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Sample records for prostate tumor cell

  1. [Circulating tumor cells and advanced prostate cancer].

    PubMed

    Murez, Thibaut; Droupy, Stéphane; Rebillard, Xavier; Alix-Panabieres, Catherine

    2012-07-01

    Despite development and widespread of PSA, current tools evaluating prostate cancer still give inconsistent or insufficiently relevant results. As encouraging data raised from circulating tumor cells detection in colon or breast cancer, they were evaluated as a surrogate prostate cancer biomarker. Tumor cells need to leave their surrounding primary environment and to survive in mesenchymal environment before they spill and metastasize. Basic research revealed several mutations required through a complex transition phenomenon, including dormancy steps. Circulating cells detection techniques are based on molecular and immunologic methods. Most of them need an enrichment step to improve sensibility and/or specificity. As of today, Veridex' CellSearch is the only FDA approved technique in the evaluation of castration resistant prostate cancer response to new drugs. Clinical research using other techniques highlighted the need for clinical endpoints, as there's no relevant tool and as techniques' target differ. Further studies are required to improve circulating tumors cells' staging and prognosis value. Cellular characterization may be the way to identify metastasis development potential more than the spillage burden. Those techniques still need improvements before they are included in daily practice decisional trees.

  2. [Circulating tumor cells and prostate cancer prognosis].

    PubMed

    Capoun, Otakar; Soukup, Viktor; Mikulová, Veronika; Jančíková, Markéta; Honová, Hana; Kološtová, Katarína; Zima, Tomáš; Hanuš, Tomáš

    2014-01-01

    Prostate cancer (PC) is the most common malignant disease in men. Prognosis of patients with metastatic PC is generally unfavourable; however there are significant differences in survival at this stage of the disease. The definition of prognosis is essential for the selection of therapy, respecting an individual risk. In recent years, the association between circulating tumor cells (CTC) detection and response to PC treatment has been widely investigated. Detection of CTC is based on a metastatic process theory and uses well-known tumor-specific antigens on the cell surface. Individual methods assess CTC with different sensitivity and are not yet efficient at the localised PC stage. Only the method of immunomagnetic separation and semi-automatic visualisation (CellSearchTM) has been validated and approved for the use in the PC management. Assessment of the CTC count directly correlates with the prognosis of patients with castration-resistant PC. Change in the CTC count during the therapy also considerably improves risk estimation and represents a marker of overall survival. New methods of CTC cultivation and gene profiling may contribute to individualisation of the treatment similarly to breast cancer. The authors present a review article about theory, methods of detection and clinical use of CTC in castration-resistant PC.

  3. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

    DTIC Science & Technology

    2016-10-01

    Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

  4. Adipose Tissue Derived Stem Cells Promote Prostate Tumor Growth

    PubMed Central

    Prantl, Lukas; Muehlberg, Fabian; Navone, Nora M.; Song, Yao-Hua; Vykoukal, Jody; Logothetis, Christopher J.; Alt, Eckhard U.

    2016-01-01

    BACKGROUND Recent evidence indicates that cancer stem cells play an important role in tumor initiation and maintenance. Additionally, the effect of tissue-resident stem cells located in the surrounding healthy tissue on tumor progression has been demonstrated. While most knowledge has been derived from studies of breast cancer cells, little is known regarding the influence of tissue resident stem cells on the tumor biology of prostate cancer. METHODS Twenty male athymic Swiss nu/nu mice (age: 6–8 weeks) were randomized into two treatment groups: 1) subcutaneous injection of 106 MDA PCa 118b human prostate cancer cells into the upper back or 2) subcutaneous injection of 106 MDA PCa 118b cells mixed directly with 105 GFP-labeled human adipose tissue-derived stem cells (hASCs). Tumor growth and volumes over the ensuing 3 weeks were assessed using calipers and micro-computed tomography. Immunohistochemistry was performed to identify engrafted hASCs in tumor sections. RESULTS At 3 weeks after injection, the mean tumor volume in the MDA PCa 118b/hASC co-injection group (1019.95 ± 73.49 mm3) was significantly higher than that in the MDA PCa 118b-only group (308.70 ± 21.06 mm3). Engrafted hASCs exhibited the nuclear marker of proliferation Ki67 and expressed markers for endothelial differentiation, indicating their engraftment in tumor vessels. CONCLUSION Our study revealed for the first time that ASCs subcutaneously co-injected with prostate cancer cells engraft and promote tumor progression. Further evaluation of the cross-talk between tumor and local tissue-resident stem cells may lead to new strategies for prostate cancer therapy. PMID:20564322

  5. Circulating tumor cells in prostate cancer: beyond enumeration.

    PubMed

    Chen, Jie-Fu; Lu, Yi-Tsung; Cheng, Shirley; Tseng, Hsian-Rong; Figlin, Robert A; Posadas, Edwin M

    2017-01-01

    Circulating tumor cells (CTCs) are a population of rare cancer cells that have detached from the primary tumor and/or metastatic lesions and entered the peripheral circulation. Enumeration of CTCs has demonstrated value as a prognostic biomarker, and newer studies have pointed to information beyond enumeration that is of critical importance in prostate cancer. Technologic advances that permit examination of the morphology, function, and molecular content of CTCs have made it possible to measure these factors as part of liquid biopsy. These advances provide a way to study tumor evolution and the development of resistance to therapy. Recent breakthroughs have created new applications for CTCs that will affect the care of patients with prostate cancer.

  6. Radiosensitization of Prostate Tumor Cells by Prenyltransferase Inhibitors

    DTIC Science & Technology

    1999-10-01

    and predicts a positive effect on the response to radiotherapy. Reportable Outcomes: 1. Development of new cell lines derived from immortalized human ...548-552. 14 Employment 1993 - 1996 Biologist, Laboratory of Mammalian Genes and Development , National Institute of Child Health and Human ...the use of prenyltransferase inhibitors. We have examined both rodent and human prostate tumor cell lines in vitro and determined that radiation

  7. Phase transitions in tumor growth: II prostate cancer cell lines

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, A.; De Miguel, M. P.; Izquierdo-Kulich, E.; Royuela-García, M.; Tejera, E.; Nieto-Villar, J. M.

    2015-05-01

    We propose a mechanism for prostate cancer cell lines growth, LNCaP and PC3 based on a Gompertz dynamics. This growth exhibits a multifractal behavior and a "second order" phase transition. Finally, it was found that the cellular line PC3 exhibits a higher value of entropy production rate compared to LNCaP, which is indicative of the robustness of PC3, over to LNCaP and may be a quantitative index of metastatic potential tumors.

  8. Hedgehog signaling in myofibroblasts directly promotes prostate tumor cell growth†

    PubMed Central

    Domenech, Maribella; Bjerregaard, Robert; Bushman, Wade; Beebe, David J.

