Both tumorigenic cell lines grow more rapidly than the parent RWPE-1 cell line in monolayer culture. Further, while RWPE-1 cells do not form colonies in agar, both tumorigenic cell lines do, with a colony forming efficiency (CFE) of 1.85 and 2.04% for WPE1-NB14 and WPE1-NB11 cells, respectively. Both RA and 4-HPR inhibited anchorage-dependent growth of all cell lines and anchorage-independent growth of WPE1-NB14 and WPE1-NB11 cells, in a dose-dependent manner, however, 10 times more RA than 4-HPR was required to produce the same effect. RWPE-1 cells are not invasive but WPE1-NB11 cells are significantly more invasive than WPE1-NB14 cells. Both RA and 4-HPR inhibited invasion in vitro by WPE1-NB11 and WPE1-NB14 cells where the more malignant WPE1-NB11 cells showed greater inhibition of invasion by 4-HPR than by RA. Overall, 4-HPR was more effective than RA in inhibiting growth and invasion but the response varied amongst the cell lines. These three cell lines mimic progressive steps in carcinogenesis and progression, from immortalized, non-tumorigenic RWPE-1 cells, to the less malignant WPE1-NB14 to the more malignant WPE1-NB11 cells, and provide powerful models for studies on secondary and tertiary prevention, i.e. promotion and progression stages, respectively

  2. Human Papilloma Virus Detection by INNOLiPA HPV in Prostate Tissue from Men of Northeast Mexico

    PubMed

    Dávila-Rodríguez, Martha I; Ignacio Morales, Cesar V; Aragón Tovar, Anel R; Olache Jimenez, Delia; Castelán Maldonado, Edmundo; Lara Miranda, Sandra; Cortés Gutiérrez, Elva I

    2016-11-01

    Background: Prostatic adenocarcinoma by Prosate cancer (PCa) is the most prevalent cancer and the second cause of cancer-related death among men in the Western world. Human papilloma virus (HPV) may be considered as a preventable risk factor. In this study, we assessed the frequencies of HPV infection in prostatic adenocarcinoma and benign prostatic hyperplasia (BPH) cases in Northeast Mexico. Materials and Methods: A total of 87 paraffin-embedded blocks (from 25 and 62 patients with definite diagnoses of BPH and adenocarcinoma, respectively) were selected and subjected to INNOLiPA HPV Genotyping to detect 28 high- and low-risk HPV types. The rates of infection were compared in the two studied groups. Results: INNOLiPA HPV demonstrated great sensitivity for HPV detection on paraffin-embedded tissue. Global prevalence was 14.9% (13/87). HPV infection was positive in 19.4% (12/62) of patients with adenocarcinoma and 4.0% (1/25) of patients with BPH. HPV-11, which is considered to be low risk, was more prevalent. Interestingly, one patient with BPH and six with prostate cancer showed examples considered to be high risk (HPV-18, -51, -52, and -66). Conclusion: A higher rate of HPV infection among Mexican patients with prostatic carcinoma than among those with BPH was observed. HPV infections may thus contribute to the risk of prostate cancer. Further studies are required to elucidate any roles of HPV infection in prostate disease in Mexico and the effect of prevention and treatment of HPV infection on prostatic adenocarcinoma. Creative Commons Attribution License

  3. Human Papilloma Virus Detection by INNOLiPA HPV in Prostate Tissue from Men of Northeast Mexico

    PubMed Central

    Rodriguez, Martha I Dávila; Morales, Cesar V Ignacio; Tovar, Anel R Aragón; Jimenez, Delia Olache; Maldonado, Edmundo Castelán; Miranda, Sandra Lara; Gutiérrez, Elva I Cortés

    2016-01-01

    Background: Prostatic adenocarcinoma by Prosate cancer (PCa) is the most prevalent cancer and the second cause of cancer-related death among men in the Western world. Human papilloma virus (HPV) may be considered as a preventable risk factor. In this study, we assessed the frequencies of HPV infection in prostatic adenocarcinoma and benign prostatic hyperplasia (BPH) cases in Northeast Mexico. Materials and Methods: A total of 87 paraffin-embedded blocks (from 25 and 62 patients with definite diagnoses of BPH and adenocarcinoma, respectively) were selected and subjected to INNOLiPA HPV Genotyping to detect 28 high- and low-risk HPV types. The rates of infection were compared in the two studied groups. Results: INNOLiPA HPV demonstrated great sensitivity for HPV detection on paraffin-embedded tissue. Global prevalence was 14.9% (13/87). HPV infection was positive in 19.4% (12/62) of patients with adenocarcinoma and 4.0% (1/25) of patients with BPH. HPV-11, which is considered to be low risk, was more prevalent. Interestingly, one patient with BPH and six with prostate cancer showed examples considered to be high risk (HPV-18, -51, -52, and -66). Conclusion: A higher rate of HPV infection among Mexican patients with prostatic carcinoma than among those with BPH was observed. HPV infections may thus contribute to the risk of prostate cancer. Further studies are required to elucidate any roles of HPV infection in prostate disease in Mexico and the effect of prevention and treatment of HPV infection on prostatic adenocarcinoma. PMID:28030912

  4. Development of an orthotopic model of human metastatic prostate cancer in the NOD-SCIDγ mouse (Mus musculus) anterior prostate.

    PubMed

    Cifuentes, Federico F; Valenzuela, Rodrigo H; Contreras, Héctor R; Castellón, Enrique A

    2015-10-01

    Prostate cancer is one of the most prevalent oncological diseases in males worldwide, and the mortalities resulting from this type of cancer are mainly due to metastasis. The most common models for the study of metastasis are transgenic and immunocompromised mice, which enable the study of the metastatic process in a controlled way by the injection of prostate cancer cells into the mice. In the present study, NOD-SCIDγ mice were injected orthotopically with PC3 cells in the anterior prostate in order to establish a metastatic model. The results demonstrated the development and growth of a primary tumor that preceded the formation of micrometastases in the lung, liver and pancreas, followed by macrometastases in the liver. This model adequately represents the dynamics of the metastatic process, and may be useful for novel therapeutic assays and post-surgical relapse studies.

  5. Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth

    PubMed Central

    Dauchy, Robert T; Hoffman, Aaron E; Wren-Dail, Melissa A; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Xiang, Shulin; Yuan, Lin; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Smith, Kara; Blask, David E

    2015-01-01

    Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462–484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake–metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities. PMID:26678364

  6. Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth.

    PubMed

    Dauchy, Robert T; Hoffman, Aaron E; Wren-Dail, Melissa A; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Xiang, Shulin; Yuan, Lin; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Smith, Kara; Blask, David E

    2015-12-01

    Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.

  7. The activation of OR51E1 causes growth suppression of human prostate cancer cells.

    PubMed

    Maßberg, Désirée; Jovancevic, Nikolina; Offermann, Anne; Simon, Annika; Baniahmad, Aria; Perner, Sven; Pungsrinont, Thanakorn; Luko, Katarina; Philippou, Stathis; Ubrig, Burkhard; Heiland, Markus; Weber, Lea; Altmüller, Janine; Becker, Christian; Gisselmann, Günter; Gelis, Lian; Hatt, Hanns

    2016-07-26

    The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

  8. Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer.

    PubMed

    Kurlender, Lisa; Yousef, George M; Memari, Nader; Robb, John-Desmond; Michael, Iacovos P; Borgoño, Carla; Katsaros, Dionyssios; Stephan, Carsten; Jung, Klaus; Diamandis, Eleftherios P

    2004-01-01

    The presence of more than one mRNA form is common among kallikrein genes. We identified an mRNA transcript of the human kallikrein gene 5 (KLK5), denoted KLK5 splice variant 1 (KLK5-SV1). This variant has a different 5'-splice site, but encodes the same protein as the classical KLK5 transcript. RT-PCR analysis of this variant transcript expression in 29 human tissues indicated highest expression in the cervix, salivary gland, kidney, mammary gland, and skin. Comparative analysis of the expression levels of KLK5-SV1, another splice variant named KLK5 splice variant 2 (KLK5-SV2), and the classical KLK5 form showed that out of all three mRNA transcripts, the classical form is predominantly expressed (found in more tissues and at higher expression levels) followed by KLK5-SV1. KLK5-SV1 is expressed at high levels in ovarian, pancreatic, breast and prostate cancer cell lines. KLK5-SV1 was also found to be expressed in 9/10 ovarian cancer tissues, but it was not found in one normal ovarian tissue tested. Hormonal regulation experiments suggest that KLK5-SV1 is regulated by steroid hormones in the BT-474 breast cancer cell line. Furthermore, this variant had significantly higher expression in normal prostate tissues compared to their matched cancer tissue counterparts. KLK5-SV1 may have clinical utility in various malignancies and should be further explored as a potential new biomarker for prostate and ovarian cancer.

  9. In vitro study on the vaporization ratio of 2-microm laser in human prostatic tissue.

    PubMed

    Yang, Yong; Sun, Dongchong; Wei, Zhitao; Xu, Feng; Hong, Baofa; Zhang, Xu

    2010-04-01

    In this study, the vaporization ratio of the 2-mum laser in the prostatic tissue with benign prostatic hyperplasia was examined in vitro, to explore a technique to estimate the clearance rate of prostatic tissue during the transurethral vaporesection of the prostate. A total of 9 fresh prostatic tissue specimens were obtained by open surgery and the wet weight of the prostatic tissue were measured immediately after the sample collection. Under the simulated conditions of transurethral vaporesection of the prostate by 2-microm laser, each prostate gland was completely vaporesected into fragments with a diameter of less than 1.0 cm in vitro. After the vaporesection, the whole fragments of prostatic tissue were collected and measured. Then the lost weight of prostatic tissue, the weight of the collected prostatic tissue and the ratio of the lost weight of prostatic tissue to the wet weight of the prostate glandular organ specimen were calculated. The correlation between the weight of collected prostatic tissue and the weight of the whole glandular organ was analyzed. All the experimental procedures were carried out by one operator. Wet weight of the prostatic gland specimen and the weight of the harvested prostatic tissues after the procedure were recorded. With respect to the wet weight of prostate gland specimen, the percentage of the weight of collected prostatic tissue was (34.45 + or - 1.51) %, and the percentage of the lost weight of prostatic tissue was (65.55 + or - 1.51)%. Satisfactory linear relationship was observed between the weight of collected prostatic tissue and the wet weight of prostate gland specimen [y = 3.245 x -6.475 (t=15.097, P=0.000)]. It is concluded that under the simulated conditions of transurethral vaporesection of the prostate by 2-mum laser, the vaporization ratio of prostatic tissue can be calculated on the basis of the weight of collected prostatic tissue, and thereby the clearance of prostatic tissue during the formal operation by 2

  10. [Screening and bioinformatics analysis of differentially expressed genes in hyperplastic scar].

    PubMed

    Hu, Yanghong; Hu, Yangliu; Liu, Dewu; Yu, Jianxing; Liu, Deming

    2014-06-01

    To screen differentially expressed genes in hyperplastic scar to explore the pathogenesis of hyperplastic scar and identify new therapeutic targets. Three pairs of surgical specimens of hyperplastic scar and adjacent normal skin tissues were collected to investigate the differentially expressed genes in hyperplastic scar using Agilent gene oligonucletide microarray and clustering analysis. DAVID Bioinformatics Resources 6.7 was used for GO analysis and pathway analysis. Distinctly different gene expression profiles were found between hyperplastic scar tissues and normal skin tissues. Compared with normal skin tissue, hyperplastic scar tissues showed 3142 up-regulated and 2984 down-regulated genes by two folds and 28 up-regulated and 44 down-regulated genes by 5 folds after repeating the experiment once; after repeating the experiment twice, 3004 genes were found up-regulated and 3038 down-regulated by 2 folds and 25 up-regulated and 38 down-regulated by 5 folds in hyperplastic scars. In all the 3 specimens, 1920 genes were up-regulated and 1912 down-regulated by 2 folds and 18 up-regulated and 29 down-regulated by 5 folds. The dysregulated genes in hyperplastic scar were involved in cell cycles, cell proliferation, immune response and cell adhesion (CDKN1C, CDKN2A, CTNNA3, COL6A3, and HOXB4) and in signaling pathway of focal adhesion, TGF-beta signaling pathway, p53 signaling pathway, cell cycle, and tumor-associated pathways (TGFβ1, CDKN1C, CDKN2A, CDC14A , ITGB6, and EGF).

  11. Comparison of quantum-dots- and fluorescein-isothiocyanate-based technology for detecting prostate-specific antigen expression in human prostate cancer.

    PubMed

    Ruan, Y; Yu, W; Cheng, F; Zhang, X; Rao, T; Xia, Y; Larré, S

    2011-06-01

    Quantum dots (QDs) are a new class of fluorescent labelling for biological and biomedical applications. In this study, the authors evaluated the sensitivity and stability of quantum-dots-based immunolabelling, in comparison with the conventional fluorescein-isothiocyanate-based immunolabelling (FITC), for detecting prostate-specific antigen (PSA) expression in human prostate cancer. The authors' data revealed that the two methods had similar sensitivity in differential display of the PSA expression correlated with tumour stage and grade (=0.88, p<0.001). Moreover, the intensity of QDs fluorescence remain stable for 10 days after conjugation to the PSA protein in 97% of the cases and more than 1 month in 92% of the cases, although the FITC fluorescence became undetectable after 6 min for all cases.

  12. Transcriptional responses to hyperplastic MRL signalling in Drosophila

    PubMed Central

    Dodgson, Lauren; Mason, David; Falciani, Francesco

    2017-01-01

    Recent work has implicated the actin cytoskeleton in tissue size control and tumourigenesis, but how changes in actin dynamics contribute to hyperplastic growth is still unclear. Overexpression of Pico, the only Drosophila Mig-10/RIAM/Lamellipodin adapter protein family member, has been linked to tissue overgrowth via its effect on the myocardin-related transcription factor (Mrtf), an F-actin sensor capable of activating serum response factor (SRF). Transcriptional changes induced by acute Mrtf/SRF signalling have been largely linked to actin biosynthesis and cytoskeletal regulation. However, by RNA profiling, we find that the common response to chronic mrtf and pico overexpression in wing discs was upregulation of ribosome protein and mitochondrial genes, which are conserved targets for Mrtf/SRF and are known growth drivers. Consistent with their ability to induce a common transcriptional response and activate SRF signalling in vitro, we found that both pico and mrtf stimulate expression of an SRF-responsive reporter gene in wing discs. In a functional genetic screen, we also identified deterin, which encodes Drosophila Survivin, as a putative Mrtf/SRF target that is necessary for pico-mediated tissue overgrowth by suppressing proliferation-associated cell death. Taken together, our findings raise the possibility that distinct targets of Mrtf/SRF may be transcriptionally induced depending on the duration of upstream signalling. PMID:28148822

  13. Lysyl hydroxylation in collagens from hyperplastic callus and embryonic bones.

    PubMed Central

    Lehmann, H W; Bodo, M; Frohn, C; Nerlich, A; Rimek, D; Notbohm, H; Müller, P K

    1992-01-01

    Tissue from two patients with osteogenesis imperfecta suffering from a hyperplastic callus was studied. Although collagen type I from the compact bone and the skin and fibroblast cultures of these patients showed normal lysyl hydroxylation, collagen types I, II, III and V from the callus tissue were markedly overhydroxylated. Furthermore, the overhydroxylation of lysine residues covered almost equally the entire alpha 1 (I) collagen chain, as demonstrated by the analysis of individual CNBr-derived peptides. In addition, collagen type I was isolated from femoral compact bone of 33 individuals who died between the 16th week of gestational age and 22 years. Lysyl hydroxylation rapidly decreased in both collagen alpha 1 (I) and alpha 2 (I) chains during fetal development, and only little in the postnatal period. The transient increase in lysyl hydroxylation and the involvement of various collagen types in callus tissue argue for a regulatory mechanism that may operate in bone repair and during fetal development. Images Fig. 1. Fig. 3. PMID:1546948

  14. Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer.