    2012-01-01

    Despite strong evidence for the involvement of the stroma in Hedgehog signaling, little is known about the identity of the stromal cells and the signaling mechanisms that mediate the growth promoting effect of Hh signaling. We developed an in vitro co-culture model using microchannel technology to examine the effect of paracrine Hh signaling on proliferation of prostate cancer cells. We show here that activation of Hh signaling in myofibroblasts is sufficient to accelerate tumor cell growth. This effect was independent of any direct effect of Hh ligand on tumor cells or other cellular components of the tumor stroma. Further, the trophic effect of Hh pathway activation in myofibroblasts does not require collaboration of other elements of the stroma or direct physical interaction with the cancer cells. By isolating the tropic effect of Hh pathway activation in prostate stroma, we have taken the first step toward identifying cell-specific mechanisms that mediate the effect of paracrine Hh signaling on tumor growth. PMID:22234342

  9. Morphological Differences between Circulating Tumor Cells from Prostate Cancer Patients and Cultured Prostate Cancer Cells

    PubMed Central

    Park, Sunyoung; Ang, Richard R.; Duffy, Simon P.; Bazov, Jenny; Chi, Kim N.; Black, Peter C.; Ma, Hongshen

    2014-01-01

    Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile. PMID:24416373

  10. Perioperative Search for Circulating Tumor Cells in Patients Undergoing Prostate Brachytherapy for Clinically Nonmetastatic Prostate Cancer

    PubMed Central

    Tsumura, Hideyasu; Satoh, Takefumi; Ishiyama, Hiromichi; Tabata, Ken-ichi; Takenaka, Kouji; Sekiguchi, Akane; Nakamura, Masaki; Kitano, Masashi; Hayakawa, Kazushige; Iwamura, Masatsugu

    2017-01-01

    Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT). Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative) and again immediately after the surgical manipulation (intraoperative). Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs) using the CellSearch System. While no preoperative samples showed CTCs (0%), they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012). Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA) at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites. PMID:28085051

  11. HLA Class II Antigen Presentation in Prostate Cancer Cells: A Novel Approach to Prostate Tumor Immunotherapy.

    PubMed

    Doonan, Bently Patrick; Haque, Azizul

    2010-01-01

    Prostate cancer is a deadly disease that is in drastic need of new treatment strategies for late stage and metastatic prostate cancer. Immunotherapy has emerged as a viable option to fill this void. Clinical trials have been conducted that induce tumor clearance through cytotoxic T lymphocyte (CTL) activation, these studies have had mixed outcomes with the overlying problem being the lack of a complete immune response with sustained killing and the formation of tumor specific memory cells. To overcome this, we have outlined the need for activating the HLA class II pathway in inducing a sustained CD8+ T cell response and the development of effective memory. We have also discussed the ability of prostate cancer cells to express stable HLA class II molecules that can be manipulated for tumor antigen (Ag) processing and presentation. This review also sets to outline new directions that exist for the use of class II-restricted Ags/peptides in devising cancer vaccines as well as combined chemoimmunotherapy. A better understanding of these concepts will improve future cancer vaccine studies and further the field of cancer immunobiology.

  12. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2008-01-01

    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  13. Immunological Targeting of Tumor Initiating Prostate Cancer Cells

    DTIC Science & Technology

    2014-10-01

    clinically using well-accepted immuno-competent animal models. 2) Keywords: Prostate Cancer , Lymphocyte, Vaccine , Antibody 3) Overall Project Summary...generating a novel prostate cancer vaccine aimed at targeting the castration resistant epithelial cells left behind after initial androgen ablation. 6...of origin for prostate cancer . Nature 461:495-500. 2. Drake,C.G., E.J.Lipson, and J.R.Brahmer. 2014. Breathing new life into immunotherapy

  14. Optical Strategies for Studying Metastatic Mechanisms, Tumor Cell Detection and Treatment of Prostate Cancer

    DTIC Science & Technology

    2005-10-01

    undesirable side effects. The objective of this proposal is to evaluate the effect of photodynamic therapy ( PDT ) on prostate tumors in order to design...optimal treatment regimens. We have established subcurative PDT conditions in 2 prostate cancer cell lines. Using these conditions we observed a transient...Ab to detect circulating prostate cancer cells. The results obtained establishes that PDT alters cellular-molecular processes such as cell adhesion

  15. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer.

    PubMed

    Hu, Z; Garen, A

    2001-10-09

    The efficacy and safety of an immunoconjugate (icon) molecule, composed of a mutated mouse factor VII (mfVII) targeting domain and the Fc effector domain of an IgG1 Ig (mfVII/Fc icon), was tested with a severe combined immunodeficient (SCID) mouse model of human prostatic cancer and an immunocompetent mouse model of mouse prostatic cancer. The SCID mice were first injected s.c. with a human prostatic tumor line, forming a skin tumor that produces a high blood titer of prostate-specific antigen and metastasizes to bone. The icon was encoded in a replication-incompetent adenoviral vector that was injected directly into the skin tumor. The tumor cells infected by the vector synthesize and secrete the icon into the blood, and the blood-borne icon binds with high affinity and specificity to mouse tissue factor expressed on endothelial cells lining the lumen of the tumor vasculature and to human tissue factor expressed on the tumor cells. The Fc domain of the icon activates a cytolytic immune attack against cells that bind the icon. The immunotherapy tests in SCID mice demonstrated that intratumoral injections of the adenoviral vector encoding the mfVII/human Fc icon resulted in long-term regression of the injected human prostatic tumor and also of a distant uninjected tumor, without associated toxicity to the mice. Comparable results were obtained with a SCID mouse model of human melanoma. At the end of the experiments the mice appeared to be free of viable tumor cells. This protocol also could be efficacious for treating cancer patients who have vascularized tumors.

  16. 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

  17. Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity

    PubMed Central

    Krönig, Malte; Walter, Max; Drendel, Vanessa; Werner, Martin; Jilg, Cordula A.; Richter, Andreas S.; Backofen, Rolf; McGarry, David; Follo, Marie; Schultze-Seemann, Wolfgang; Schüle, Roland

    2015-01-01

    A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer. PMID:25514598

  18. Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype1

    PubMed Central

    Bergström, Sofia Halin; Rudolfsson, Stina H; Bergh, Anders

    2016-01-01

    Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor–positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone. PMID:26992916

  19. Prostate Tumor Overexpressed-1 (PTOV1) promotes docetaxel-resistance and survival of castration resistant prostate cancer cells

    PubMed Central

    Cánovas, Verónica; Puñal, Yolanda; Maggio, Valentina; Redondo, Enric; Marín, Mercedes; Mellado, Begoña; Olivan, Mireia; Lleonart, Matilde; Planas, Jacques; Morote, Juan; Paciucci, Rosanna

    2017-01-01

    Metastatic prostate cancer is presently incurable. The oncogenic protein PTOV1, first described in prostate cancer, was reported as overexpressed and significantly correlated with poor survival in numerous tumors. Here, we investigated the role of PTOV1 in prostate cancer survival to docetaxel and self-renewal ability. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression (ABCB1, CCNG2 and TUBB2B). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression (ALDH1A1, LIN28A, MYC and NANOG). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance (CCNG2) and self-renewal (ALDH1A1, MYC) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and self-renewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1, ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis. PMID:28938627

  20. Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin.

    PubMed

    Sroka, Isis C; Chopra, Harsharon; Das, Lipsa; Gard, Jaime M C; Nagle, Raymond B; Cress, Anne E

    2016-02-01

    Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non-myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3-2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin. © 2015 Wiley Periodicals, Inc.

  1. TOPK is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer

    PubMed Central

    Shi, Changhong; Hu, Peizhen; Yan, Wei; Wang, Zhe; Duan, Qiuhong; Lu, Fan; Qin, Lipeng; Lu, Tao; Xiao, Juanjuan; Wang, Yingmei; Zhu, Feng; Shao, Chen

    2015-01-01

    Circulating tumor cells (CTCs) are important for metastasis in prostate cancer. T-LAK cell-originated protein kinase (TOPK) is highly expressed in cancer cells. Herein, we established a xenograft animal model, isolated and cultured the CTCs, and found CTCs have significantly greater migratory capacity than parental cells. TOPK is more highly expressed in the CTCs than in parental cells and is also highly expressed in the metastatic nodules caused by CTCs in mice. Knocking down TOPK decreased the migration of CTCs both in vitro and in vivo. TOPK was modulated by the PI3K/PTEN and ERK pathways during the metastasis of prostate cancer. High levels of TOPK in the tumors of patients were correlated with advanced stages of prostate cancer, especially for high-risk patients of Gleason score≥8, PSA>20ng/ml. In summary, TOPK was speculated to be one of a potential marker and therapeutic target in advanced prostate cancer. PMID:25881543

  2. Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

    PubMed Central

    Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

    2016-01-01

    Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

  3. Impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    PubMed Central

    Chen, Zhe (Jay); Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that the procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations depends strongly on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al. (Int. J. Radiat. Oncol. Biol. Phys. 41, 1069–1077–1998) was used to characterize the edema evolutions observed previously during clinical PIB for prostate cancer. The concept of biologically effective dose (BED), taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not taken into account appropriately, can increase the cell survival and decrease the probability of local control of PIB. The edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life for radioactive decay and decreasing energy of the photons energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days

  4. The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    NASA Astrophysics Data System (ADS)

    (Jay Chen, Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-08-01

    Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069-77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days) is longer than

  5. 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

  6. BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone

    DTIC Science & Technology

    2011-10-01

    by activation of the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 ( NDRG1 ). These results strongly suggest that the BMP7...cells and that this induction is mediated by activation of the tumor metastasis suppressor gene, NDRG1 (N-myc downstream regulated gene 1...Therefore, we hypothesize that a prostatic tumor stem cell becomes dormant in the bone through the BMP7-mediated activation of p38 and NDRG1 . BODY

  7. Downregulation of key regulatory proteins in androgen dependent prostate tumor cells by oncolytic reovirus.

    PubMed

    Gupta-Saraf, Pooja; Meseke, Tyler; Miller, Cathy L

    2015-11-01

    As prostate tumor cell growth depends on hormones, androgen ablation is an effective therapy for prostate cancer (PCa). However, progression of PCa cells to androgen independent growth (castrate resistant prostate cancer, CRPC) results in relapse and mortality. Hypoxia, a microenvironment of low oxygen that modifies the activity of PCa regulatory proteins including the androgen receptor (AR), plays a critical role in progression to CRPC. Therapies targeting hypoxia and the AR may lengthen the time to CRPC progression thereby increasing survival time of PCa patients. Mammalian Orthoreovirus (MRV) has shown promise for the treatment of prostate tumors in vitro and in vivo. In this study, we found that MRV infection induces downregulation of proteins implicated in CRPC progression, interferes with hypoxia-induced AR activity, and induces apoptosis in androgen dependent cells. This suggests MRV possesses traits that could be exploited to create novel therapies for the inhibition of progression to CRPC.

  8. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways

    PubMed Central

    Coleman, Ilsa; Lakely, Bryce; Coleman, Roger; Larson, Sandy; Aguirre-Ghiso, Julio A.; Xia, Jing; Gulati, Roman; Nelson, Peter S.; Montgomery, Bruce; Lange, Paul; Snyder, Linda A.; Vessella, Robert L.; Morrissey, Colm

    2014-01-01

    Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM+/CD45− cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention. PMID:25301725

  9. Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells

    DTIC Science & Technology

    2015-10-01

    We hope we can validate whether tumor Oct4 can be targeted to inhibit prostate cancer progression and metastasis. In addition, we will map out the...Introduction Background: Genome -wide association studies (GWAS) have linked human chromosome 8q24.21 region with increased risk for prostatic carcinoma...al., 2013). To map the sequences or residues which are critical for the different function between POU5F1B and OCT4 would provide more clues for

  10. Sunitinib reduces tumor hypoxia and angiogenesis, and radiosensitizes prostate cancer stem-like cells.

    PubMed

    Diaz, Roque; Nguewa, Paul A; Redrado, Miriam; Manrique, Irene; Calvo, Alfonso

    2015-08-01

    The need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi-tyrosine kinase inhibitor that mainly targets membrane-bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericytes. However, recent studies suggest a direct effect on tumor cells. In the present study, we have evaluated both direct and indirect effects of Sunitinib in prostate cancer and how this drug regulates hypoxia, using in vitro and in vivo models. We have used both in vitro (PC-3, DU145, and LNCaP cells) and in vivo (PC-3 xenografts) models to study the effect of Sunitinib in prostate cancer. Analysis of hypoxia based on HIF-1α expression and FMISO uptake was conducted. ALDH activity was used to analyze cancer stem cells (CSC). Sunitinib strongly reduced proliferation of PC-3 and DU-145 cells in a dose dependent manner, and decreased levels of p-Akt, p-Erk1/2, and Id-1, compared to untreated cells. A 3-fold reduction in tumor growth was also observed (P < 0.001 with respect to controls). Depletion of Hif-1α levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFRβ, Hif-1α, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH + cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity. Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden. © 2015 Wiley Periodicals, Inc.

  11. Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression.

    PubMed

    Chen, Xiaowan; Li, Chenli; He, Tiantian; Mao, Jiating; Li, Chunmei; Lyu, Jianxin; Meng, Qing H

    2016-05-03

    Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose- and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.

  12. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

    PubMed Central

    2013-01-01

    Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage

  13. THE TMEFF2 TUMOR SUPPRESSOR MODULATES INTEGRIN EXPRESSION, RHOA ACTIVATION AND MIGRATION OF PROSTATE CANCER CELLS

    PubMed Central

    Chen, Xiaofei; Corbin, Joshua M.; Tipton, Greg J.; Yang, Li V.; Asch, Adam S.; Ruiz-Echevarría, Maria J.

    2014-01-01

    Cell adhesion and migration play important roles in physiological and pathological states, including embryonic development and cancer invasion and metastasis. The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed mainly in brain and prostate and its expression is deregulated in prostate cancer. We have previously shown that TMEFF2 can function as a tumor suppressor by inhibiting cell migration and invasion of prostate cells. However, the molecular mechanisms involved in this inhibition are not clear. In this study we demonstrate that TMEFF2 affects cell adhesion and migration of prostate cancer cells and that this effect correlates with changes in integrin expression and RhoA activation. Deletion of a 13 basic-rich amino acid region in the cytoplasmic domain of TMEFF2 prevented these effects. Overexpression of TMEFF2 reduced cell attachment and migration on vitronectin and caused a concomitant decrease in RhoA activation, stress fiber formation and expression of αv, β1 and β3 integrin subunits. Conversely, TMEFF2 interference in 22Rv1 prostate cancer cells resulted in increased integrin expression. Results obtained with a double TRAMP/TMEFF2 transgenic mouse also indicated that TMEFF2 expression reduced integrin expression in the mouse prostate. In summary, the data presented here indicate an important role of TMEFF2 in regulating cell adhesion and migration that involves integrin signaling and is mediated by its cytoplasmic domain. PMID:24632071

  14. Single Cell Characterization of Prostate Cancer Circulating Tumor Cells

    DTIC Science & Technology

    2011-08-01

    single cell sequencing protocol for CTCs (Figure 3). So far, using their protocol we have done whole transcriptome amplification and mRNA seq on 6 single...perform additional single cell sequencing profiles. In our application we also hypothesized that there would be heterogeneity in gene expression

  15. Single Cell Characterization of Prostate Cancer-Circulating Tumor Cells

    DTIC Science & Technology

    2013-09-01

    CONTRACTING ORGANIZATION: Stanford University Stanford, CA , 94305 REPORT DATE: September 2013 TYPE OF REPORT: Final PREPARED FOR: U.S...ORGANIZATION NAME(S) AND ADDRESS(ES) Stanford University Stanford, CA , 94305 8. PERFORMING ORGANIZATION REPORT NUMBER...of technology and cost. We have begun using NexGen single cell sequencing methodology developed at Illumina Inc. (Hayward, CA ) to interrogate gene

  16. Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer.