    PubMed

    Cai, Bing; Chen, Wei; Pan, Yue; Chen, Hongde; Zhang, Yirong; Weng, Zhiliang; Li, Yeping

    2017-07-01

    We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer. MiR-500 expression was assessed by qRT-PCR in prostate cancer cell lines and primary tumors. Cancer patients' clinicopathological factors and overall survival were analyzed according to endogenous miR-500 level. MiR-500 was downregulated in DU145 and VCaP cells. Its effect on prostate cancer proliferation, invasion in vitro, and tumorigenicity in vivo, were probed. Possible downstream target of miR-500, TFPI was assessed by luciferase assay and qRT-PCR in prostate cancer cells. In miR-500-downregulated DU145 and VCaP cells, TFPI was silenced to see whether it was directly involved in the regulation of miR-500 in prostate cancer. TFPI alone was either upregulated or downregulated in DU145 and VCaP cells. Their effect on prostate cancer development was further evaluated. MiR-500 is upregulated in both prostate cancer cells and primary tumors. In prostate cancer patients, high miR-500 expression is associated with poor prognosis and overall survival. In DU145 and VCaP cells, miR-500 downregulation inhibited cancer proliferation, invasion in vitro, and explant growth in vivo. TFPI was verified to be associated with miR-500 in prostate cancer. Downregulation of TFPI reversed anti-cancer effects of miR-500 downregulation in prostate cancer cells. However, neither TFPI upregulation nor downregulation alone had any functional impact on prostate cancer development. MiR-500 may be a potential biomarker and molecular target in prostate cancer. TFPI may conditionally regulate prostate cancer in miR-500-downregualted prostate cancer cells. © 2017 Wiley Periodicals, Inc.

  15. A Prospective Randomized Trial of Two Different Prostate Biopsy Schemes

    ClinicalTrials.gov

    2016-07-03

    Prostate Cancer; Local Anesthesia; Prostate-Specific Antigen/Blood; Biopsy/Methods; Image-guided Biopsy/Methods; Prostatic Neoplasms/Diagnosis; Prostate/Pathology; Prospective Studies; Humans; Male; Ultrasonography, Interventional/Methods

  16. Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas.

    PubMed

    Goldstein, Neal S; Bhanot, Punam; Odish, Eva; Hunter, Susan

    2003-06-01

    We compared hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas to incidental hyperplastic polyps to identify distinguishing morphologic criteria. The study group included 106 hyperplastic-like, nonadenomatous, serrated polyps, most from the ascending colon in 91 patients; the control group included 106 rectosigmoid hyperplastic polyps from 106 patients in whom adenocarcinoma did not develop. Study group polyps had an expanded crypt proliferative zone, a serrated architectural outline that became apparent in the basilar crypt regions, basilar crypt dilation, inverted crypts, and a predominance of dysmaturational crypts (crypts with minimal cell maturation). In contrast, control group polyps had a proliferative zone confined to the basal crypt region, serrated architecture that became apparent in the superficial crypt region, rare to no basilar crypt dilation, and rare or no dysmaturational crypts. Hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas had a distinctive constellation of morphologic features related to altered and decreased cell function and control that resulted in dysmaturational crypts. Dysmaturation constitutes a range of morphologic alterations, some of which overlap with incidental-type innocuous hyperplastic polyps. The morphologic features described herein provide initial guidelines to identify this potentially important subset of premalignant serrated-like polyps.

  17. Diffusion-weighted single-shot echo planar MR imaging of normal human prostate using different b values.

    PubMed

    Shi, Haojun; Kong, Xiangquan; Feng, Gansheng; Xu, Haibo; Liu, Dingxi; Yu, Qun

    2008-12-01

    This study examined the effect of different b values on diffusion-weighted MR imaging (DWI) of human prostate by using single-shot spin echo echo planar imaging (SE-EPI) sequences, observed the normal appearances and measured apparent diffusion coefficient (ADC) values in anatomical regions of normal prostate. Twenty-four healthy volunteers (mean age: 32 y) were studied by using a 1.5T system with a phased array surface multicoil. Two kinds of single-shot SE-EPI sequence were used to perform DWI in the prostate in volunteers, with five b values being 0, 30, 300, 500 to 1000 s/mm(2). The image quality with different imaging parameters was analyzed and the ADC values in anatomical regions of normal prostate were measured. DWI of prostate was successfully obtained in all volunteers. The images were of good quality, without artifacts containing pixels within the prostate. The contrast was good between the different anatomical regions of the prostatic gland, i.e., the peripheral zone (PZ), which exhibited higher signal intensity, and the central gland (CG). Signal intensity contrast was related to the magnitude of b values. The ADC values in PZ and CG were (1.27+/-0.22)x10(-3) mm(2)/s and (1.01+/-0.17)x10(-3) mm(2)/s, respectively. The ADC values were found to be significantly higher in PZ than in CG (P<0.05, paired t-test). Significant differences were found between the slice-selecting component and both the read-out and phase-encoding components of the ADC values. It is concluded that SE-EPI is a suitable DWI sequence for human prostate. The contrast between PZ and CG is good when b values are low, while the diffusion and ADC values are accurate when b values are high. ADC values are higher in PZ than in CG in normal prostate. Diffusional anisotropy is present in normal prostatic tissue.

  18. Gene Expression in Single Cells Isolated from the CWR-R1 Prostate Cancer Cell Line and Human Prostate Tissue Based on the Side Population Phenotype

    PubMed Central

    Gangavarapu, Kalyan J; Miller, Austin; Huss, Wendy J

    2016-01-01

    Defining biological signals at the single cell level can identify cancer initiating driver mutations. Techniques to isolate single cells such as microfluidics sorting and magnetic capturing systems have limitations such as: high cost, labor intense, and the requirement of a large number of cells. Therefore, the goal of our current study is to identify a cost and labor effective, reliable, and reproducible technique that allows single cell isolation for analysis to promote regular laboratory use, including standard reverse transcription PCR (RT-PCR). In the current study, we utilized single prostate cells isolated from the CWR-R1 prostate cancer cell line and human prostate clinical specimens, based on the ATP binding cassette (ABC) transporter efflux of dye cycle violet (DCV), side population assay. Expression of four genes: ABCG2; Aldehyde dehydrogenase1A1 (ALDH1A1); androgen receptor (AR); and embryonic stem cell marker, Oct-4, were determined. Results from the current study in the CWR-R1 cell line showed ABCG2 and ALDH1A1 gene expression in 67% of single side population cells and in 17% or 100% of non-side population cells respectively. Studies using single cells isolated from clinical specimens showed that the Oct-4 gene is detected in only 22% of single side population cells and in 78% of single non-side population cells. Whereas, AR gene expression is in 100% single side population and non-side population cells isolated from the same human prostate clinical specimen. These studies show that performing RT-PCR on single cells isolated by FACS can be successfully conducted to determine gene expression in single cells from cell lines and enzymatically digested tissue. While these studies provide a simple yes/no expression readout, the more sensitive quantitative RT-PCR would be able to provide even more information if necessary. PMID:27785389

  19. Anti-tumor activity of oxypeucedanin from Ostericum koreanum against human prostate carcinoma DU145 cells.

    PubMed

    Kang, Tae Jin; Lee, Sook Yeon; Singh, Rana P; Agarwal, Rajesh; Yim, Dong Sool

    2009-01-01

    Oxypeucedanin has been reported to have various biological activities. We investigated the efficacy of a coumarin compound, oxypeucedanin, from Ostericum koreanum against the human prostate carcinoma cell line DU145. Oxypeucedanin (C(16)H(14)O(5), mw: 286) was isolated through silica gel chromatography and characterized by NMR. The cells were treated with oxypeucedanin (25, 50, and 100 microM) for 24-72 hours, and cell growth and death were then assayed. The cell cycle progression and apoptotic effects were also assessed by western blotting. Treatment with oxypeucedanin inhibited cell growth and induced cell death in DU145 cells. Furthermore, oxypeucedanin-induced cell growth inhibition was associated with an increase in G2-M arrest in cell cycle progression in DU145 cells in a dose and time-dependent manner. G2-M arrest by oxypeucedanin was associated with decreased levels of cyclin A, cyclin B1, Cdc2, and pCdc2. Oxypeucedanin-induced cell death was associated with significant increases in apoptosis and cleaved caspase-3 and poly-(ADP-ribose) polymerase. These finding suggest a novel anticancer effect for oxypeucedanin, mediated via induction of G2-M cell cycle arrest and apoptosis in human prostate carcinoma DU145 cells.

  20. Inducible expression of cancer-testis antigens in human prostate cancer

    PubMed Central

    Heninger, Erika; Krueger, Timothy E.G.; Thiede, Stephanie M.; Sperger, Jamie M.; Byers, Brianna L.; Kircher, Madison R.; Kosoff, David; Yang, Bing; Jarrard, David F.; McNeel, Douglas G.; Lang, Joshua M.

    2016-01-01

    Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2′-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors. PMID:27769045

  1. Anticancer activity of some polyamine derivatives on human prostate and breast cancer cell lines.

    PubMed

    Szumilak, Marta; Galdyszynska, Malgorzata; Dominska, Kamila; Stanczak, Andrzej; Piastowska-Ciesielska, Agnieszka

    2017-01-01

    The aim of this study was to expand our knowledge about anticancer activity of some polyamine derivatives with quinoline or chromane as terminal moieties. Tested compounds were evaluated in vitro towards metastatic human prostate adenocarcinoma (PC3), human carcinoma (DU145) and mammary gland adenocarcinoma (MCF7) cell lines. Cell viability was estimated on the basis of mitochondrial metabolic activity using water-soluble tetrazolium WST1 to establish effective concentrations of the tested compounds under experimental conditions. Cytotoxic potential of polyamine derivatives was determined by the measurement of lactate dehydrogenase activity released from damaged cells, changes in mitochondrial membrane potential, the cell cycle distribution analysis and apoptosis assay. It was revealed that the tested polyamine derivatives differed markedly in their antiproliferative activity. Bischromane derivative 5a exhibited a rather cytostatic than cytotoxic effect on the tested cells, whereas quinoline derivative 3a caused changes in cell membrane integrity, inhibited cell cycle progression, as well as induced apoptosis of prostate and breast cancer cells which suggest its potential application in cancer therapy.

  2. Personalized Medicine Approaches in Prostate Cancer Employing Patient Derived 3D Organoids and Humanized Mice

    PubMed Central

    Bartucci, Monica; Ferrari, Anna C.; Kim, Isaac Yi; Ploss, Alexander; Yarmush, Martin; Sabaawy, Hatem E.

    2016-01-01

    Prostate cancer (PCa) is the most common malignancy and the second most common cause of cancer death in Western men. Despite its prevalence, PCa has proven very difficult to propagate in vitro. PCa represents a complex organ-like multicellular structure maintained by the dynamic interaction of tumoral cells with parenchymal stroma, endothelial and immune cells, and components of the extracellular matrix (ECM). The lack of PCa models that recapitulate this intricate system has hampered progress toward understanding disease progression and lackluster therapeutic responses. Tissue slices, monolayer cultures and genetically engineered mouse models (GEMM) fail to mimic the complexities of the PCa microenvironment or reproduce the diverse mechanisms of therapy resistance. Moreover, patient derived xenografts (PDXs) are expensive, time consuming, difficult to establish for prostate cancer, lack immune cell-tumor regulation, and often tumors undergo selective engraftments. Here, we describe an interdisciplinary approach using primary PCa and tumor initiating cells (TICs), three-dimensional (3D) tissue engineering, genetic and morphometric profiling, and humanized mice to generate patient-derived organoids for examining personalized therapeutic responses in vitro and in mice co-engrafted with a human immune system (HIS), employing adaptive T-cell- and chimeric antigen receptor- (CAR) immunotherapy. The development of patient specific therapies targeting the vulnerabilities of cancer, when combined with antiproliferative and immunotherapy approaches could help to achieve the full transformative power of cancer precision medicine. PMID:27446916

  3. Prostate Cancer Skeletal Metastases: Pathobiology and Interventions

    DTIC Science & Technology

    2005-02-01

    in higher levels in prostate carcinoma than in benign prostatic hyperplasia [35, 36], and is found in human metastatic lesions in bone [37]. However...compared to normal controls, benign prostatic hyperplasia , prostatitis, and localized or recurrent disease. In an animal model, prostate tumor cells...Malakouti S, Antar S, Kukreja S. Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia . Hum

  4. Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells

    SciTech Connect

    Li Hongzhen; Zhou Jianjun; Miki, Jun; Furusato, Bungo; Gu Yongpeng; Srivastava, Shiv; McLeod, David G.; Vogel, Jonathan C.; Rhim, Johng S.

    2008-01-01

    Understanding prostate stem cells may provide insight into the origin of prostate cancer. Primary cells have been cultured from human prostate tissue but they usually survive only 15-20 population doublings before undergoing senescence. We report here that RC-170N/h/clone 7 cells, a clonal cell line from hTERT-immortalized primary non-malignant tissue-derived human prostate epithelial cell line (RC170N/h), retain multipotent stem cell properties. The RC-170N/h/clone 7 cells expressed a human embryonic stem cell marker, Oct-4, and potential prostate epithelial stem cell markers, CD133, integrin {alpha}2{beta}1{sup hi} and CD44. The RC-170N/h/clone 7 cells proliferated in KGM and Dulbecco's Modified Eagle Medium with 10% fetal bovine serum and 5 {mu}g/ml insulin (DMEM + 10% FBS + Ins.) medium, and differentiated into epithelial stem cells that expressed epithelial cell markers, including CK5/14, CD44, p63 and cytokeratin 18 (CK18); as well as the mesenchymal cell markers, vimentin, desmin; the neuron and neuroendocrine cell marker, chromogranin A. Furthermore the RC170 N/h/clone 7 cells differentiated into multi tissues when transplanted into the sub-renal capsule and subcutaneously of NOD-SCID mice. The results indicate that RC170N/h/clone 7 cells retain the properties of multipotent stem cells and will be useful as a novel cell model for studying the mechanisms of human prostate stem cell differentiation and transformation.