    PubMed

    Schwarzenbach, Heidi; Alix-Panabières, Catherine; Müller, Imke; Letang, Nicolas; Vendrell, Jean-Pierre; Rebillard, Xavier; Pantel, Klaus

    2009-02-01

    Circulating cell-free DNA in the blood of cancer patients harbors tumor-specific aberrations. Here, we investigated whether this DNA might also reflect the presence of circulating tumor cells (CTC). To identify the source of cell-free DNA in blood, plasma derived from 81 patients with prostate cancer was examined for CTCs and cell-free DNA. An epithelial immunospot assay was applied for detection of CTCs, and a PCR-based fluorescence microsatellite analysis with a panel of 14 polymorphic markers was used for detection of allelic imbalances (AI). The plasma DNA levels significantly correlated with the diagnosis subgroups of localized (stage M0, n = 69) and metastasized prostate cancer (stage M1, n = 12; P = 0.03) and with the tumor stage of these patients (P < 0.005). AI was found on cell-free DNA in plasma from 45.0% and 58.5% of M0 and M1 patients, respectively. Detection of CTCs showed that 71.0% or 92.0% of the M0 and M1 patients harbored 1 to 40 CTCs in their blood, respectively. The occurrence of CTCs correlated with tumor stage (P < 0.03) and increasing Gleason scores (P = 0.04). Notably, significant associations of the number of CTCs with the AI frequencies at the markers D8S137 (P = 0.03), D9S171 (P = 0.04), and D17S855 (P = 0.02) encoding the cytoskeletal protein dematin, the inhibitor of the cyclin-dependent kinase CDKN2/p16 and BRCA1, respectively, were observed. These findings show, for the first time, a relationship between the occurrence of CTCs and circulating tumor-associated DNA in blood, which, therefore, might become a valuable new source for monitoring metastatic progression in cancer patients.

  17. BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone

    DTIC Science & Technology

    2012-10-01

    suppressor gene, N-myc downstream regulated gene 1 ( NDRG1 ). These results strongly suggest that the BMP7-NDRG1axis plays a critical role in dormancy...induction is mediated by activation of the tumor metastasis suppressor gene, NDRG1 (N-myc downstream regulated gene 1). Therefore, we hypothesize that a...prostatic tumor stem cell becomes dormant in the bone through the BMP7-mediated activation of p38 and NDRG1 . BODY Task 1. To clarify the

  18. TMPRSS2-ERG Fusion Gene Expression in Prostate Tumor Cells and Its Clinical and Biological Significance in Prostate Cancer Progression

    PubMed Central

    St. John, Jason; Powell, Katelyn; Conley-LaComb, M. Katie; Chinni, Sreenivasa R.

    2012-01-01

    TMPRSS2-Ets gene fusions were identified in prostate cancers where the promoter of transmembrane protease, serine 2 (TMPRSS2) fused with coding sequence of the erythroblastosis virus E26 (Ets) gene family members. TMPRSS2 is an androgen responsive transmembrane serine protease. Ets family members are oncogenic transcription factors that contain a highly conserved Ets DNA binding domain and an N-terminal regulatory domain. Fusion of these gene results in androgen dependent transcription of Ets factor in prostate tumor cells. The ERG is the most common fusion partner with TMPRSS2 promoter in prostate cancer patients. The high prevalence of these gene fusions, in particular TMPRSS2-ERG, makes them attractive as potential diagnostic and prognostic indicators, as well as making them a potential target for tailored therapies. This review focuses on the clinical and biological significance of TMPRSS2-ERG fusions and their role in PC development and progression. PMID:23264855

  19. Hyaluronan Tumor Cell Interactions in Prostate Cancer Growth and Survival

    DTIC Science & Technology

    2009-12-01

    Score (Figure 2B). Elevated levels of both HA (Figure 3A) and Hyal- 1(Figure 3B) were also observed in both BPH and prostate cancer, with a...elevated in BPH , and most strongly elevated in prostate carcinomas (Figure 2B). The intensity of RHAMM staining increased as a function of Gleason...by co-precipitation. Studies are currently underway to test this model in the prostate cancer model. 2. RHAMM expression should enhance the level of

  20. Isolation of prostate tumor initiating cells (TICs) through their dielectrophoretic signature.

    PubMed

    Salmanzadeh, Alireza; Romero, Lina; Shafiee, Hadi; Gallo-Villanueva, Roberto C; Stremler, Mark A; Cramer, Scott D; Davalos, Rafael V

    2012-01-07

    In this study, the dielectrophoretic response of prostate tumor initiating cells (TICs) was investigated in a microfluidic system utilizing contactless dielectrophoresis (cDEP). The dielectrophoretic response of prostate TICs was observed to be distinctively different than that for non-TICs, enabling them to be sorted using cDEP. Culturing the sorted TICs generated spheroids, indicating that they were indeed initiating cells. This study presents the first marker-free TIC separation from non-TICs utilizing their electrical fingerprints through dielectrophoresis.

  1. 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.

  2. The same and not the same: heterogeneous functional activation of prostate tumor cells by TLR ligation

    PubMed Central

    2014-01-01

    Background Many types of tumors are organized in a hierarchy of heterogeneous cell populations with different molecular signature. Such heterogeneity may be associated with different responsiveness to microenvironment stimuli. In the present study, the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA), as well-known mediators of inflammation, on cancerous behavior of three prostate tumor cells, LNCaP, PC3 and DU145, were investigated. Methods Expression of TLR1-10, CD14 and MyD88 transcripts was investigated by RT-PCR. Protein expression of TLR2 and 4 was scrutinized by flow cytometry, immunofluorescent staining and Western blotting. Experiments were set up to assess the effects of LPS and LTA at different concentrations and times on cell proliferation, extracellular matrix invasion, adhesion and cytokine production. Results We showed that prostate cancer cell lines differentially express TLR1-10, MyD88 and CD14 transcripts. DU145 failed to express TLR4 gene. Positively-identified TLR2 protein in all prostate cancer cells and TLR4 protein in PC3 and LNCaP by Western blotting was not accompanied by cell surface expression, as judged by flow cytometry. Immunofluorescent staining clearly demonstrated predominantly perinuclear localization of TLR2 and TLR4. LTA activation of all prostate cancer cells significantly increased cell proliferation. Regardless of lacking TLR4, DU145 cells proliferated in response to LPS treatment. While LPS caused increased invasiveness of LNCaP, invasive capacity of PC3 was significantly reduced after LPS or LTA stimulation. Stimulation of all prostate tumor cells with LTA was associated with increased cell adhesion and IL-8 production. IL-6 production, however, was differentially regulated by LPS stimulation in prostate tumor cells. Conclusion The data shows that cancer cells originated from the same histologically origin exhibit heterogeneous response to the same TLR ligand. Therefore, a thorough and comprehensive judgment

  3. 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

  4. PSMA-homing dsRNA chimeric protein vector kills prostate cancer cells and activates anti-tumor bystander responses

    PubMed Central

    Langut, Yael; Edinger, Nufar; Flashner-Abramson, Efrat; Melamed-Book, Naomi; Lebendiker, Mario; Levi-Kalisman, Yael; Klein, Shoshana; Levitzki, Alexander

    2017-01-01

    The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells. The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells. The treatment causes the targeted cancer cells to undergo apoptosis and to secrete toxic cytokines. In a bystander effect, these cytokines kill neighboring cancer cells that do not necessarily overexpress PSMA, and activate immune cells that enhance the killing effect. The strong effects of the targeted polyIC are demonstrated on both 2D cell cultures and 3D tumor spheroids. PMID:28445962

  5. [Abberant methylation of p16, HIC1, N33 and GSTP1 genes in tumor epitelium and tumor-associated stromal cells of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Alekseev, B Ia; Adnreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2007-01-01

    The methylation status of four genes significant in prostate carcinogenesis p16, HIC1, N33 and GSTP1, were evaluated using quantitative methylationsensitive polymerase chain reaction. Tumor epithelia, tumor-associated stroma, normal epithelia, foci of PIN and benign prostate hyperplasia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens of patients with localized prostate cancer by using laser capture microdissection. We found high levels of gene methylation in the tumor epithelium and tumor-associated stromal cells and some methylation in both hyperplastic epithelium and stromal cells in normal-appearing tissues located adjacent to tumors. Promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may play an important role in cancer development and progression. We examined the promoter methylation status of pl6, HIC1, N33 and GSTP1 in prostate biopsy fragments and prostate tissues after radical prostatectomy from patients with adenocarcinoma without laser capture microdissection. Methylation frequencies of all genes in tumor samples were considerably lower than frequencies in microdissected tumour samples (HIC1, 71 versus 89%; p16, 22 versus 78%; GSTP1, 32 versus 100%; N33, 20 versus 33%). The laser capture microdissection is required procedure in methylation studies taking into account multifocality and heterogenity of prostate cancer tissue.