  5. Alteration of glyoxalase genes expression in response to testosterone in LNCaP and PC3 human prostate cancer cells.

    PubMed

    Antognelli, Cinzia; Del Buono, Chiara; Baldracchini, Francesca; Talesa, Vincenzo; Cottini, Emanuele; Brancadoro, Celestino; Zucchi, Alessandro; Mearini, Ettore

    2007-12-01

    Glyoxalase system, a ubiquitous detoxification pathway protecting against cellular damage caused by potent cytotoxic metabolites, is involved in the regulation of cellular growth. Aberrations in the expression of glyoxalase genes in several human cancers have been reported. Recently, we described a possible regulatory effect by estrogens on glyoxalase genes in human breast cancer cell lines. This result, along with those ones regarding changes in glyoxalases activity and expression in other human hormone-regulated cancers, such as prostate cancer, has prompted us to investigate whether also androgens, whose functional role in prostate cancer pathogenesis is well known, could modulate glyoxalases gene expression. Therefore, we treated LNCaP androgen-responsive and PC3 androgen-independent human prostate cancer cell lines with testosterone at the concentrations of 1 nM and 100 nM. After a two days treatment, glyoxalases mRNA levels as well as cell proliferation were evaluated by real-time RT-PCR analysis and [3H]thymidine incorporation, respectively. Results pointed out that testosterone affects the expression of glyoxalase system genes and cell proliferation in a different manner in the two cell lines. The possibility that modulation of glyoxalase genes expression by testosterone is due to glyoxalases-mediated intracellular response mechanisms to the androgen-induced oxidative stress or to the presence of androgen response elements (ARE) in glyoxalase promoters are discussed. Knowledge regarding the regulation of glyoxalases by testosterone may provide insights into the importance of these enzymes in human prostate carcinomas in vivo.

  6. Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo.

    PubMed

    Landriscina, Matteo; Bagalà, Cinzia; Piscazzi, Annamaria; Schinzari, Giovanni; Quirino, Michela; Fabiano, Annarita; Bianchetti, Sara; Cassano, Alessandra; Sica, Gigliola; Barone, Carlo

    2009-05-15

    Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors. Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent phenotype (i.e., K5, EGFR1, EGF and VEGF-A). Furthermore, nevirapine down-regulated the growth of prostate carcinoma xenografts in athymic mice and induced a differentiated phenotype in vivo with increased K18 expression. Interestingly, the drug restored androgen signaling by enhancing the ability of tumor cells to respond to dihydrotestosterone stimulation and to the antiproliferative activity of the androgen receptor blocker bicalutamide. Finally, nevirapine pretreatment increased the susceptibility of tumor cells to docetaxel, by enhancing their ability to undergo apoptosis. These data suggest that nevirapine may be clinically tested in human hormone-refractory prostate carcinoma to restore the susceptibility to androgen deprivation therapy or to docetaxel. 2009 Wiley-Liss, Inc.

  7. Effects of a human plasma membrane-associated sialidase siRNA on prostate cancer invasion

    SciTech Connect

    Li, Xiaojie; Zhang, Ling; Shao, Yueting; Liang, Zuowen; Shao, Chen; Wang, Bo; Guo, Baofeng; Li, Na; Zhao, Xuejian; Li, Yang; Xu, Deqi

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer Neu3 is as one of the sialidases and regulates cell surface functions. Black-Right-Pointing-Pointer A Neu3-specific siRNA inhibited prostrate cancer cell invasion and migration. Black-Right-Pointing-Pointer The Neu3-specific siRNA inhibited prostate cancer metastasis in mice. Black-Right-Pointing-Pointer Targeting Neu3 may have utility for gene-based therapy of human cancer metastasis. -- Abstract: Human plasma membrane-associated sialidase (Neu3) is one of several sialidases that hydrolyze sialic acids in the terminal position of the carbohydrate groups of glycolipids and glycoproteins. Neu3 is mainly localized in plasma membranes and plays crucial roles in the regulation of cell surface functions. In this study, we investigated the effects and molecular mechanisms of Neu3 on cell invasion and migration in vivo and in vitro. Initially, we found that the levels of Neu3 expression were higher in prostate cancer tissues and cell lines than in normal prostate tissues based on RT-PCR and Western blotting analyses. We then applied a Neu3 siRNA approach to block Neu3 signaling using PC-3M cells as model cells. Transwell invasion assays and wound assays showed significantly decreased invasion and migration potential in the Neu3 siRNA-transfected cells. RT-PCR and Western blotting analyses revealed that Neu3 knockdown decreased the expressions of the matrix metalloproteinases MMP-2 and MMP-9. In vivo, mice injected with PC-3M cell tumors were evaluated by SPECT/CT to determine the presence of bone metastases. Mice treated with attenuated Salmonella carrying the Neu3 siRNA developed fewer bone metastases than mice treated with attenuated Salmonella carrying a control Scramble siRNA, attenuated Salmonella alone or PBS. The results for bone metastasis detection by pathology were consistent with the data obtained by SPECT/CT. Tumor blocks were evaluated by histochemical, RT-PCR and Western blotting analyses. The results revealed

  8. Xanthohumol impairs human prostate cancer cell growth and invasion and diminishes the incidence and progression of advanced tumors in TRAMP mice.

    PubMed

    Venè, Roberta; Benelli, Roberto; Minghelli, Simona; Astigiano, Simonetta; Tosetti, Francesca; Ferrari, Nicoletta

    2012-12-06

    Despite recent advances in understanding the biological basis of prostate cancer, management of the disease, especially in the phase resistant to androgen ablation, remains a significant challenge. The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention to prevent or eradicate prostate malignancies. In this study, we have used human hormone-resistant prostate cancer cells, DU145 and PC3, as an in vitro model to assess the efficacy of xanthohumol (XN) against cell growth, motility and invasion. We observed that treatment of prostate cancer cells with low micromolar doses of XN inhibits proliferation and modulates focal adhesion kinase (FAK) and AKT phosphorylation leading to reduced cell migration and invasion. Oxidative stress by increased production of reactive oxygen species (ROS) was associated with these effects. Transgenic adenocarcinoma of the mouse prostate (TRAMP) transgenic mice were used as an in vivo model of prostate adenocarcinoma. Oral gavage of XN, three times per week, beginning at 4 wks of age, induced a decrease in the average weight of the urogenital (UG) tract, delayed advanced tumor progression and inhibited the growth of poorly differentiated prostate carcinoma. The ability of XN to inhibit prostate cancer in vitro and in vivo suggests that XN may be a novel agent for the management of prostate cancer.

  9. Antiproliferative effect of polyphenols and sterols of virgin argan oil on human prostate cancer cell lines.

    PubMed

    Bennani, H; Drissi, A; Giton, F; Kheuang, L; Fiet, J; Adlouni, A

    2007-01-01

    The aim of our study has to evaluate the antiproliferative effect of polyphenols and sterols extracted from the virgin argan oil on three human prostatic cell lines (DU145, LNCaP, and PC3). Cytotoxicity, anti-proliferative effects and nuclear morphological changes of cells were analyzed after treatment with sterols and polyphenols. The results were compared to 2-methoxyestradiol (2ME(2)) as positive control. Polyphenols and sterols of virgin argan oil and 2ME(2) exhibited a dose-response cytotoxic effect and antiproliferative action on the three tested cell lines. The antiproliferative effect of polyphenols was similar for the DU145 and LNCaP cell lines; the GI(50) (defined as the concentration inhibiting growth by 50% in comparison with the control) was respectively 73 and 70microg/ml. The antiproliferative effect of sterols was 46 and 60microg/ml as GI(50) for the DU145 and LNCaP cell lines. For the PC3 cell line, the best antiproliferative effect was obtained by argan sterols with GI(50)=43microg/ml. On the other hand, the nuclear morphology analyses have shown an increased proportion of pro-apoptotic of nuclei in LNCaP cell treated with IC(50) of polyphenols or sterols compared to control cells. Our results show for the first time the antiproliferative and pro-apoptotic effects of polyphenols and sterols extracted from virgin argan oil and confirm the antiproliferative and pro-apoptotic effects of 2ME(2) on prostate cancer cell lines. These data suggest that argan oil may be interesting in the development of new strategies for prostate cancer prevention.

  10. Association of Human Development Index with global bladder, kidney, prostate and testis cancer incidence and mortality.

    PubMed

    Greiman, Alyssa K; Rosoff, James S; Prasad, Sandip M

    2017-05-08

    To describe contemporary worldwide age-standardized incidence and mortality rates for bladder, kidney, prostate and testis cancer and their association with development. We obtained gender-specific, age-standardized incidence and mortality rates for 184 countries and 16 major world regions from the GLOBOCAN 2012 database. We compared the mortality-to-incidence ratios (MIRs) at national and regional levels in males and females, and assessed the association with socio-economic development using the 2014 United Nations Human Development Index (HDI). Age-standardized incidence rates were 2.9 (bladder) to 7.4 (testis) times higher for genitourinary malignancies in more developed countries compared with less developed countries. Age-standardized mortality rates were 1.5-2.2 times higher in more vs less developed countries for prostate, bladder and kidney cancer, with no variation in mortality rates observed in testis cancer. There was a strong inverse relationship between HDI and MIR in testis (regression coefficient 1.65, R(2) = 0.78), prostate (regression coefficient -1.56, R(2) = 0.85), kidney (regression coefficient -1.34, R(2) = 0.74), and bladder cancer (regression coefficient -1.01, R(2) = 0.80). While incidence and mortality rates for genitourinary cancers vary widely throughout the world, the MIR is highest in less developed countries for all four major genitourinary malignancies. Further research is needed to understand whether differences in comorbidities, exposures, time to diagnosis, access to healthcare, diagnostic techniques or treatment options explain the observed inequalities in genitourinary cancer outcomes. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

  11. Cryosurgical technique: assessment of the fundamental variables using human prostate cancer model systems.

    PubMed

    Klossner, Daniel P; Robilotto, Anthony T; Clarke, Dominic M; VanBuskirk, Robert G; Baust, John M; Gage, Andrew A; Baust, John G

    2007-12-01

    Cryosurgery offers a promising therapeutic alternative for the treatment of prostate cancer. While often successful, complete cryoablation of cancerous tissues sometimes fails due to technical challenges. Factors such as the end temperature, cooling rate, duration of the freezing episode, and repetition of the freezing cycle have been reported to influence cryosurgical outcome. Accordingly, we investigated the effects of these variables in an in vitro prostate cancer model. Human prostate cancer PC-3 and LNCaP cultures were exposed to a range of sub-zero temperatures (-5 to -40 degrees C), and cells were thawed followed by return to 37 degrees C. Post-thaw viability was assessed using a variety of fluorescent probes including alamarBlue (metabolic activity), calceinAM (membrane integrity), and propidium iodide (necrosis). Freeze duration following ice nucleation was investigated using single and double freezing cycles (5, 10, and 20 min). The results demonstrated that lower freezing temperatures yielded greater cell death, and that LNCaP cells were more susceptible to freezing than PC-3 cells. At -15 degrees C, PC-3 yielded approximately 55% viability versus approximately 20% viability for LNCaP. Double freezing cycles were found to be more than twice as destructive versus a single freeze-thaw cycle. Both cell types experienced increased cell death when exposed to freezing temperatures for longer durations. When thawing rates were considered, passive (slower) thawing following freezing yielded greater cell death than active (faster) thawing. A 20% difference in viability between passive and active thawing was observed for PC-3 for a 10 min freeze. Finally, the results demonstrate that just reaching -40 degrees C in vitro may not be sufficient to obtain complete cell death. The data support the use of extended freeze times, multiple freeze-thaw cycles, and passive thawing to provide maximum cell destruction.

  12. Honokiol activates reactive oxygen species-mediated cytoprotective autophagy in human prostate cancer cells.

    PubMed

    Hahm, Eun-Ryeong; Sakao, Kozue; Singh, Shivendra V

    2014-09-01

    Honokiol (HNK), derived from the bark of an oriental medicinal plant (Magnolia officinalis), is a promising anticancer agent with preclinical in vitro (PC-3 and LNCaP cells) and in vivo (PC-3 xenografts) efficacy against prostate cancer. However, the mechanisms affecting anticancer response to HNK are not fully understood. Human (androgen-independent PC-3 and androgen-responsive LNCaP) and murine (Myc-CaP) prostate cancer cells, and PC-3 tumor xenografts were used for various assays. Autophagy was assessed by transmission electron microscopy, immunofluorescence (LC3 puncta), and immunoblotting (LC3BII detection). Cell viability was determined by trypan blue assay. Apoptosis was quantitated by DNA fragmentation detection and Annexin V/propidium iodide assay. Reactive oxygen species (ROS) were detected by electron paramagnetic resonance spectrometry and flow cytometric/microscopic analysis of MitoSOX red fluorescence. Exposure of PC-3, LNCaP, and Myc-CaP cells to pharmacologic doses of HNK resulted in autophagy induction. The PC-3 tumor xenografts from HNK-treated mice contained higher levels of LC3BII protein compared with control tumors. Cell viability inhibition and apoptosis induction resulting from HNK exposure were significantly augmented by pharmacological inhibition of autophagy using 3-methyladenine as well as RNA interference of autophagy regulator ATG5. HNK-mediated increase in levels of LC3BII protein was partially but markedly diminished in the presence of antioxidants, including N-acetylcysteine, polyethylene glycol-conjugated (PEG)-superoxide dismutase, and PEG-catalase. On the other hand, antioxidants had no impact on HNK-induced apoptosis. In conclusion, the present study demonstrates, for the first time, that HNK induces ROS-mediated cytoprotective autophagy in prostate cancer cells. © 2014 Wiley Periodicals, Inc.

  13. Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer

    PubMed Central

    Kim, Howard S.; Masko, Elizabeth M.; Poulton, Susan L.; Kennedy, Kelly M.; Pizzo, Salvatore V.; Dewhirst, Mark W.; Freedland, Stephen J.

    2012-01-01

    OBJECTIVES To determine if a no-carbohydrate ketogenic diet (NCKD) and lactate transporter inhibition can exert a synergistic effect on delaying prostate tumour growth in a xenograft mouse model of human prostate cancer. MATERIALS AND METHODS 120 nude athymic male mice (aged 6–8 weeks) were injected s.c. in the flank with 1.0 x 105 LAPC-4 prostate cancer cells. Mice were randomized to one of four treatment groups: Western diet (WD, 35% fat, 16% protein, 49% carbohydrate) and vehicle (Veh) treatment; WD and mono-carboxylate transporter-1 (MCT1) inhibition via α-cyano-4-hydroxycinnamate (CHC) delivered through a mini osmotic pump; NCKD (84% fat, 16% protein, 0% carbohydrate) plus Veh ; or NCKD and MCT1 inhibition. Mice were fed and weighed three times per week and feed was adjusted to maintain similar body weights. Tumour size was measured twice weekly and the combined effect of treatment was tested via Kruskal – Wallis analysis of all four groups. Independent effects of treatment (NCKD vs. WD and CHC vs. Veh) on tumour volume were tested using linear regression analysis. All mice were killed on Day 53 (conclusion of pump ejection), and serum and tumour sections were analysed for various markers. Again, combined and independent effects of treatment were tested using Kruskal – Wallis and linear regression analysis, respectively. RESULTS There were no significant differences in tumour volumes among the four groups (P=0.09). When testing the independent effects of treatment, NCKD was significantly associated with lower tumour volumes at the end of the experiment (P=0.026), while CHC administration was not (P=0.981). However, CHC was associated with increased necrotic fraction (P<0.001). CONCLUSIONS Differences in tumour volumes were observed only in comparisons between mice fed a NCKD and mice fed a WD. MCT1 inhibition did not have a significant effect on tumour volume, although it was associated with increased necrotic fraction. PMID:22394625

  14. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.