  6. Using circulating tumor cells to inform on prostate cancer biology and clinical utility

    PubMed Central

    Li, Jing; Gregory, Simon G.; Garcia-Blanco, Mariano A.; Armstrong, Andrew J.

    2016-01-01

    Substantial advances in the molecular biology of prostate cancer have led to the approval of multiple new systemic agents to treat men with metastatic castration-resistant prostate cancer (mCRPC). These treatments encompass androgen receptor directed therapies, immunotherapies, bone targeting radiopharmaceuticals and cytotoxic chemotherapies. There is, however, great heterogeneity in the degree of patient benefit with these agents, thus fueling the need to develop predictive biomarkers that are able to rationally guide therapy. Circulating tumor cells (CTCs) have the potential to provide an assessment of tumor-specific biomarkers through a non-invasive, repeatable “liquid biopsy” of a patient’s cancer at a given point in time. CTCs have been extensively studied in men with mCRPC, where CTC enumeration using the Cellsearch® method has been validated and FDA approved to be used in conjunction with other clinical parameters as a prognostic biomarker in metastatic prostate cancer. In addition to enumeration, more sophisticated molecular profiling of CTCs is now feasible and may provide more clinical utility as it may reflect tumor evolution within an individual particularly under the pressure of systemic therapies. Here, we review technologies used to detect and characterize CTCs, and the potential biological and clinical utility of CTC molecular profiling in men with metastatic prostate cancer. PMID:26079252

  7. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    USDA-ARS?s Scientific Manuscript database

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  8. Gene Targets in Prostate Tumor Cells that Mediate Aberrant Growth and Invasiveness

    DTIC Science & Technology

    2005-02-01

    Craig A. Hauser , Ph.D. Gabriele Foos, Ph.D. CONTRACTING ORGANIZATION: The Burnham Institute La Jolla, California 92037 REPORT DATE: February 2005 TYPE...NUMBERS Gene Targets in Prostate Tumor Cells that Mediate DAMD17-02-1-0019 Aberrant Growth and Invasiveness 6. AUTHOR(S) Craig A. Hauser , Ph.D. Gabriele...REPORTABLE OUTCOMES Foos G, Hauser CA (2004) The role of Ets transcription factors in mediating cellular transformation. In: Handbook of Experimental

  9. Oncogenic LINE-1 Retroelements Sustain Prostate Tumor Cells and Promote Metastatic Progression

    DTIC Science & Technology

    2015-10-01

    RNA -sequencing data that we are part way through processing, but suggests so far significant activation of non-coding RNA sequences derived from RNA ...metastasis tumor tissues in the UTHSCSA tissue bank, however the RNA was not considered of sufficient quality to submit for RNA sequencing. We did RNA ...sequencing of LNCaP cell line RNA as this is derived from a prostate cancer lymph node metastatic deposit, although the bioinformatics analysis has

  10. 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.

  11. 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

  12. CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells.

    PubMed

    Olson, Brian M; McNeel, Douglas G

    2011-06-01

    The androgen receptor (AR) is a hormone receptor that plays a critical role in prostate cancer, and depletion of its ligand has long been the cornerstone of treatment for metastatic disease. Here, we evaluate the AR ligand-binding domain (LBD) as an immunological target, seeking to identify HLA-A2-restricted epitopes recognized by T cells in prostate cancer patients. Ten AR LBD-derived, HLA-A2-binding peptides were identified and ranked with respect to HLA-A2 affinity and were used to culture peptide-specific T cells from HLA-A2+ prostate cancer patients. These T-cell cultures identified peptide-specific T cells specific for all ten peptides in at least one patient, and T cells specific for peptides AR805 and AR811 were detected in over half of patients. Peptide-specific CD8+ T-cell clones were then isolated and characterized for prostate cancer cytotoxicity and cytokine expression, identifying that AR805 and AR811 CD8+ T-cell clones could lyse prostate cancer cells in an HLA-A2-restricted fashion, but only AR811 CTL had polyfunctional cytokine expression. Epitopes were confirmed using immunization studies in HLA-A2 transgenic mice, in which the AR LBD is an autologous antigen with an identical protein sequence, which showed that mice immunized with AR811 developed peptide-specific CTL that lyse HLA-A2+ prostate cancer cells. These data show that AR805 and AR811 are HLA-A2-restricted epitopes for which CTL can be commonly detected in prostate cancer patients. Moreover, CTL responses specific for AR811 can be elicited by direct immunization of A2/DR1 mice. These findings suggest that it may be possible to elicit an anti-prostate tumor immune response by augmenting CTL populations using AR LBD-based vaccines.

  13. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

    Recurrent Non-small Cell Lung Cancer; Recurrent Prostate Cancer; Stage III Prostate Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  14. Malignant phyllodes tumor of the prostate.

    PubMed

    Kim, H S; Lee, J H; Nam, J H; Lee, M C; Park, C S; Juhng, S W; Ro, J Y; Choi, C

    1999-12-01

    Phyllodes tumor of the prostate is rare. We have recently experienced a case of phyllodes tumor of the prostate in a 57-year-old man who complained of urinary retention for 1 year. The epithelial components were positive reactivity for prostate specific antigen. The stromal cells showed nuclear atypia with increased mitotic activity. The tumor was diagnosed as a malignant phyllodes tumor as it invaded into the urinary bladder and rectum, and grew rapidly immediately after operation. We describe the morphological features and immunohistochemical findings of malignant phyllodes tumor and review the literature.

  15. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.

    PubMed

    Labrecque, Mark P; Takhar, Mandeep K; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J; Massah, Shabnam; Haegert, Anne; Bell, Robert H; Altamirano-Dimas, Manuel; Collins, Colin C; Lee, Frank J S; Prefontaine, Gratien G; Cox, Michael E; Beischlag, Timothy V

    2016-04-26

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies.

  16. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    PubMed Central

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  17. Complement C1q Activates Tumor Suppressor WWOX to Induce Apoptosis in Prostate Cancer Cells

    PubMed Central

    Hong, Qunying; Sze, Chun-I; Lin, Sing-Ru; Lee, Ming-Hui; He, Ruei-Yu; Schultz, Lori; Chang, Jean-Yun; Chen, Shean-Jen; Boackle, Robert J.; Hsu, Li-Jin; Chang, Nan-Shan

    2009-01-01

    Background Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1) and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells. Methodology/Principal Findings DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated complement protein. Under complement C1q- or C6-free conditions, WOX1 and ERK were mainly present in the cytoplasm without phosphorylation, whereas phosphorylated JNK1 was greatly accumulated in the nuclei. Exogenous C1q rapidly restored the WOX1 activation (with Tyr33 phosphorylation) in less than 2 hr. Without serum complement C9, p53 became activated, and hyaluronan (HA) reversed the effect. Under C6-free conditions, HA induced activation of STAT3, an enhancer of metastasis. Notably, exogenous C1q significantly induced apoptosis of WOX1-overexpressing DU145 cells, but not vehicle-expressing cells. A dominant negative and Y33R mutant of WOX1 blocked the apoptotic effect. C1q did not enhance p53-mediated apoptosis. By total internal reflection fluorescence (TIRF) microscopy, it was determined that C1q destabilized adherence of WOX1-expressing DU145 cells by partial detaching and inducing formation of clustered microvilli for focal adhesion particularly in between cells. These cells then underwent shrinkage, membrane blebbing and death. Remarkably, as determined by immunostaining, benign prostatic hyperplasia and prostate cancer were shown to have a significantly reduced expression of tissue C1q, compared to age-matched normal prostate tissues. Conclusions/Significance We conclude that complement C1q may induce apoptosis of prostate cancer cells by activating WOX1 and destabilizing cell adhesion. Downregulation of C1q enhances prostate hyperplasia and cancerous formation due to

  18. MicroRNA-302a Suppresses Tumor Cell Proliferation by Inhibiting AKT in Prostate Cancer

    PubMed Central

    Zhang, Gui-Ming; Bao, Chun-Yang; Wan, Fang-Ning; Cao, Da-Long; Qin, Xiao-Jian; Zhang, Hai-Liang; Zhu, Yao; Dai, Bo; Shi, Guo-Hai; Ye, Ding-Wei

    2015-01-01

    Micro (mi) RNAs are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in prostate cancer (PCa). MiRNA-302a expression was detected in 44 PCa tissues and 10 normal prostate tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on PCa cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal prostate tissues, miRNA-302a expression was downregulated in PCa tissues, and was even lower in PCa tissues with a Gleason score ≥8. Overexpression of miRNA-302a induced G1/S cell cycle arrest in PCa cells, and suppressed PCa cell proliferation both in vitro and in vivo. Furthermore, miRNA-302a inhibits AKT expression by directly binding to its 3΄ untranslated region, resulting in subsequent alterations of the AKT-GSK3β-cyclin D1 and AKT-p27Kip1 pathway. These results reveal miRNA-302a as a tumor suppressor in PCa, suggesting that miRNA-302a may be used as a potential target for therapeutic intervention in PCa. PMID:25922934

  19. 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.

  20. Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone

    PubMed Central

    Zhang, Baohui; Huo, Lihong; Lai, Kevin; Li, Xinmin; Galet, Colette; Grogan, Tristan R.; Elashoff, David; Freedland, Stephen J.; Rettig, Matthew; Aronson, William J.; Knudsen, Beatrice S.; Lewis, Michael S.; Garraway, Isla P.

    2016-01-01

    Background Benign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation. To identify the TIC niche in human prostate tissue, differential keratin (KRT) expression was evaluated. Results Gene expression data generated from Affymetrix Gene Chip human U133 Plus 2.0 array of sorted adult and fetal epithelial cells revealed KRT13 to be significantly enriched in FC and TIC compared to basal cells (BC) and luminal cells (LC) (p<0.001). Enriched KRT13 expression was confirmed by RT-PCR and cytospin immunostaining. Immunohistochemical analysis of KRT13 expression revealed rare KRT13+ epithelia throughout prostatic ducts/acini in adult tissue specimens and differentiated tubules in 24-week recombinant grafts, In contrast, abundant KRT13 expression was observed in developing ducts/acini in fetal prostate and cord-like structures composing 8-week recombinant grafts. Immunostaining of a prostate tissue microarray revealed KRT13+ tumor foci in approximately 9% of cases, and this subset displayed significantly shorter time to recurrence (p = 0.031), metastases (p = 0.032), and decreased overall survival (p = 0.004). Diagnostic prostate needle biopsies (PNBX) from untreated patients with concurrent bone metastases (clinical stage M1) displayed KRT13+ tumor foci, as did bone metastatic foci. Conclusions The expression profile of KRT13 in benign fetal and adult prostate tissue and in recombinant grafts, as well as the frequency of KRT13 expression in primary and metastatic prostate cancer indicates that it

  1. CD54-NOTCH1 axis controls tumor initiation and cancer stem cell functions in human prostate cancer

    PubMed Central

    Li, Chong; Liu, Shengwu; Yan, Ruping; Han, Ning; Wong, Kwok-Kin; Li, Lei

    2017-01-01

    Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration. Additional in vitro and in vivo assays showed that CD54 played a critical role in the self-renewal and tumorigenesis of prostate CSCs. Moreover, silencing CD54 greatly reduced the tumorigenesis of prostate cancers both in vitro and in vivo and significantly extended the survival time of tumor-bearing mice in a prostate cancer xenograft model. Dissection of the molecular mechanism revealed that the p38-Notch1 axis was the main downstream signaling pathway in CD54-mediated regulation of CSCs in prostate cancers. Together, these results established that CD54 could be a novel reliable prostate CSC marker and provided a new potential therapeutic target in prostate cancer via CD54-Notch1 signaling. PMID:28042317

  2. [State of the art about new therapeutic vaccines in prostate cancer: dendritic cells, engineered tumor cells and recombinant virus].

    PubMed

    Eymard, Jean-Christophe; Gervais, Alban; Jarcau, Rosana; Bernard, Jacky

    2007-07-01

    Therapeutic vaccines for prostate cancer were initially reported as limited with low immunological responses and uncertain clinical benefit. Recently, new methods become available, such preparations of well-characterized autologous dendritic cells, and use of gene therapy tools to increase whole-tumor cells or host tissue immunogenicity. These are able to enhance and diversify therapeutic options. Indeed, several vaccinal approaches are being investigated, including optimized mature dendritic cells, allogeneic genetically modified tumor cells, or viral vectors. Due to the description of immunological and clinical responses, large phase III randomized trials are now conducted. After summarizing the mechanistic basis for these approaches, this review describes the experience with the most recent and promising clinical studies and introduces short-term perspectives that could lead to improvement in healthcare offer for prostate cancer patients.

  3. CCR 20th Anniversary Commentary: Circulating Tumor Cells in Prostate Cancer.

    PubMed

    Mehra, Niven; Zafeiriou, Zafeiris; Lorente, David; Terstappen, Leon W M M; de Bono, Johann S

    2015-11-15

    Circulating tumor cells (CTC) have substantial promise for multipurpose biomarker studies in prostate cancer. The IMMC-38 trial conducted by de Bono and colleagues, which was published in the October 1, 2008, issue of Clinical Cancer Research, demonstrated for the first time that CTCs are the most accurate and independent predictor of overall survival in metastatic prostate cancer. Since the publication of prospective trials demonstrating prognostic utility, CTCs have been utilized for nucleic acid analyses, for protein analyses, and in intermediate endpoint studies. CTC studies are also now facilitating the analysis of intrapatient heterogeneity. See related article by de Bono et al., Clin Cancer Res 2008;14(19) October 1, 2008;6302-9.

  4. Landscape phage fusion protein-mediated targeting of nanomedicines enhances their prostate tumor cell association and cytotoxic efficiency.