    PubMed

    Chen, Jayson X; Li, Guangxun; Wang, Hong; Liu, Anna; Lee, Mao-Jung; Reuhl, Kenneth; Suh, Nanjoo; Bosland, Maarten C; Yang, Chung S

    2016-02-01

    Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Human Prostate Cancer Cells Secrete Neuro-Protective Factors in Response to Cryotherapy

    PubMed Central

    Gupta, Seema; Varghese, Mini; Shareef, Mohammed M.; Ahmed, Mansoor M.

    2010-01-01

    Cryoablation is one of the established treatment modalities for prostate cancer management. Although, it is target specific, it may still lead to damage to the nerve fibers around the prostate tumor. In this study, by directly exposing the co-cultures of prostate cancer cells, PC-3 and Schwann cell-Dorsal Root Ganglion neuron (SC-DRG) to cryo-shock and by exposing SC-DRG to cryo-shock conditioned media (CSCM) obtained from PC-3 cells, robust neuro-protective effects were observed. Since this neuro-protective effect originated from cryotherapy-treated PC-3 cells, the presence of putative factors secreted by PC-3 cells in the medium following cryo-shock was analyzed. Using human cytokine antibody array analysis, differential release of cytokines in CSCM was observed with induced release of cytokines involved in neuro-protection like IL-1α, MIP-4, MIP-5, Leptin, IL-15 and ICAM-1 with simultaneous inhibition of TNFRI and TNFRII that are implicated in killing of nerve cells. Further, using Matrix Assisted Laser Desorption/Ionization-Time Of Flight (MALDI-TOF) sequencing, two proteins were identified namely, CypA (cyclophilin A) and NM23 (nonmetastatic protein 23) in the CSCM. CypA functions as a mediator of intracellular as well as extracellular neuro-protective mechanisms and NM23 has been implicated as a potential suppressor protein of tumor metastasis. Thus, this study revealed the presence of factors in CSCM that has the potential to protect normal neuronal cells and suppress metastasis. PMID:20401329

  16. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

    PubMed Central

    Chen, Jayson X.; Li, Guangxun; Wang, Hong; Liu, Anna; Lee, Mao-Jung; Reuhl, Kenneth; Suh, Nanjoo; Bosland, Maarten C.; Yang, Chung S.

    2015-01-01

    Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. PMID:26582657

  17. Visualization of early prostatic adenocarcinoma as a stem cell disease.

    PubMed

    Jiang, Maggie Y; Lee, Tammy L; Hao, Su-Shin; Mahooti, Sepi; Baird, Stephen M; Donoghue, Daniel J; Haas, Martin

    2016-11-15

    Prostate Cancer represents the second leading cause of cancer death among men in the United States, and the third leading cause of cancer death among men in Europe. We have previously shown that cells possessing Cancer Stem Cell (CSC) characteristics can be grown from human PrCa tissue harvested at the time of prostatectomy. However, the cellular origin of these CSCs was not previously known. In most cases, simple hematoxylin and eosin (H&E) stained sections are sufficient to make a definitive diagnosis of prostatic adenocarcinoma (PrCa) in needle biopsy samples. We utilized six different antibodies specific for stem cell antigens to examine paraffin sections of PrCa taken at the time of needle-biopsy diagnosis. These antisera were specific for CD44, CD133, ALDH7A1, LGR-5, Oct-4 and NANOG. We demonstrate specific staining of tumor cells with all six antisera specific for stem cell antigens. Some of these antibodies also react with cells of hyperplastic glands, but the patterns of reactivity differ from those of malignant glands. These findings demonstrate that at the time of diagnosis, PrCa consists of cells exhibiting properties of CSCs and consistent with the possibility that PrCa is a stem cell disease.

  18. Visualization of early prostatic adenocarcinoma as a stem cell disease

    PubMed Central

    Jiang, Maggie Y.; Lee, Tammy L.; Hao, Su-Shin; Mahooti, Sepi; Baird, Stephen M.; Donoghue, Daniel J.; Haas, Martin

    2016-01-01

    Prostate Cancer represents the second leading cause of cancer death among men in the United States, and the third leading cause of cancer death among men in Europe. We have previously shown that cells possessing Cancer Stem Cell (CSC) characteristics can be grown from human PrCa tissue harvested at the time of prostatectomy. However, the cellular origin of these CSCs was not previously known. In most cases, simple hematoxylin and eosin (H&E) stained sections are sufficient to make a definitive diagnosis of prostatic adenocarcinoma (PrCa) in needle biopsy samples. We utilized six different antibodies specific for stem cell antigens to examine paraffin sections of PrCa taken at the time of needle-biopsy diagnosis. These antisera were specific for CD44, CD133, ALDH7A1, LGR-5, Oct-4 and NANOG. We demonstrate specific staining of tumor cells with all six antisera specific for stem cell antigens. Some of these antibodies also react with cells of hyperplastic glands, but the patterns of reactivity differ from those of malignant glands. These findings demonstrate that at the time of diagnosis, PrCa consists of cells exhibiting properties of CSCs and consistent with the possibility that PrCa is a stem cell disease. PMID:27764770

  19. Directed Differentiation of Human Embryonic Stem Cells into Prostate Organoids In Vitro and its Perturbation by Low-Dose Bisphenol A Exposure.

    PubMed

    Calderon-Gierszal, Esther L; Prins, Gail S

    2015-01-01

    Studies using rodent and adult human prostate stem-progenitor cell models suggest that developmental exposure to the endocrine disruptor Bisphenol-A (BPA) can predispose to prostate carcinogenesis with aging. Unknown at present is whether the embryonic human prostate is equally susceptible to BPA during its natural developmental window. To address this unmet need, we herein report the construction of a pioneer in vitro human prostate developmental model to study the effects of BPA. The directed differentiation of human embryonic stem cells (hESC) into prostatic organoids in a spatial system was accomplished with precise temporal control of growth factors and steroids. Activin-induced definitive endoderm was driven to prostate specification by combined exposure to WNT10B and FGF10. Matrigel culture for 20-30 days in medium containing R-Spondin-1, Noggin, EGF, retinoic acid and testosterone was sufficient for mature prostate organoid development. Immunofluorescence and gene expression analysis confirmed that organoids exhibited cytodifferentiation and functional properties of the human prostate. Exposure to 1 nM or 10 nM BPA throughout differentiation culture disturbed early morphogenesis in a dose-dependent manner with 1 nM BPA increasing and 10 nM BPA reducing the number of branched structures formed. While differentiation of branched structures to mature organoids seemed largely unaffected by BPA exposure, the stem-like cell population increased, appearing as focal stem cell nests that have not properly entered lineage commitment rather than the rare isolated stem cells found in normally differentiated structures. These findings provide the first direct evidence that low-dose BPA exposure targets hESC and perturbs morphogenesis as the embryonic cells differentiate towards human prostate organoids, suggesting that the developing human prostate may be susceptible to disruption by in utero BPA exposures.

  20. Differential levels of human leukocyte antigen-class I, multidrug-resistance 1 and androgen receptor expressions in untreated prostate cancer cells: the robustness of prostate cancer.

    PubMed

    Homma, Shigenori; Komohara, Yoshihiro; Harada, Mamoru; Saya, Hideyuki; Todo, Satoru; Itoh, Kyogo; Noguchi, Masanori

    2007-08-01

    Tumors are highly robust and maintain their proliferative potential against a wide range of both host-defense mechanisms and anticancer therapies. One of the approaches to overcome cancer robustness could be combined therapy in which each modality imposes independent selective pressures against the acquired mutation of cancer. To develop such a therapy, it is crucial to understand the magnitude of acquired mutations. In this study, we investigated the levels of human leukocyte antigen (HLA)-class I, multidrug-resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostatectomy. The mean percentages of cancer cells expressing HLA-class I, MDR and AR among the 10 cancer samples were 41, 35 and 74%, respectively. In addition, double-staining of HLA and MDR revealed the four definite populations (HLA+/MDR+, HLA+/MDR-, HLA-/MDR+ and HLA-/MDR-) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22 and 38%, respectively. Similar results were obtained by double-staining of HLA and AR, except for 2 cases in which HLA-/AR+ cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutations, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.

  1. Hypermethylation of CpG islands in primary and metastatic human prostate cancer.

    PubMed

    Yegnasubramanian, Srinivasan; Kowalski, Jeanne; Gonzalgo, Mark L; Zahurak, Marianna; Piantadosi, Steven; Walsh, Patrick C; Bova, G Steven; De Marzo, Angelo M; Isaacs, William B; Nelson, William G

    2004-03-15

    Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.

  2. Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells

    SciTech Connect

    Srivastava, Janmejai K.; Gupta, Sanjay . E-mail: sanjay.gupta@case.edu

    2006-07-28

    One of the requisite of cancer chemopreventive agent is elimination of damaged or malignant cells through cell cycle inhibition or induction of apoptosis without affecting normal cells. In this study, employing normal human prostate epithelial cells (PrEC), virally transformed normal human prostate epithelial cells (PZ-HPV-7), and human prostate cancer cells (LNCaP, DU145, and PC-3), we evaluated the growth-inhibitory and apoptotic effects of tocotrienol-rich fraction (TRF) extracted from palm oil. TRF treatment to PrEC and PZ-HPV-7 resulted in almost identical growth-inhibitory responses of low magnitude. In sharp contrast, TRF treatment resulted in significant decreases in cell viability and colony formation in all three prostate cancer cell lines. The IC{sub 5} values after 24 h TRF treatment in LNCaP, PC-3, and DU145 cells were in the order 16.5, 17.5, and 22.0 {mu}g/ml. TRF treatment resulted in significant apoptosis in all the cell lines as evident from (i) DNA fragmentation (ii) fluorescence microscopy, and (iii) cell death detection ELISA, whereas the PrEC and PZ-HPV-7 cells did not undergo apoptosis, but showed modestly decreased cell viability only at a high dose of 80 {mu}g/ml. In cell cycle analysis, TRF (10-40 {mu}g/ml) resulted in a dose-dependent G0/G1 phase arrest and sub G1 accumulation in all three cancer cell lines but not in PZ-HPV-7 cells. These results suggest that the palm oil derivative TRF is capable of selectively inhibiting cellular proliferation and accelerating apoptotic events in prostate cancer cells. TRF offers significant promise as a chemopreventive and/or therapeutic agent against prostate cancer.

  3. HLA-A2-restricted cytotoxic T lymphocyte epitopes from human hepsin as novel targets for prostate cancer immunotherapy.

    PubMed

    Guo, J; Li, G; Tang, J; Cao, X-B; Zhou, Q-Y; Fan, Z-J; Zhu, B; Pan, X-H

    2013-09-01

    Hepsin is a type II transmembrane serine protease that is overexpressed in prostate cancer, and it is associated with prostate cancer cellular migration and invasion. Therefore, HPN is a biomarker for prostate cancer. CD8(+) T cells play an important role in tumour immunity. This study predicted and identified HLA-A2-restricted cytotoxic T lymphocyte (CTL) epitopes in human hepsin protein. HLA-A2-restricted CTL epitopes were identified using the following four-step procedure: (1) a computer program generated predicted epitopes from the amino acid sequence of human hepsin; (2) an HLA-A2-binding assay detected the affinity of the predicted epitopes to the HLA-A2 molecule; (3) the primary T cell response against the predicted epitopes was stimulated in vitro; and (4) the induced CTLs towards different types of hepsin- or HLA-A2-expressing prostate cancer cells were detected. Five candidate peptides were identified. The effectors that were induced by human hepsin epitopes containing residues 229 to 237 (Hpn229; GLQLGVQAV), 268 to 276 (Hpn268; PLTEYIQPV) and 191 to 199 (Hpn199; SLLSGDWVL) effectively lysed LNCaP prostate cancer cells that were hepsin-positive and HLA-A2 matched. These peptide-specific CTLs did not lyse normal liver cells with low hepsin levels. Hpn229, Hpn268 and Hpn199 increased the frequency of IFN-γ-producing T cells compared with the negative peptide. These results suggest that the Hpn229, Hpn268 and Hpn199 epitopes are novel HLA-A2-restricted CTL epitopes that are capable of inducing hepsin-specific CTLs in vitro. Hpn229, Hpn268 and Hpn199 peptide-based vaccines may be useful for immunotherapy in patients with prostate cancer.

  4. Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer.

    PubMed

    Okino, Steven T; Pookot, Deepa; Li, Long-Cheng; Zhao, Hong; Urakami, Shinji; Shiina, Hiroaki; Igawa, Mikio; Dahiya, Rajvir

    2006-08-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is a toxic environmental contaminant that works through dioxin response elements (DRE) to activate gene expression. We tested the hypothesis that cancer-related epigenetic changes suppress dioxin activation of the cytochrome P4501A1 (CYP1A1) gene. 5-Aza-2'-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation, increases TCDD-inducible CYP1A1 mRNA expression in cancerous LNCaP cells but not in noncancerous PWR-1E and RWPE-1 cells (all human prostate cell lines). Bisulfite DNA sequencing shows that the TCDD-responsive CYP1A1 enhancer is highly methylated in LNCaP cells but not in RWPE-1 cells. In vivo footprinting experiments reveal that unmethylated DRE sites do not bind protein in response to TCDD in LNCaP cells, whereas inducible DRE occupancy occurs in RWPE-1 cells. Pretreatment of LNCaP cells with 5-aza-CdR partially restores TCDD-inducible DRE occupancy, showing that DNA methylation indirectly suppresses DRE occupancy. Chromatin immunoprecipitation experiments reveal that LNCaP cells lack trimethyl histone H3 lysine 4, a mark of active genes, on the CYP1A1 regulatory region, whereas this histone modification is prevalent in PWR-1E and RWPE-1 cells. We also analyzed CYP1A1 enhancer methylation in human prostate tissue DNA. We do not detect CYP1A1 enhancer methylation in 30 DNA samples isolated from noncancerous prostate tissue. In contrast, 11 of 30 prostate tumor DNA samples have detectable CYP1A1 enhancer methylation, indicating that it is hypermethylated in prostate tumors. This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness.

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

    SciTech Connect

    Valiante, Salvatore; Liguori, Giovanna; Tafuri, Simona; Pavone, Luigi Michele; Campese, Roberto; Monaco, Roberto; Iachetta, Giuseppina; Assisi, Loredana; Mirabella, Nicola; Forte, Maurizio; Costagliola, Anna; Vittoria, Alfredo

    2015-09-04

    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 in 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.

  6. 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.

  7. Prostate biopsy

    MedlinePlus

    ... prostate biopsy; Fine needle biopsy of the prostate; Core biopsy of the prostate; Targeted prostate biopsy; Prostate ... to the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein ...

  8. Enrichment of prostate cancer stem-like cells from human prostate cancer cell lines by culture in serum-free medium and chemoradiotherapy.

    PubMed

    Wang, Lei; Huang, Xing; Zheng, Xinmin; Wang, Xinghuan; Li, Shiwen; Zhang, Lin; Yang, Zhonghua; Xia, Zhiping

    2013-01-01

    The discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. As CSCs demonstrate resistance to chemoradiation therapy relative to other cancer cells, this allows the enrichment of CSC populations by killing apoptosis-susceptible cancer cells. In this study, three commonly used human prostate cancer (PCa) cell lines (DU145, PC-3 and LNCaP) were examined for their expression of the putative stem cell markers CD133 and CD44 via flow cytometric analysis. Under normal culture conditions, CD133(+)/CD44(+) cells were only present in the DU145 cell line, and comprised only a minor percentage (0.1% ± 0.01%) of the total population. However, the proportion of these CD133(+)/CD44(+) prostate CSCs could be increased in these cell lines via culture in serum-free medium (SFM), or through chemotherapy or radiotherapy. Indeed, after culture in SFM, the proportion of CD133(+)/CD44(+) cells in DU145 and PC-3 had increased to 10.3% and 3.0%, respectively. Moreover, the proportion had increased to 9.8% enriched by chemotherapy and 3.5% by radiotherapy in DU145. Colony-formation tests, cell invasion assays, and tumor xenografts in BALB/c nude mice were used to evaluate the stem cell properties of CD133(+)/CD44(+) PCa cells that were isolated via fluorescence-activated cell sorting (FACS). CD133(+)/CD44(+) cells had an enhanced colony-formation capability and invasive ability in vitro, and displayed greater tumorigenic properties in vivo. These results demonstrate the presence of CD133(+)/CD44(+) prostate CSCs in established PCa cell lines and that populations of these cells can be enriched by culture in SFM or chemoradiotherapy. Finding novel therapies to override chemoradiation resistance in the prostate CSCs is the key to improve long-term results in PCa management.

  9. A human novel gene DERPC on 16q22.1 inhibits prostate tumor cell growth and its expression is decreased in prostate and renal tumors.

    PubMed Central

    Sun, Mei; Ma, Lanfeng; Xu, Linda; Li, Jia; Zhang, Wei; Petrovics, Gyorgy; Makarem, Mazen; Sesterhenn, Isabell; Zhang, Mei; Blanchette-Mackie, E. Joan; Moul, Judd; Srivastava, Shiv; Zou, Zhiqiang

    2002-01-01

    BACKGROUND: Deletion of chromosome 16q is frequently associated with diverse tumors. Numerous studies strongly suggest the presence of one or more tumor suppressor genes on chromosome 16q22 to 16qter including the widely studied cadherin gene family. However, the specific tumor suppressor genes residing in this region need better definition and characterization. MATERIAL AND METHODS: Standard molecular biology approaches have been used to clone and characterize the DERPC cDNA and its protein product on chromosome 16q22.1. Northern blotting was used to define the expression pattern in a multiple human tissue blots. DERPC expression was examined in multi-tumor array (Clontech, CA, USA) dot blot as well as in laser capture microdissection (LCM) derived prostate cancer (CaP) specimens by quantitative RT-PCR. Western blot analysis and a fluorescent microscopy were used to characterize the molecular size and the cellular location of green fluorescent protein (GFP)-tagged DERPC fusion proteins. A colony formation assay was conducted to determine the effects of DERPC expression on tumor cell growth. RESULTS: A novel gene DERPC (Decreased Expression in Renal and Prostate Cancer) was identified and characterized. DERPC encoded a strong basic, proline- and glycine-rich nuclear protein. DERPC was ubiquitously expressed, with abundant expression in kidney, skeletal muscle, testis, liver, ovary, and heart and moderate expression in prostate. DERPC expression was reduced in renal (67%) and prostate tumors (33%). Expression of DERPC has inhibitory potential on CaP cell growth. Further, overexpression of DERPC in LNCaP cells caused alterations of nuclear morphology. CONCLUSION: This study suggests that decreased expression of DERPC may be implicated in tumorigenesis of renal and CaPs. PMID:12477976

  10. [The clinicopathologic observation of eosinophilic hyperplastic lymphogranuloma in the orbit].

    PubMed

    Lin, Jin-Yong; Zhao, Hong; Yang, Zhen-Hai

    2011-05-01

    To improve the knowledge of the clinicopathologic features of eosinophilic hyperplastic lymphogranuloma (Kimura disease) in the orbit. It was a retrospective case series study. The clinical and pathological characteristic of 9 cases of Kimura disease from the pathology department of Tianjin Eye Hospital were reviewed, immunohistochemical staining was performed, including for CD20, D79a, CD3, CD45Ro, CD34, Ki67 and IgE. In the 9 cases, 7 cases were male, 2 cases were female; the age of onset were from 13 to 62 years, medium age was 25 years; 7 cases were simple, 2 case were bilateral orbit. These lesions occurred in the superior or superotemporal quadrant of the orbit and the majority of cases extended into deep orbital tissues, 6 cases involved the lacrimal gland, 5 case involved the lateral rectus muscle. The clinical features mainly included lid swelling, eye redness, proptosis and palpable mass, and the disease course ranged from 6 months to 15 years. 3 lymph node enlargements in the submandibular regions and 1 subcutaneous nodule on the bilateral elbow were found in one case. The documentation of peripheral-blood eosinophilia (11% - 14%) was found in 3 cases. The pathological characteristics of Kimura disease were lymphoid tissue hyperplasia with prominent lymphoid follicles, conspicuous eosinophils infiltration and capillary proliferation. Immunohistochemical study in our cases revealed B cells in lymphoid follicles and mostly T cells in the interfollicular regions. Kimura disease of orbit is an uncommon lymphoid hyperplasia with prominent eosinophils infiltration and capillary vessels, which commonly occur superotemporal quadrant of the orbit, easy to involve lacrimal gland and lateral rectus muscle.

  11. Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3

    PubMed Central

    ARAS, BEKIR; YERLIKAYA, AZMI

    2016-01-01

    Novel treatment modalities are urgently required for androgen-independent prostate cancer. In order to develop an alternative treatment for prostate cancer, the cytotoxic effects of the 26S proteasome inhibitor bortezomib, either alone or in combination with the two commonly used chemotherapeutic agents irinotecan and etoposide, on the human prostate cancer cell line PC-3 were evaluated in the present study. The PC-3 cell line was maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and treated with various doses of bortezomib, irinotecan, etoposide or their combinations. The growth inhibitory and cytotoxic effects were determined by water-soluble tetrazolium (WST)-1 assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or iCELLigence system. The combination index values were determined by the Chou-Talalay method. The half maximal inhibitory concentration (IC50) value of bortezomib on the PC-3 cell line was determined to be 53.4 nM by WST-1 assay, whereas the IC50 values of irinotecan and etoposide were determined to be 2.1 and 26.5 µM, respectively. These results suggest that the 26S proteasome inhibitor bortezomib is more potent, compared with irinotecan and etoposide, in the androgen-insensitive and tumor protein p53-null cell line PC-3. The combined effects of bortezomib+irinotecan and bortezomib+etoposide were also tested on PC-3 cells. The effect of bortezomib+irinotecan combination was not significantly different than that produced by either monotherapy, according to the results of iCELLigence system and MTT assay. However, 40 nM bortezomib+5 µM etoposide or 40 nM bortezomib+20 µM etoposide combinations were observed to be more effective than each drug tested alone. The results of the current study suggest that bortezomib and etoposide combination may be additionally evaluated in clinical trials for the treatment of hormone-refractory prostate cancer. PMID:27123085

  12. Development of peptide-containing nerves in the human fetal prostate gland.

    PubMed Central

    Jen, P Y; Dixon, J S

    1995-01-01

    Immunohistochemical methods were used to study the developing peptidergic innervation of the human fetal prostate gland in a series of specimens ranging in gestational age from 13 to 30 wk. The overall innervation of each specimen was visualised using protein gene product 9.5 (PGP), a general nerve marker. The onset and development of specific neuropeptide-containing subpopulations were investigated using antisera to neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), bombesin (BOM), somatostatin (SOM), leu-enkephalin (l-ENK) and met-enkephalin (m-ENK). In addition the occurrence and distribution of presumptive noradrenergic nerves was studied using antisera to dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH). At 13 wk numerous branching PGP-immunoreactive (-IR) nerves were observed in the capsule of the developing prostate gland and surrounding the preprostatic urethra but the remainder of the gland was devoid of nerves. The majority of nerves in the capsule contained D beta H and TH and were presumed to be noradrenergic in type while other nerves (in decreasing numbers) contained NPY, l-ENK, SP and CGRP. Nerves associated with the preprostatic urethra did not contain any of the neuropeptides under investigation. At 17 wk the density of nerves in the capsule had increased and occasional m-ENK-, VIP- and BOM-IR nerve fibres were also observed. In addition PGP, D beta H-, TH-, NPY- and l-ENK-IR nerves occurred in association with smooth muscle bundles which at 17 wk were present in the outer part of the gland. Occasional PGP-IR nerves were also present at the base of the epithelium forming some of the prostatic glands. At 23 wk some of the subepithelial nerves showed immunoreactivity for NPY, VIP or l-ENK. At 26 wk smooth muscle bundles occurred throughout the gland and were richly innervated by PGP, D beta H and TH-IR nerves while a less dense plexus was formed by NPY- and l

  13. Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

    PubMed

    Sáez, C; González-Baena, A C; Japón, M A; Giráldez, J; Segura, D I; Rodríguez-Vallejo, J M; González-Esteban, J; Miranda, G; Torrubia, F

    1999-07-01

    The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of b

  14. Galectin-3 regulates p21 stability in human prostate cancer cells

    PubMed Central

    Wang, Yi; Balan, Vitaly; Kho, Dhonghyo; Hogan, Victor; Nangia-Makker, Pratima; Raz, Avraham

    2014-01-01

    Galectin-3 (Gal-3) is a multifunctional protein involved in cancer through regulation of cell adhesion, cell growth, apoptosis, and metastasis, while p21 (Cip1/WAF1) is a negative regulator of the cell cycle, involved in apoptosis, transcription, DNA repair and metastasis. The results presented here demonstrate for the first time that the level of Gal-3 protein is associated with the level of p21 protein expression in human prostate cancer cells and the effects of Gal-3 on cell growth and apoptosis were reversed by modulating p21 expression level. Furthermore, Gal-3 regulates p21 expression at the post-translational level by stabilizing p21 protein via the carbohydrate-recognition domain (CRD). This is the first report suggesting a molecular function not yet described for Gal-3 as the regulator of p21 protein stability. This study provides a unique insight into the relationship of these two molecules during prostate cancer progression, and may provide a novel therapeutic target. PMID:23160381

  15. Synergistic cytotoxic effects of zoledronic acid and radiation in human prostate cancer and myeloma cell lines

    SciTech Connect

    Algur, Ece; Macklis, Roger M.; Haefeli, Urs O. . E-mail: uhafeli@interchange.ubc.ca

    2005-02-01

    Purpose: The clinical use of the potent bisphosphonate zoledronic acid has increased recently, especially for the treatment of bone metastases. Synergistic effects with chemotherapeutic agents (e.g., doxorubicin, paclitaxel) have been shown. It is not known whether similar synergistic effects exist with radiation. Methods and materials: IM-9 myeloma cells and C4-2 prostate cancer cells were treated with up to 200 {mu}M concentrations of zoledronic acid, irradiated with single doses of up to 1,000 cGy, or exposed to combinations of both treatments. Cell viability was then determined via yellow dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay and the affected fractions analyzed using the median effect principal, a method developed and validated by Chou and Talalay. Results: A statistically significant synergistic cytotoxic effect of the combination of zoledronic acid and radiation was documented. The extent of the effect was cell type-dependent, with the C4-2 cells showing a greater synergistic effect than the IM-9 cells. Conclusions: The combined use of zoledronic acid and radiotherapy shows enhanced in vitro cytotoxicity for two human prostate and myeloma cancer cell lines over that expected for a simple additive effect from each treatment alone. A clinical trial is under way to test this combination therapy.

  16. Calprotectin induces cell death in human prostate cancer cell (LNCaP) through survivin protein alteration.

    PubMed

    Sattari, Mina; Pazhang, Yaghub; Imani, Mehdi

    2014-11-01

    Calprotectin (CP), an abundant heterodimeric cytosolic protein of neutrophils, conveys a variety of functions such as tumor cell growth arrest and antimicrobial activity. We investigated CP activity and its possible apoptosis-inducing mechanism of action against an antiandrogen therapy-resistance prostate cancer cell line LNCaP. Cell viability and Annexin V FITC assays were performed in order to investigate its cell death activity and apoptosis, respectively. In order to address cell death inducing mechanism(s), immunocytochemistry and immunobloting analysis, reactive oxygen species (ROS) and nitric oxide (NO) measurements were performed. The effective concentration of CP against LNCaP promoting LNCaP cell death was 200 µg/mL. ROS and NO levels of cells remarkably were enhanced following treatment with 50 and 100 µg/mL of CP, respectively. Protein expression of anti-apoptotic protein survivin was significantly decreased after administration of tumor cells with CP. Our data indicate that CP regulates the LNCaP cells viability via survivin-mediated pathway and ROS and NO enhancement. Thus, inhibition of survivin expression, enhancement of ROS and NO level by CP or other similar pharmaceutical agents might be effective in lowering the malignant proliferation of human prostate cancer cells.

  17. Immunolocalisation of ghrelin and obestatin in human testis, seminal vesicles, prostate and spermatozoa.

    PubMed

    Moretti, E; Vindigni, C; Tripodi, S A; Mazzi, L; Nuti, R; Figura, N; Collodel, G

    2014-01-01

    The role of ghrelin and obestatin in male reproduction has not completely been clarified. We explored ghrelin and obestatin localisation in the male reproductive system. Polyclonal antibodies anti-ghrelin and anti-obestatin were used to detect the expression of these hormones in human testis, prostate and seminal vesicles by immunocytochemistry, while in ejaculated and swim up selected spermatozoa by immunofluorescence. Sertoli cells were positive for both peptides and Leydig cells for ghrelin; germ cells were negative for both hormones. Mild signals for ghrelin and obestatin were observed in rete testis; efferent ductules were the most immune reactive region for both peptides. Epididymis was moderately positive for ghrelin; vas deferens and seminal vesicles showed intense obestatin and moderate ghrelin labelling; prostate tissue expressed obestatin alone. Ejaculated and selected spermatozoa were positive for both peptides in different head and tail regions. This study confirms ghrelin localisation in Leydig and Sertoli cells; the finding that ghrelin is expressed in rete testis, epididymis, vas deferens and seminal vesicles is novel, as well as the localisation of obestatin in almost all tracts of the male reproductive system. This research could offer insights for stimulating other studies, particularly on the role of obestatin in sperm physiology, which is still obscure.

  18. Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer.

    PubMed

    Di Donato, Marzia; Cernera, Gustavo; Giovannelli, Pia; Galasso, Giovanni; Bilancio, Antonio; Migliaccio, Antimo; Castoria, Gabriella

    2017-12-05

    Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Delivery of retinoic acid to LNCap human prostate cancer cells using solid lipid nanoparticles.