    PubMed

    Jayanna, Prashanth K; Bedi, Deepa; Gillespie, James W; DeInnocentes, Patricia; Wang, Tao; Torchilin, Vladimir P; Bird, Richard C; Petrenko, Valery A

    2010-08-01

    Tumor-specific cytotoxicity of drugs can be enhanced by targeting them to tumor receptors using tumor-specific ligands. Phage display offers a high-throughput approach to screen for the targeting ligands. We have successfully isolated phage fusion peptides selective and specific for PC3 prostate cancer cells. Also, we have demonstrated a novel approach of targeting liposomes through tumor-specific phage fusion coat proteins, exploiting the intrinsic properties of the phage coat protein as an integral membrane protein. Here we describe the production of Rhodamine-labeled liposomes as well as doxorubicin-loaded long-circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides, as an extension of our previous studies. Targeting of labeled liposomes was demonstrated using fluorescence microscopy as well as flow cytometry. Targeting of doxorubicin-loaded liposomes enhanced their cytotoxic effect against PC3 cells in vitro, indicating a possible therapeutic advantage. The simplicity of the approach for generating targeted liposomes coupled with the ability to rapidly obtain tumor-specific phage fusion proteins via phage display may contribute to a combinatorial system for the production of targeted liposomal therapeutics for advanced stages of prostate tumor. From the clinical editor: This paper demonstrates targeting cytotoxic agents to tumor receptors using tumor-specific ligands. The authors describe the production of Rhodamine-labeled liposomes as well as doxorubicin loaded long circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides. This approach may be especially relevant for advanced prostate tumors. 2010 Elsevier Inc. All rights reserved.

  5. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

    SciTech Connect

    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  6. Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

    SciTech Connect

    Tian Junqiang; Ning Shouchen; Knox, Susan J.

    2010-09-01

    Purpose: We have previously shown that sodium selenite (SSE) increases radiation-induced cell killing of human prostate carcinoma cells in vitro. In this study we further evaluated the in vivo radiosensitizing effect of SSE in prostate cancer xenograft tumors and normal radiosensitive intestinal crypt cells. Methods and Materials: Immunodeficient (SCID) mice with hormone-independent LAPC-4 (HI-LAPC-4) and PC-3 xenograft tumors (approximately 200 mm{sup 3}) were divided into four groups: control (untreated), radiation therapy (XRT, local irradiation), SSE (2 mg/kg, intraperitoneally, 3 times/week), and XRT plus SSE. The XRT was given at the beginning of the regimen as a single dose of 5 Gy for HI-LAPC-4 tumors and a single dose of 7 Gy followed by a fractional dose of 3 Gy/d for 5 days for PC-3 tumors. The tumor volume was measured 3 times per week. The radiosensitizing effect of SSE on normal intestinal epithelial cells was assessed by use of a crypt cell microcolony assay. Results: In the efficacy study, SSE alone significantly inhibited the tumor growth in HI-LAPC-4 tumors but not PC-3 tumors. Sodium selenite significantly enhanced the XRT-induced tumor growth inhibition in both HI-LAPC-4 and PC-3 tumors. In the toxicity study, SSE did not affect the intestinal crypt cell survival either alone or in combination with XRT. Conclusions: Sodium selenite significantly enhances the effect of radiation on well-established hormone-independent prostate tumors and does not sensitize the intestinal epithelial cells to radiation. These results suggest that SSE may increase the therapeutic index of XRT for the treatment of prostate cancer.

  7. Hyaluronan Tumor Cell Interactions in Prostate Cancer Growth and Survival

    DTIC Science & Technology

    2006-12-01

    shown that Rhamm can replace CD44 as an HA receptor in promoting collagen induced arthritis .[39] The inflamed joints of the knockout mice showed...Mohapatra, S., et al., Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression. J Exp Med, 1996. 183(4): p...increases at this stage of the cell cycle.[ 1 , 12, 13] Small (2500 dalton) HA oligosaccharides, or truncated constructs of cellular HA receptors that

  8. Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses.

    PubMed

    Jachetti, Elena; Mazzoleni, Stefania; Grioni, Matteo; Ricupito, Alessia; Brambillasca, Chiara; Generoso, Luca; Calcinotto, Arianna; Freschi, Massimo; Mondino, Anna; Galli, Rossella; Bellone, Matteo

    2013-05-01

    According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSCs induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSCs and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer.

  9. Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses

    PubMed Central

    Jachetti, Elena; Mazzoleni, Stefania; Grioni, Matteo; Ricupito, Alessia; Brambillasca, Chiara; Generoso, Luca; Calcinotto, Arianna; Freschi, Massimo; Mondino, Anna; Galli, Rossella; Bellone, Matteo

    2013-01-01

    According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSCs induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSCs and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer. PMID:23762811

  10. Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells.

    PubMed

    Kikuno, Nobuyuki; Shiina, Hiroaki; Urakami, Shinji; Kawamoto, Ken; Hirata, Hiroshi; Tanaka, Yuichiro; Majid, Shahana; Igawa, Mikio; Dahiya, Rajvir

    2008-08-01

    Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappaB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer.

  11. Dormant Circulating Tumor Cells in Prostate Cancer: Therapeutic, Clinical and Biological Implications.

    PubMed

    Alvarez-Cubero, Maria J; Vázquez-Alonso, Fernando; Puche-Sanz, Ignacio; Ortega, F Gabriel; Martin-Prieto, M; Garcia-Puche, José L; Pascual-Geler, Manrique; Lorente, José A; Cozar-Olmo, José M; Serrano, Maria J

    2016-01-01

    Circulating Tumor Cells (CTCs) are a valuable prognostic factor in several solid tumors. By understanding the biological characteristics of CTCs we could better understand the biology of metastasis. CTCs usually adopt a dormant state that is believed to be a strategy to survive in extreme conditions. To enter a dormant state, CTCs undergo numerous phenotypic, genetic and functional mutations that significantly affect the efficacy of the therapies used to kill dormant CTCs. Hence, understanding the biological events involved in the dormancy process of CTCs would allow the identification of new therapeutic targets. Some experimental studies or preclinical models have explored these biological events, as well as the molecular factors that contribute to the maintenance of and release from dormancy. However, few studies have assessed the effects of anticancer therapies on dormant cells. This study reviews current the data currently available on cell dormancy mechanisms in prostate cancer, with a special focus on the functional, genetic and phenotypic plasticity of CTCs and their potential implications in the clinical and therapeutic management of prostate cancer.

  12. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2013-04-01

    epithelium , stroma, as well as immune system, and the fixed nature of the prostate model with expression of the large T antigen, which may have limited...cancer glandular architecture formed (Figure 8). Figure 8. Subcutanous TRAMP Model to Recapitulate Prostate Cancer. TRAMP C2 cells with and...model to be able to alter the aggressiveness of the tumor and specifically modulate the TLR signaling pathway in prostate epithelium , stroma, and immune

  13. Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients

    PubMed Central

    Kuske, Andra; Gorges, Tobias M.; Tennstedt, Pierre; Tiebel, Anne-Kathrin; Pompe, Raisa; Preißer, Felix; Prues, Sandra; Mazel, Martine; Markou, Athina; Lianidou, Evi; Peine, Sven; Alix-Panabières, Catherine; Riethdorf, Sabine; Beyer, Burkhard; Schlomm, Thorsten; Pantel, Klaus

    2016-01-01

    The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non-metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring ≥5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p < 0.0001) and clinical tumor stage (p = 0.04), while the other assays showed no significant correlations. In conclusion, CTC-based liquid biopsies have the potential to monitor MRD in patients with non-metastatic prostate cancer. PMID:28000772

  14. Influence of Anti-Mouse Interferon Serum on the Growth and Metastasis of Tumor Cells Persistently Infected with Virus and of Human Prostatic Tumors in Athymic Nude Mice

    NASA Astrophysics Data System (ADS)

    Reid, Lola M.; Minato, Nagahiro; Gresser, Ion; Holland, John; Kadish, Anna; Bloom, Barry R.

    1981-02-01

    Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF--NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.