    PubMed

    Akanda, Mushfiq H; Rai, Rajeev; Slipper, Ian J; Chowdhry, Babur Z; Lamprou, Dimitrios; Getti, Giulia; Douroumis, Dennis

    2015-09-30

    In this study retinoic acid (RTA) loaded solid lipid nanoparticles (SLNs) were optimized by tuning the process parameters (pressure/temperature) and using different lipids to develop nanodispersions with enhanced anticancer activity. The RTA-SLN dispersions were produced by high-pressure homogenization and characterized in terms of particle size, zeta potential, drug entrapment efficiency, stability, transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and in vitro drug release. Thermal and X-ray analysis showed the RTA to be in the amorphous state, whilst microscopic images revealed a spherical shape and uniform particle size distribution of the nanoparticles. Anticancer efficiency was evaluated by incubating RTA-SLNs with human prostate cancer (LNCap) cells, which demonstrated reduced cell viability with increased drug concentrations (9.53% at 200 ug/ml) while blank SLNs displayed negligible cytotoxicity. The cellular uptake of SLN showed localization within the cytoplasm of cells and flow cytometry analysis indicated an increase in the fraction of cells expressing early apoptotic markers, suggesting that the RTA loaded SLNs are able to induce apoptosis in LNCap cells. The RTA-SLN dispersions have the potential to be used for prostate anticancer treatment.

  20. Stromal-epithelial paracrine interactions in the neoplastic rat and human prostate.

    PubMed

    Djakiew, D; Pflug, B; Onoda, M

    1993-01-01

    Homotypic paracrine interactions in the rat and human prostate have been investigated using prostatic stromal cells and neoplastic epithelial cells (PA-III, rat; TSU-pr1, human). Secretory proteins prepared from each cell type were used to determine the dose dependent regulation of growth (DNA synthesis) of the corresponding homotypic responder cell, as determined by 3H-thymidine incorporation. PA-III secretory protein stimulated rat stromal cell proliferation by 1.8-fold. This stimulatory activity of PA-III protein on stromal cell proliferation was partially reduced (approximately 35%) by treatment with nerve growth factor (NGF) antibody, whereas neither acidic fibroblast growth factor (aFGF) antibody nor basic fibroblast growth factor (bFGF) antibody immunoneutralized the stimulatory activity of PA-III cell protein. In the corresponding opposite interaction, rat stromal cell protein modulated PA-III growth in a biphasic manner. At lower concentrations of stromal cell protein (1.25 micrograms/ml) PA-III cell growth was stimulated by 1.6-fold, whereas at higher concentrations of protein (100 micrograms/ml) PA-III cell growth was inhibited to 60%. Treatment of the stromal cell protein (1.25 micrograms/ml and 100 micrograms/ml) with NGF antibody reduced PA-III cell relative growth to approximately 30% and 5%, respectively. bFGF antibody treatment of stromal cell protein at 1.25 micrograms/ml did not influence relative growth, whereas bFGF antibody treatment of 100 micrograms/ml stromal cell protein reduced relative growth by an additional 40%. Treatment of the stromal cell protein (1.25 micrograms/ml and 100 micrograms/ml) with aFGF antibodies reduced relative growth from that observed at these two protein concentrations by approximately 50% in both cases. Human epithelial TSU-pr1 protein stimulated human stromal cell proliferation approximately 1.7-fold. Treatment of TSU-pr1 protein with NGF antibody resulted in stimulation of human stromal cell proliferation (4

  1. Responsiveness of human prostate carcinoma bone tumors to interleukin-2 therapy in a mouse xenograft tumor model.

    PubMed

    Kocheril, S V; Grignon, D J; Wang, C Y; Maughan, R L; Montecillo, E J; Talati, B; Tekyi-Mensah, S; Pontes, J e; Hillman, G G

    1999-01-01

    We have tested an immunotherapy approach for the treatment of metastatic prostate carcinoma using a bone tumor model. Human PC-3 prostate carcinoma tumor cells were heterotransplanted into the femur cavity of athymic Balb/c nude mice. Tumor cells replaced marrow cells in the bone cavity, invaded adjacent bone and muscle tissues, and formed a palpable tumor at the hip joint. PC-3/IF cell lines, generated from bone tumors by serial in vivo passages, grew with faster kinetics in the femur and metastasized to inguinal lymph nodes. Established tumors were treated with systemic interleukin-2 (IL-2) injections. IL-2 significantly inhibited the formation of palpable tumors and prolonged mouse survival at nontoxic low doses. Histologically IL-2 caused vascular damage and infiltration of polymorphonuclear cells and lymphocytes in the tumor as well as necrotic areas with apoptotic cells. These findings suggest destruction of tumor cells by systemic IL-2 therapy and IL-2 responsiveness of prostate carcinoma bone tumors.

  2. No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses.

    PubMed

    Groom, Harriet C T; Warren, Anne Y; Neal, David E; Bishop, Kate N

    2012-01-01

    The prevalence of specific infections in UK prostate cancer patients was investigated. Serum from 84 patients and 62 controls was tested for neutralisation of xenotropic murine leukaemia virus-related virus (XMRV) Envelope. No reactivity was found in the patient samples. In addition, a further 100 prostate DNA samples were tested for XMRV, BK virus, Trichomonas vaginalis and human papilloma viruses by nucleic acid detection techniques. Despite demonstrating DNA integrity and assay sensitivity, we failed to detect the presence of any of these agents in DNA samples, bar one sample that was weakly positive for HPV16. Therefore we conclude that these infections are absent in this typical cohort of men with prostate cancer.

  3. Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

    PubMed Central

    Yue, Shuhua; Li, Junjie; Lee, Seung-Young; Lee, Hyeon Jeong; Shao, Tian; Song, Bing; Cheng, Liang; Masterson, Timothy A.; Liu, Xiaoqi; Ratliff, Timothy L.; Cheng, Ji-Xin

    2014-01-01

    Summary Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism. PMID:24606897

  4. Cytosine deaminase-expressing human neural stem cells inhibit tumor growth in prostate cancer-bearing mice.

    PubMed

    Lee, Hong Jun; Doo, Seung Whan; Kim, Dae Hong; Cha, Young Joo; Kim, Jae Heon; Song, Yun Seob; Kim, Seung U

    2013-07-10

    Prostate cancer is the most common malignancy among men. Prostate cancer-related deaths are largely attributable to the development of hormone resistance in the tumor. No effective chemotherapy has yet been developed for advanced prostate cancer. It is desirable if a drug can be delivered directly and specifically to prostate cancer cells. Stem cells have selective migration ability toward cancer cells and therapeutic genes can be easily transduced into stem cells. In one form of gene therapy for cancer, the stem cells carry a gene encoding an enzyme that transforms an inert prodrug into a toxic product. Cytosine deaminase (CD) transforms the pro-drug 5-fluorocytosine into highly cytotoxic 5-fluorouracil (5-FU). The migration of the genetically modified stem cells was monitored by molecular magnetic resonance imaging, after labeling the stem cells with fluorescent magnetic nanoparticles (MNPs). Human neural stem cells encoding CD (HB1.F3.CD) were prepared and labeled with MNP. In tumor-bearing C57B mice, systemically transplanted HB1.F3.CD stem cells migrated toward the tumor and in combination with prodrug 5-FC, the volume of tumor implant was significantly reduced. These findings may contribute to development of a new selective chemotherapeutic strategy against prostate cancer.

  5. Loss of Nkx3.1 expression in the transgenic adenocarcinoma of mouse prostate model.

    PubMed

    Bethel, Carlise R; Bieberich, Charles J

    2007-12-01

    The transgenic adenocarcinoma of mouse prostate (TRAMP) model has been extensively characterized at the histological and molecular levels, and has been shown to mimic significant features of human prostate cancer. However, the status of Nkx3.1 expression in the TRAMP model has not been elucidated. Immunohistochemical analyses were performed using dorsal, lateral, and ventral prostate (VP) lobes from ages 6 to 30 weeks. Quantitative RT-PCR analyses were performed to determine relative mRNA expression. Heterogeneous loss of Nkx3.1 was observed in hyperplastic lesions of the ventral, dorsal, and lateral lobes. At 6 weeks of age, the ventral lobe displayed profound loss of Nkx3.1. Diminished Nkx3.1 protein was observed in well- to moderately-differentiated cancer lesions of all lobes. Poorly differentiated (PD) tumors stained negatively for Nkx3.1. Quantitative RT-PCR analyses revealed the presence of Nkx3.1 mRNA in each lobe at all ages, albeit reduced to variable levels. These data suggest that disease progression in the TRAMP model may be driven by loss of function of Nkx3.1, in addition to p53 and Rb. Lobe-specific disease progression in the TRAMP model correlates with the reduction of Nkx3.1 protein. Regulation of Nkx3.1 expression during tumorigenesis appears to occur by post-transcriptional and post-translational mechanisms.

  6. Exploiting Novel Polyamine Regulatory Responses to a Therapeutic Advantage in Human Prostatic Carcinoma: A Preclinical Study (Prostate)

    DTIC Science & Technology

    1999-09-01

    Ph.D. CONTRACTING ORGANIZATION: Roswell Park Cancer Institute. Elm & Carlton Streets Buffalo , New York 14263 REPORT DATE: September 1999 TYPE OF...ORGANIZATION Roswell Park Cancer Institute REPORT NUMBER Elm & Carlton Streets Buffalo , New York 14263 e-mail: Porter@sc3101 .med.buffalo.edu 9. SPONSORING...growth, the gland produces massive quantities for export into semen . It might, therefore, be expected that prostatic tumors could exhibit unique polyamine

  7. Expression of IL-17A, E, and F and their receptors in human prostatic cancer: Comparison with benign prostatic hyperplasia.

    PubMed

    Liu, Yanbo; Zhao, Xiaohui; Sun, Xuemei; Li, Yongmei; Wang, Zhenjiang; Jiang, Jing; Han, Huiming; Shen, Weigao; Corrigan, Chris J; Sun, Ying

    2015-12-01

    Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are the most common urological diseases in elderly men. Although studies suggest the cytokine family might be associated with BPH and PCa, there has been no systematic comparisons of expression of IL-17A, E, F and their receptors, infiltration of inflammatory cells, and changes in structural cells in PCa and BPH. Immunohistochemistry was employed to evaluate immunoreactivity for IL-17A, E, F and their receptors IL-17RA, IL-17BR, and IL-17CR, infiltration of inflammatory cells, and changes in structural cells including endothelial cells, fibroblasts, and smooth muscle cells in prostate tissues from subjects with PCa or BPH as well as controls. Immunostaining showed that expression of immunoreactivity for IL-17A, IL-17RA, IL-17E, and IL-17F was significantly elevated in prostatic tissue from BPH and PCa compared with that in controls, which was accompanied by increased numbers of infiltrating inflammatory cells and CD31(+) blood vessels. Compared with BPH, PCa was characterized by reduced immunoreactivity for IL-17BR and reduced numbers of CD68(+) macrophages, fibroblasts, and smooth muscle cells, although there was a trend for these changes to correlate with disease severity in both PCa and BPH. Our data are compatible with hypothesis that IL-17A acting through IL-17RA, but not IL-17CR contribute to the pathogenesis of BPH and PCa. In contrast, IL-17E interacting with the IL-17BR might have an anti-tumor effect. © 2015 Wiley Periodicals, Inc.

  8. Bik reduces hyperplastic cells by increasing Bak and activating DAPk1 to juxtapose ER and mitochondria.

    PubMed

    Mebratu, Yohannes A; Leyva-Baca, Ivan; Wathelet, Marc G; Lacey, Neal; Chand, Hitendra S; Choi, Augustine M K; Tesfaigzi, Yohannes

    2017-10-06

    Bik reduces hyperplastic epithelial cells by releasing calcium from endoplasmic reticulum stores and causing apoptosis, but the detailed mechanisms are not known. Here we report that Bik dissociates the Bak/Bcl-2 complex to enrich for ER-associated Bak and interacts with the kinase domain of DAPk1 to form Bik-DAPk1-ERK1/2-Bak complex. Bik also disrupts the Bcl2-IP3R interaction to cause ER Ca(2+) release. The ER-associated Bak interacts with the kinase and calmodulin domains of DAPk1 to increase the contact sites of ER and mitochondria, and facilitate ER Ca(2+) uptake by mitochondria. Although the Bik BH3 helix was sufficient to enrich for ER-Bak and elicit ER Ca(2+) release, Bik-induced mitochondrial Ca(2+) uptake is blocked with reduced Bak levels. Further, the Bik-derived peptide reduces allergen- and cigarette smoke-induced mucous cell hyperplasia in mice and in differentiated primary human airway epithelial cultures. Therefore, Bik peptides may have therapeutic potential in airway diseases associated with chronic mucous hypersecretion.Bcl-2 interacting killer (Bik) decreases airway epithelial hyperplasia via apoptosis mediated by calcium release from the endoplasmic reticulum (ER), but the mechanism is unclear. Here the authors show that Bik promotes Bak enrichment at the ER to tether mitochondria for efficient calcium transfer.

  9. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer

    DOE PAGES

    Xu, Weidong; Neill, Thomas; Yang, Yuefeng; ...

    2014-12-11

    In an effort to develop a new therapy for prostate cancer bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β- catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels, and inhibited tumor cell migration. To examine the anti-tumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle tomore » establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum TRACP 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia, and an increase in the animal survival. Finally, based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for prostate cancer bone metastasis.« less

  10. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer

    SciTech Connect

    Xu, Weidong; Neill, Thomas; Yang, Yuefeng; Hu, Zebin; Cleveland, Elyse; Wu, Ying; Hutten, Ryan; Xiao, Xianghui; Stock, Stuart R.; Shevrin, Daniel; Kaul, Karen; Brendler, Charles; Iozzo, Renato V.; Seth, Prem

    2014-12-11

    In an effort to develop a new therapy for prostate cancer bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β- catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels, and inhibited tumor cell migration. To examine the anti-tumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum TRACP 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia, and an increase in the animal survival. Finally, based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for prostate cancer bone metastasis.

  11. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer

    PubMed Central

    Xu, Weidong; Neill, Thomas; Yang, Yuefeng; Hu, Zebin; Cleveland, Elyse; Wu, Ying; Hutten, Ryan; Xiao, Xianghui; Stock, Stuart R.; Shevrin, Daniel; Kaul, Karen; Brendler, Charles; Iozzo, Renato V.; Seth, Prem

    2014-01-01

    In an effort to develop a new therapy for prostate cancer bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels, and inhibited tumor cell migration. To examine the anti-tumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum TRACP 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia, and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for prostate cancer bone metastasis. PMID:25503693

  12. 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

  13. Exploiting the Innate Antitumor Activity of Human Gamma-Delta T-Cells for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2005-04-01

    Manassas, Vir- that the majority of ex vivo, expanded, apoptosis resistant ginia) and the normal human keratinocyte cell line HaCat ŗ ’y-T cells expressed...provided the HaCat cell line . Blood, 102: 200, 2003 10. Ottones, F., Liautard, J., Gross, A., Rabenoelina, F., Liautard, REFERENCES J. P. and Favero...against human prostate cancer cell lines . Purpose and scope: The aims of this project are, 1) to more precisely characterize the extent and breadth

  14. Ca²⁺ Movement Induced by Deltamethrin in PC3 Human Prostate Cancer Cells.

    PubMed

    Lee, Hai-Hsiang; Chou, Chiang-Ting; Liang, Wei-Zhe; Chen, Wei-Chuan; Wang, Jue-Long; Yeh, Jeng-Hsien; Kuo, Chun-Chi; Shieh, Pochuen; Kuo, Daih-Huang; Chen, Fu-An; Jan, Chung-Ren

    2016-06-30

    This study explored the effect of deltamethrin, a pesticide, on intracellular free Ca²⁺ concentration ([Ca²⁺]i) in PC3 human prostate cancer cells. Deltamethrin at concentrations between 5 μM and 20 μM evoked [Ca²⁺]i rises in a concentration-dependent manner. This Ca²⁺ signal was inhibited by 22% by removal of extracellular Ca²⁺. Nifedipine, econazole, and SKF96365 also inhibited the Ca²⁺ signal. Treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) in Ca²⁺-free medium nearly abolished deltamethrin-induced [Ca²⁺]i rises. Treatment with deltamethrin also inhibited most of BHQ-induced [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter deltamethrin-evoked [Ca²⁺]i rises. Deltamethrin killed cells at concentrations of 20-100 μM in a concentration-dependent fashion. Chelation of cytosolic Ca²⁺ with 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) did not prevent deltamethrin's cytotoxicity. Together, in PC3 human prostate cancer cells, deltamethrin induced [Ca²⁺]i rises that involved Ca²⁺ entry through store-operated Ca²⁺ channels and PLC-independent Ca²⁺ release from the endoplasmic reticulum. Deltamethrin induced cytotoxicity in a Ca²⁺-independent manner.

  15. The natural flavonoid apigenin sensitizes human CD44(+) prostate cancer stem cells to cisplatin therapy.

    PubMed

    Erdogan, Suat; Turkekul, Kader; Serttas, Rıza; Erdogan, Zeynep

    2017-04-01

    Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death among men. Development of chemoresistance, tumor relapse and metastasis remain major barriers to effective treatment and all been identified to be associated with cancer stem cells (CSCs). Natural flavonoids such as apigenin have been shown to have the ability to improve the therapeutic efficacy of common chemotherapy agents through CSCs sensitization. Thus, the aim of this study was to evaluate the combination of apigenin with cisplatin on CD44(+) PCa stem cell growth and migration. Platinum-based anti-neoplastic drugs have been used to treat a number of malignancies including PCa. However, acquired resistance and side effects unfortunately have limited cisplatin's use. A CD44(+) subpopulation was isolated from human androgen-independent PC3 PCa cells by using human CD44-PE antibody. IC50 values were determined by MTT test. RT-qPCR, Western blot analyses and image-based cytometer were used to investigate apoptosis, cell cycle and their underlying molecular mechanisms. Cell migration was evaluated by wound healing test. The combination of the IC50 doses of apigenin (15μM) and cisplatin (7.5μM) for 48h significantly enhanced cisplatin's cytotoxic and apoptotic effects through downregulation of Bcl-2, sharpin and survivin; and upregulation of caspase-8, Apaf-1 and p53 mRNA expression. The combined therapy suppressed the phosphorylation of p-PI3K and p-Akt, inhibited the protein expression of NF-κB, and downregulated the cell cycle by upregulating p21, as well as cyclin dependent kinases CDK-2, -4, and -6. Apigenin significantly increased the inhibitory effects of cisplatin on cell migration via downregulation of Snail expression. In conclusion, our study showed the possible therapeutic approach of using apigenin to potentially increase the effects of cisplatin by targeting CSCs subset in prostate cancer.

  16. Volume-regulated chloride conductance in the LNCaP human prostate cancer cell line.

    PubMed

    Shuba, Y M; Prevarskaya, N; Lemonnier, L; Van Coppenolle, F; Kostyuk, P G; Mauroy, B; Skryma, R

    2000-10-01

    Patch-clamp recordings were used to study ion currents induced by cell swelling caused by hypotonicity in human prostate cancer epithelial cells, LNCaP. The reversal potential of the swelling-evoked current suggested that Cl(-) was the primary charge carrier (termed I(Cl,swell)). The selectivity sequence of the underlying volume-regulated anion channels (VRACs) for different anions was Br(-) approximately I(-) > Cl(-) > F(-) > methanesulfonate > glutamate, with relative permeability numbers of 1.26, 1.20, 1.0, 0.77, 0.49, and 0.036, respectively. The current-voltage patterns of the whole cell currents as well as single-channel currents showed moderate outward rectification. Unitary VRAC conductance was determined at 9.6 +/- 1.8 pS. Conventional Cl(-) channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 microM) and DIDS (100 microM) inhibited whole cell I(Cl,swell) in a voltage-dependent manner, with the block decreasing from 39.6 +/- 9.7% and 71.0 +/- 11. 0% at +50 mV to 26.2 +/- 7.2% and 14.5 +/- 6.6% at -100 mV, respectively. Verapamil (50 microM), a standard Ca(2+) antagonist and P-glycoprotein function inhibitor, depressed the current by a maximum of 15%. Protein tyrosine kinase inhibitors downregulated I(Cl,swell) (genistein with an IC(50) of 2.6 microM and lavendustin A by 60 +/- 14% at 1 microM). The protein tyrosine phosphatase inhibitor sodium orthovanadate (500 microM) stimulated I(Cl,swell) by 54 +/- 11%. We conclude that VRACs in human prostate cancer epithelial cells are modulated via protein tyrosine phosphorylation.

  17. DNA fragmentation and apoptosis induced by safranal in human prostate cancer cell line

    PubMed Central

    Samarghandian, Saeed; Shabestari, Mahmoud M

    2013-01-01

    Objectives: Apoptosis, an important mechanism that contributes to cell growth reduction, is reported to be induced by Crocus sativus (Saffron) in different cancer types. However, limited effort has been made to correlate these effects to the active ingredients of saffron. The present study was designed to elucidate cytotoxic and apoptosis induction by safranal, the major coloring compound in saffron, in a human prostate cancer cell line (PC-3). Materials and Methods: PC-3 and human fetal lung fibroblast (MRC-5) cells were cultured and exposed to safranal (5, 10, 15, and 20 μg/ml). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to assess cytotoxicity. DNA fragmentation was assessed by gel electrophoresis. Cells were incubated with different concentrations of safranal, and cell morphologic changes and apoptosis were determined by the normal inverted microscope, Annexin V, and propidium iodide, followed by flow cytometric analysis, respectively. Results: MTT assay revealed a remarkable and concentration-dependent cytotoxic effect of safranal on PC-3 cells in comparison with non-malignant cell line. The morphologic alterations of the cells confirmed the MTT results. The IC50 values against PC-3 cells were found to be 13.0 ΁ 0.07 and 6.4 ΁ 0.09 μg/ml at 48 and 72 h, respectively. Safranal induced an early and late apoptosis in the flow cytometry histogram of treated cells, indicating apoptosis is involved in this toxicity. DNA analysis revealed typical ladders as early as 48 and 72 h after treatment, indicative of apoptosis. Conclusions: Our preclinical study demonstrated a prostate cancer cell line to be highly sensitive to safranal-mediated growth inhibition and apoptotic cell death. Although the molecular mechanisms of safranal action are not clearly understood, it appears to have potential as a therapeutic agent. PMID:24082436

  18. Molecular characteristics of colorectal serrated polyps and hyperplastic polyps

    PubMed Central

    Sambuudash, Otgontuya; Kim, Hee Man; Jo, Hannah; Kim, Hyun Sik; Lee, Kyong Joo; Park, Hong Jun; Kim, Jae Woo; Cho, Mee Yon; Kim, Hyun-Soo

    2016-01-01

    Abstract The serrated neoplasia pathway of colorectal carcinogenesis is characterized by BRAF mutation and aberrant DNA methylation, which have not been reported on Korean patients. The aim of this study was to investigate BRAF mutation and DNA methylation in colorectal serrated polyps and the right colon. Between 2005 and 2013, 146 colon polyps (47 tubular adenomas [TAs], 53 traditional serrated adenomas [TSAs], 17 sessile serrated adenomas/polyps [SSAs], and 29 hyperplastic polyps in the proximal colon [PHPs]) were collected from patients. Paraffin-embedded colon polyp tissue was used for DNA extraction. BRAF V600E mutation was identified through polymerase chain reaction (PCR) and pyrosequencing assay. The methylation status of the long interspersed nucleotide element-1, insulin-like growth factor binding protein 7 (IGFBP7), mutL homolog 1 (hMLH1), and CD133 genes were evaluated through disulfite conversion, PCR, and pyrosequencing assay. BRAF V600E mutation was found in 2.1% of TAs, 47.2% of TSAs, 41.2% of SSAs, and 20.7% of PHPs. TSA and SSA had higher BRAF mutation rates than did TA (P < 0.0001). TSA had higher BRAF mutation rates than did PHP (P = 0.018). IGFBP7 hypermethylation was found in 17% of TAs, 37.7% of TSAs, 88.2% of SSAs, and 37.5% of PHPs. TSA and SSA had higher hypermethylation of IGFBP7 than did TA (P = 0.021 and P < 0.0001, respectively). SSA had higher hypermethylation of IGFBP7 than did PHP (P = 0.002). hMLH1 hypermethylation was found in 2.1% of TAs, 5.7% of TSAs, 0% of SSAs, and 0% of PHPs. CD133 hypermethylation was found in 21.3% of TAs, 9.4% of TSAs, 35.3% of SSAs, and 17.4% of PHPs. BRAF mutation and methylation in TSA and SSA are different from those in PHP in Koreans. These findings suggested that PHP may have different molecular characteristics compared with other serrated polyps. PMID:27930579

  19. Androgen-sensitive microsomal signaling networks coupled to the proliferation and differentiation of human prostate cancer cells.

    PubMed

    Martinez, Harryl D; Hsiao, Jordy J; Jasavala, Rohini J; Hinkson, Izumi V; Eng, Jimmy K; Wright, Michael E

    2011-10-01

    Increasing evidence suggests that the disruption of androgen-mediated cellular processes, such as cell proliferation and cell differentiation, contributes to the development of early-stage androgen-dependent prostate cancers. Large-scale mRNA profiling experiments have paved the way in identifying androgen-regulated gene networks that control the proliferation, survival, and differentiation of prostate cancer cells. Despite these extensive research efforts, it remains to be determined whether all androgen-mediated mRNA changes faithfully translate into changes in protein abundance that influence prostate tumorigenesis. Here, we report on a mass spectrometry-based quantitative proteomics analysis that identified known androgen signaling pathways and also novel, androgen-sensitive microsome-associated proteins and protein networks that had not been discovered by gene network studies in human LNCaP prostate cancer cells. Androgen-sensitive microsome-associated proteins encoded components of the insulin growth factor-1 (IGF-1), phosphoinositide 3-kinase (PI3K)/AKT, and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathways. Further bioinformatic analyses showed most of the androgen-sensitive microsome-associated protein networks play roles in cell proliferation and differentiation. Functional validation experiments showed that the androgen-sensitive microsome-associated proteins Janus kinase 2 (JAK2) and I-kappa B kinase complex-associated protein (IKAP) modulated the expression of prostate epithelial and neuronal markers, attenuated proliferation through an androgen receptor-dependent mechanism, and co-regulated androgen receptor-mediated transcription in LNCaP cells. Further biochemical analyses showed that the increased proliferation in JAK2 knockdown cells was mediated by activation of the mammalian target of rapamycin (mTOR), as determined by increased phosphorylation of several downstream targets (p70 S6 kinase

  20. Androgen-Sensitive Microsomal Signaling Networks Coupled to the Proliferation and Differentiation of Human Prostate Cancer Cells

    PubMed Central

    Martinez, Harryl D.; Hsiao, Jordy J.; Jasavala, Rohini J.; Hinkson, Izumi V.; Eng, Jimmy K.

    2011-01-01

    Increasing evidence suggests that the disruption of androgen-mediated cellular processes, such as cell proliferation and cell differentiation, contributes to the development of early-stage androgen-dependent prostate cancers. Large-scale mRNA profiling experiments have paved the way in identifying androgen-regulated gene networks that control the proliferation, survival, and differentiation of prostate cancer cells. Despite these extensive research efforts, it remains to be determined whether all androgen-mediated mRNA changes faithfully translate into changes in protein abundance that influence prostate tumorigenesis. Here, we report on a mass spectrometry–based quantitative proteomics analysis that identified known androgen signaling pathways and also novel, androgen-sensitive microsome-associated proteins and protein networks that had not been discovered by gene network studies in human LNCaP prostate cancer cells. Androgen-sensitive microsome-associated proteins encoded components of the insulin growth factor-1 (IGF-1), phosphoinositide 3-kinase (PI3K)/AKT, and extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathways. Further bioinformatic analyses showed most of the androgen-sensitive microsome-associated protein networks play roles in cell proliferation and differentiation. Functional validation experiments showed that the androgen-sensitive microsome-associated proteins Janus kinase 2 (JAK2) and I-kappa B kinase complex-associated protein (IKAP) modulated the expression of prostate epithelial and neuronal markers, attenuated proliferation through an androgen receptor–dependent mechanism, and co-regulated androgen receptor–mediated transcription in LNCaP cells. Further biochemical analyses showed that the increased proliferation in JAK2 knockdown cells was mediated by activation of the mammalian target of rapamycin (mTOR), as determined by increased phosphorylation of several downstream targets (p70 S6

  1. Identification of structural and secretory lectin-binding glycoproteins of normal and cancerous human prostate.

    PubMed

    Lad, P M; Cooper, J F; Learn, D B; Olson, C V

    1984-12-07

    We have utilized the technique of lectin-loading of SDS gels with iodinated concanavalin A and wheat germ agglutinin to identify glycoproteins in prostatic and seminal fluids as well as in prostate tissue fractions. The following subunits which bound both lectins were detected: (a) 50, 43 and 38 kDa subunits common to prostatic and seminal fluids, and an additional 55 kDa subunit which predominates only in prostatic fluid; (b) 78, 55, 50 and 43 kDa subunits in prostatic tissue cytosol and (c) 195, 170, 135, 116 and 95 kDa subunits present in the particulate fractions of prostatic tissue. Immunoblotting using specific rabbit antibodies revealed the 50 kDa band to be prostatic acid phosphatase and the 38 kDa band to be prostate-specific antigen. Interestingly, antibodies directed toward prostatic acid phosphatase were found to cross-react with the 43 kDa band. Fractionation on sucrose gradients showed that several of these particulate glycoproteins were associated with a vesicle fraction enriched in adenylate cyclase activity, implying that they are plasma membrane glycoproteins. Comparison of soluble and particulate fractions of normal and cancerous tissue homogenates was made by densitometric scanning of autoradiograms of lectin-loaded gels. Similar relative intensities of lectin-binding were obtained for corresponding proteins in normal and cancerous tissue fractions. Also, immunoblotting showed no differences in prostatic acid phosphatase or prostate-specific antigen between normal and cancerous soluble homogenate fractions. Our results suggest that major lectin-binding proteins are conserved in the transition from normal to cancerous tissue. These results may be useful in developing a multiple-marker profile of metastatic prostate cancer and for the design of imaging agents, such as monoclonal antibodies, to prominent soluble and particulate prostate glycoproteins.

  2. Loss of heterozygosity in human primary prostate carcinomas: a possible tumor suppressor gene at 7q31.1.

    PubMed

    Zenklusen, J C; Thompson, J C; Troncoso, P; Kagan, J; Conti, C J

    1994-12-15

    We studied loss of heterozygosity (LOH) on human chromosome 7q to determine the location of a putative tumor suppressor gene (TSG) in human primary prostate carcinomas. Samples were obtained from 16 primary prostate carcinomas surgically removed from patients at The University of Texas M. D. Anderson Cancer Center. Paired normal and tumor DNAs were used as template for PCR amplification of a set of 14 CA microsatellite repeats on 7q21-qter. Twelve of 16 cases studied had LOH at one or more loci on 7q. Eighty-three percent LOH (five of six informative cases) was detected with D7S522 at 7q31.1-7q31.2. Percentage of LOH was normally distributed around D7S522. The high incidence of LOH in primary prostate carcinomas suggests that there is a TSG relevant to the development of prostate cancers at 7q31.1-31.2, confirming our previous functional evidence for a TSG at this location. Further research needs to be conducted to establish the identity and function of this putative TSG.

  3. Hypoxia primes human normal prostate epithelial cells and cancer cell lines for the NLRP3 and AIM2 inflammasome activation

    PubMed Central

    Panchanathan, Ravichandran; Liu, Hongzhu; Choubey, Divaker

    2016-01-01

    The molecular mechanisms by which hypoxia contributes to prostatic chronic inflammation (PCI) remain largely unknown. Because hypoxia stimulates the transcriptional activity of NF-κB, which “primes” cells for inflammasome activation by inducing the expression of NLRP3 or AIM2 receptor and pro-IL-1β, we investigated whether hypoxia could activate the NLRP3 and AIM2 inflammasome in human normal prostate epithelial cells (PrECs) and cancer cell lines. Here we report that hypoxia (1% O2) treatment of PrECs, prostate cell lines, and a macrophage cell line (THP-1) increased the levels of NLRP3, AIM2, and pro-IL-1β. Further, hypoxia in cells potentiated activation of the NLRP3 and AIM2 inflammasome activity. Notably, hypoxia “primed” cells for NLRP3 and AIM2 inflammasome activation through stimulation of the NF-κB activity. Our observations support the idea that hypoxia in human prostatic tumors contributes to PCI, in part, by priming cells for the activation of NLRP3 and AIM2 inflammasome. PMID:27058421

  4. Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.

    PubMed

    Winter, Jean M; Gildea, Derek E; Andreas, Jonathan P; Gatti, Daniel M; Williams, Kendra A; Lee, Minnkyong; Hu, Ying; Zhang, Suiyuan; Mullikin, James C; Wolfsberg, Tyra G; McDonnell, Shannon K; Fogarty, Zachary C; Larson, Melissa C; French, Amy J; Schaid, Daniel J; Thibodeau, Stephen N; Churchill, Gary A; Crawford, Nigel P S

    2017-01-25

    It is unclear how standing genetic variation affects the prognosis of prostate cancer patients. To provide one controlled answer to this problem, we crossed a dominant, penetrant mouse model of prostate cancer to Diversity Outbred mice, a collection of animals that carries over 40 million SNPs. Integration of disease phenotype and SNP variation data in 493 F1 males identified a metastasis modifier locus on Chromosome 8 (LOD = 8.42); further analysis identified the genes Rwdd4, Cenpu, and Casp3 as functional effectors of this locus. Accordingly, analysis of over 5,300 prostate cancer patient samples revealed correlations between the presence of genetic variants at these loci, their expression levels, cancer aggressiveness, and patient survival. We also observed that ectopic overexpression of RWDD4 and CENPU increased the aggressiveness of two human prostate cancer cell lines. In aggregate, our approach demonstrates how well-characterized genetic variation in mice can be harnessed in conjunction with systems genetics approaches to identify and characterize germline modifiers of human disease processes.

  5. Multifunctional iron platinum stealth immunomicelles: targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging

    PubMed Central

    Huber, Dale L.; Monson, Todd C.; Ali, Abdul-Mehdi S.; Bisoffi, Marco; Sillerud, Laurel O.

    2011-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) are the most common type of contrast agents used in contrast agent-enhanced magnetic resonance imaging (MRI). Still, there is a great deal of room for improvement, and nanoparticles with increased MRI relaxivities are needed to increase the contrast enhancement in MRI applied to various medical conditions including cancer. We report the synthesis of superparamagnetic iron platinum nanoparticles (SIPPs) and subsequent encapsulation using PEGylated phospholipids to create stealth immunomicelles (DSPE-SIPPs) that can be specifically targeted to human prostate cancer cell lines and detected using both MRI and fluorescence imaging. SIPP cores and DSPE-SIPPs were 8.5 ± 1.6 nm and 42.9 ± 8.2 nm in diameter, respectively, and the SIPPs had a magnetic moment of 120 A m2/kg iron. J591, a monoclonal antibody against prostate specific membrane antigen (PSMA), was conjugated to the DSPE-SIPPs (J591-DSPE-SIPPs), and specific targeting of J591-DSPE-SIPPs to PSMA-expressing human prostate cancer cell lines was demonstrated using fluorescence confocal microscopy. The transverse relaxivity of the DSPE-SIPPs, measured at 4.7 Tesla, was 300.6 ± 8.5 s−1 mM−1, which is 13-fold better than commercially available SPIONs (23.8 ± 6.9 s−1 mM−1) and ~3-fold better than reported relaxivities for Feridex® and Resovist®. Our data suggest that J591-DSPE-SIPPs specifically target human prostate cancer cells in vitro, are superior contrast agents in T2-weighted MRI, and can be detected using fluorescence imaging. To our knowledge, this is the first report on the synthesis of multifunctional SIPP micelles and using SIPPs for the specific detection of prostate cancer. PMID:22121333

  6. Multifunctional iron platinum stealth immunomicelles: targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Taylor, Robert M.; Huber, Dale L.; Monson, Todd C.; Ali, Abdul-Mehdi S.; Bisoffi, Marco; Sillerud, Laurel O.

    2011-10-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) are the most common type of contrast agents used in contrast agent-enhanced magnetic resonance imaging (MRI). Still, there is a great deal of room for improvement, and nanoparticles with increased MRI relaxivities are needed to increase the contrast enhancement in MRI applied to various medical conditions including cancer. We report the synthesis of superparamagnetic iron platinum nanoparticles (SIPPs) and subsequent encapsulation using PEGylated phospholipids to create stealth immunomicelles (DSPE-SIPPs) that can be specifically targeted to human prostate cancer cell lines and detected using both MRI and fluorescence imaging. SIPP cores and DSPE-SIPPs were 8.5 ± 1.6 nm and 42.9 ± 8.2 nm in diameter, respectively, and the SIPPs had a magnetic moment of 120 A m2/kg iron. J591, a monoclonal antibody against prostate specific membrane antigen (PSMA), was conjugated to the DSPE-SIPPs (J591-DSPE-SIPPs), and specific targeting of J591-DSPE-SIPPs to PSMA-expressing human prostate cancer cell lines was demonstrated using fluorescence confocal microscopy. The transverse relaxivity of the DSPE-SIPPs, measured at 4.7 Tesla, was 300.6 ± 8.5 s-1 mM-1, which is 13-fold better than commercially available SPIONs (23.8 ± 6.9 s-1 mM-1) and 3-fold better than reported relaxivities for Feridex® and Resovist®. Our data suggest that J591-DSPE-SIPPs specifically target human prostate cancer cells in vitro, are superior contrast agents in T 2-weighted MRI, and can be detected using fluorescence imaging. To our knowledge, this is the first report on the synthesis of multifunctional SIPP micelles and using SIPPs for the specific detection of prostate cancer.

  7. Matched Cohort Analysis of Outcomes of Definitive Radiotherapy for Prostate Cancer in Human Immunodeficiency Virus-Positive Patients

    SciTech Connect

    Kahn, Shannon; Jani, Ashesh; Edelman, Scott; Rossi, Peter; Godette, Karen; Landry, Jerome; Anderson, Cynthia

    2012-05-01

    Purpose: To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT). Methods and Materials: A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months). Results: The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm{sup 3}. Conclusions: Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population.

  8. mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma

    PubMed Central

    Stelloo, Suzan; Sanders, Joyce; Nevedomskaya, Ekaterina; de Jong, Jeroen; Peters, Dennis; van Leenders, Geert J.L.H.; Jenster, Guido; Bergman, Andries M.; Zwart, Wilbert

    2016-01-01

    Prostate cancer patients with localized disease are treated with curative intent. However, the disease will recur in approximately 30% of patients with a high incidence of morbidity and mortality. Prognostic biomarkers are needed to identify patients with high risk of relapse. mTOR pathway activation is reported in prostate cancer, but clinical trials testing efficacy of mTOR inhibitors were unsuccessful. To explain this clinical observation, we studied the expression and prognostic impact of mTOR-S2448 phosphorylation in localized prostate carcinomas. mTOR-S2448 phosphorylation is indicative for an activated mTOR pathway in prostate cancer. Surprisingly, the mTOR signaling pathway is activated specifically in prostate cancer patients with a favorable outcome. Since tumors from poor-outcome patients have low levels of mTOR-S2448 phosphorylation, this may explain why mTOR inhibitors proved unsuccessful in prostate cancer trials. PMID:27096957

  9. Human CTLs to wild-type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells.

    PubMed

    Oh, SangKon; Terabe, Masaki; Pendleton, C David; Bhattacharyya, Anu; Bera, Tapan K; Epel, Malka; Reiter, Yoram; Phillips, John; Linehan, W Marston; Kasten-Sportes, Claude; Pastan, Ira; Berzofsky, Jay A

    2004-04-01

    Vaccine therapy for prostate and breast cancer may have potential for treating these major causes of death in males and females, respectively. Critical to the development of tumor-specific vaccines is finding and characterizing novel antigens to be recognized by CD8(+) T cells. To define new CD8(+) T-cell tumor antigens, we determined two wild-type HLA-A2 epitopes from a recently found tumor-associated protein, TARP (T-cell receptor gamma alternate reading frame protein), expressed in prostate and breast cancer cells. We were also able to engineer epitope-enhanced peptides by sequence modifications. Both wild-type and enhanced epitopes induced peptide-specific CD8(+) T-cell responses in A2K(b) transgenic mice. In vitro restimulation of human CD8(+) T cells from a prostate cancer patient resulted in CD8(+) T cells reactive to the peptide epitopes that could lyse HLA-A2(+) human breast cancer cells (MCF-7) expressing TARP. Epitope-specific human CD8(+) T cells were also enumerated in patients' peripheral blood by tetramer staining. Our data suggest that HLA-A2-binding TARP epitopes and enhanced epitopes discovered in this study could be incorporated into a potential vaccine for both breast and prostate cancer.

  10. Kissing molars and hyperplastic dental follicles: report of a case and literature review.

    PubMed

    Kiran, Heggavadipura Yogendraswamy; Bharani, K S N Shiva; Kamath, Rajay Agnel; Manimangalath, Girisankar; Madhushankar, G S

    2014-01-01

    "Kissing" molars are impacted permanent molars that have occlusal surfaces contacting each other in a single follicular space, with roots pointing in opposite directions. It is deemed to be appropriate to medically investigate mucopolysaccharidosis (MPS) in patients presenting with kissing molars as kissing molars have been linked with MPS. The case of bilateral occurrence of kissing molars in an 18-year-old woman is described. Pathological analysis of the follicular tissue suggested hyperplastic dental follicles. Therefore, this case report analysed the association of impacted permanent teeth with hyperplastic dental follicles, following the review of seven documented reports describing such association.

  11. Development and prevention of morphologic and ultrastructural changes in uremia-induced hyperplastic parathyroid gland.

    PubMed

    Shiizaki, Kazuhiro; Hatamura, Ikuji; Mato, Masao; Nakazawa, Eiko; Saji, Fumie; Onishi, Akira; Ogura, Manabu; Watanabe, Yuko; Kusano, Eiji

    2011-10-01

    The detailed ultrastructural changes of uremia-induced hyperplastic parathyroid gland and the effects of current medical treatments for secondary hyperparathyroidism were investigated. Marked enlargement of parathyroid cell with accumulation of mitochondria and lipids and a significant increase in the thickness of the pericapillary area with increased fibrosis and appearance of fibroblast like cells were noted in the hyperplastic gland caused by uremia and phosphate retention. These ultrastructural changes and biochemical findings indicating hyperparathyroidism were significantly suppressed by all of the treatment using phosphate restriction, calcitriol, and cinacalcet. The characteristic ultrastructural changes, including the morphologic evidence of nodule formation, were indicated.

  12. Gastric inverted hyperplastic polyp: A rare cause of iron deficiency anemia

    PubMed Central

    Yun, Jin Tak; Lee, Seung Woo; Kim, Dong Pil; Choi, Seung Hwa; Kim, Seok-Hwan; Park, Jun Kyu; Jang, Sun Hee; Park, Yun Jung; Sung, Ye Gyu; Sul, Hae Jung

    2016-01-01

    Gastric inverted hyperplastic polyp (IHP) is a rare gastric polyp characterized by the downward growth of hyperplastic mucosal components into the submucosal layer. Macroscopically, a gastric IHP resembles a subepithelial tumor (SET); as a result, accurately diagnosing gastric IHP is difficult. This issue has clinical significance because gastric IHP can be misdiagnosed as SET or as malignant neoplasm In addition, adenocarcinoma can accompany benign gastric IHP. Although in most cases, gastric IHPs are asymptomatic and are found incidentally, these polyps may cause anemia secondary to chronic bleeding. Here, we report one case involving gastric IHP accompanied by chronic iron deficiency anemia that was successfully managed using endoscopic submucosal dissection. PMID:27099452

  13. Gene transfer vectors targeted to human prostate cancer: do we need better preclinical testing systems?

    PubMed

    Maitland, Norman; Chambers, Karen; Georgopoulos, Lindsay; Simpson-Holley, Martha; Leadley, Regina; Evans, Helen; Essand, Magnus; Danielsson, Angelika; van Weerden, Wytske; de Ridder, Corrina; Kraaij, Robert; Bangma, Chris H

    2010-07-01

    Destruction of cancer cells by genetically modified viral and nonviral vectors has been the aim of many research programs. The ability to target cytotoxic gene therapies to the cells of interest is an essential prerequisite, and the treatment has always had the potential to provide better and more long-lasting therapy than existing chemotherapies. However, the potency of these infectious agents requires effective testing systems, in which hypotheses can be explored both in vitro and in vivo before the establishment of clinical trials in humans. The real prospect of off-target effects should be eliminated in the preclinical stage, if current prejudices against such therapies are to be overcome. In this review we have set out, using adenoviral vectors as a commonly used example, to discuss some of the key parameters required to develop more effective testing, and to critically assess the current cellular models for the development and testing of prostate cancer biotherapy. Only by developing models that more closely mirror human tissues will we be able to translate literature publications into clinical trials and hence into acceptable alternative treatments for the most commonly diagnosed cancer in humans.

  14. 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