  15. Mechanosensitive Ca(2+) permeant cation channels in human prostate tumor cells.

    PubMed

    Maroto, Rosario; Kurosky, Alexander; Hamill, Owen P

    2012-01-01

    The acquisition of cell motility plays a critical role in the spread of prostate cancer (PC), therefore, identifying a sensitive step that regulates PC cell migration should provide a promising target to block PC metastasis. Here, we report that a mechanosensitive Ca(2+)-permeable cation channel (MscCa) is expressed in the highly migratory/invasive human PC cell line, PC-3 and that inhibition of MscCa by Gd(3+) or GsMTx-4 blocks PC-3 cell migration and associated elevations in [Ca(2+)](i). Genetic suppression or overexpression of specific members of the canonical transient receptor potential Ca(2+) channel family (TRPC1 and TRPC3) also inhibit PC-3 cell migration, but they do so by mechanisms other that altering MscCa activity. Although LNCaP cells are nonmigratory, they also express relatively large MscCa currents, indicating that MscCa expression alone cannot confer motility on PC cells. MscCa in both cell lines show similar conductance and ion selectivity and both are functionally coupled via Ca(2+) influx to a small Ca(2+)-activated K(+) channel. However, MscCa in PC-3 and LNCaP cell patches show markedly different gating dynamics--while PC-3 cells typically express a sustained, non-inactivating MscCa current, LNCaP cells express a mechanically-fragile, rapidly inactivating MscCa current. Moreover, mechanical forces applied to the patch, can induce an irreversible transition from the transient to the sustained MscCa gating mode. Given that cancer cells experience increasing compressive and shear forces within a growing tumor, a similar shift in channel gating in situ would have significant effects on Ca(2+) signaling that may play a role in tumor progression.

  16. Phyllodes tumor of the prostate.

    PubMed

    Fujii, Tomomi; Shimada, Keiji; Tanaka, Nobumichi; Fujimoto, Kiyohide; Konishi, Noboru

    2012-03-01

    In this report, we describe a case of phyllodes tumor of the prostate with a high value of prostate-specific antigen (PSA). A 47-year-old man with symptoms of hematospermia presented with a steadily elevated serum PSA value of 60.76 ng/mL (normal range, < 4 ng/mL). A needle biopsy revealed atypical stromal cells without any evidence of malignancy. After radical prostatectomy, the tumor measured 2.9 cm in diameter and consisted of a single nodule composed of irregular, elongated epithelial ducts and atypical stromal cells with enlarged, occasionally multinucleated, pleomorphic, or hyperchromatic nuclei. Immunohistochemistry showed that the atypical stromal cells were positive for vimentin, androgen receptor, estrogen receptor, progesterone, and 5α-reductase, but negative for MIB-1, PSA, SMA, p53, desmin, CD34, c-kit, CD10, S-100, and EGFR. Excess PSA might be secreted by hyperplastic luminal cells driven by 5α-reductase-positive stromal and epithelial cells. Array-comparative genomic hybridization (array CGH) for genomic alterations revealed a gain of 11p13, which includes the WT1 gene, and a loss of 1p36.23 and 12p12.1. After surgery, the serum PSA value rapidly decreased to within the normal range; no recurrence or distant metastasis was noted after 2 years of follow up. © 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

  17. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

    SciTech Connect

    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-05-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and {beta}-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  18. Therapeutic Roles of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    DTIC Science & Technology

    2013-10-01

    CJ, Corn PG. Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 103:1665-75, (2011). PMC: 21917607. 5. MacVicar...Methods 2009;347(1–2):70–78. 30. Hurt EM, Kawasaki BT , Klarmann GJ, Thomas SB, Farrar WL. Cd44þ cd24() prostate cells are early cancer progenitor/stem

  19. The Mechanosensory Ca2+ Channel as a Central Regulator of Prostate Tumor Cell Migration and Invasiveness

    DTIC Science & Technology

    2008-01-01

    receptor‐gated channels, including the first vanilloid receptor TRP channel TRPV1 (Caterina et al., 1997). However, its application to MS channels has...1 ( TRPV1 ) in LNCaP and PC‐3 prostate cancer cells and in prostate tissue. Eur. J. Pharmacol. 515, 20–27. Sarntinoranont, M., Rooney, F., and Ferrari

  20. Reactivation of Embryonic Nodal Signaling is Associated with Tumor Progression and Promotes the Growth of Prostate Cancer Cells

    PubMed Central

    Lawrence, Mitchell G.; Margaryan, Naira V.; Loessner, Daniela; Collins, Angus; Kerr, Kris M.; Turner, Megan; Seftor, Elisabeth A.; Stephens, Carson R.; Lai, John; BioResource, APC; Postovit, Lynne-Marie; Clements, Judith A.; Hendrix, Mary J.C.

    2011-01-01

    Background Nodal is a member of the Transforming Growth Factor β (TGFβ) superfamily that directs embryonic patterning and promotes the plasticity and tumorigenicity of tumor cells, but its role in the prostate is unknown. The goal of this study was to characterize the expression and function of Nodal in prostate cancer and determine whether, like other TGFβ ligands, it modulates androgen receptor (AR) activity. Methods Nodal expression was investigated using immunohistochemistry of tissue microarrays and Western blots of prostate cell lines. The functional role of Nodal was examined using Matrigel and soft agar growth assays. Cross-talk between Nodal and AR signaling was assessed with luciferase reporter assays and expression of endogenous androgen regulated genes. Results Significantly increased Nodal expression was observed in cancer compared with benign prostate specimens. Nodal was only expressed by DU145 and PC3 cells. All cell lines expressed Nodal’s co-receptor, Cripto-1, but lacked Lefty, a critical negative regulator of Nodal signaling. Recombinant human Nodal triggered downstream Smad2 phosphorylation in DU145 and LNCaP cells, and stable transfection of pre-pro-Nodal enhanced the growth of LNCaP cells in Matrigel and soft agar. Finally, Nodal attenuated AR signaling, reducing the activity of a PSA promoter construct in luciferase assays and down-regulating the endogenous expression of androgen regulated genes. Conclusions An aberrant Nodal signaling pathway is re-expressed and functionally active in prostate cancer cells. PMID:21656830

  1. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

    DTIC Science & Technology

    2014-10-01

    Genome-wide association studies ( GWAS ) have linked human chromosome 8q24.21 region with increased risk for prostatic carcinoma but the how this region...not. Further studies should scrutinize the functional differences between these POU5F1B variants. GWAS studies and the evidence of POU5F1B

  2. A specific aptamer-cell penetrating peptides complex delivered siRNA efficiently and suppressed prostate tumor growth in vivo

    PubMed Central

    Diao, Yanjun; Liu, Jiayun; Ma, Yueyun; Su, Mingquan; Zhang, Hongyi; Hao, Xiaoke

    2016-01-01

    ABSTRACT Specific and efficient delivery of siRNA into intended tumor cells remains as a challenge, even though RNAi has been exploited as a new strategy for prostate cancer therapy. This work aims to address both specificity and efficiency of SURVIVIN-siRNA delivery by constructing a therapeutic complex using combinatorial strategies. A fusion protein STD was first expressed to serve as a backbone, consisting of streptavidin, a cell-penetrating peptide called Trans-Activator of Transcription (TAT) and a double-stranded RNA binding domain. A biotinylated Prostate Specific Membrane Antigen (PSMA) specific aptamer A10 and SURVIVIN-siRNA were then linked to STD protein to form the therapeutic complex. This complex could specifically targeted PSMA+ tumor cells. Compared to lipofectamine and A10-siRNA chimera, it demonstrated higher efficiency in delivering siRNA into target cells by 19.2% and 59.9%, and increased apoptosis by 16.8% and 26.1% respectively. Upon systemic administration, this complex also showed significant efficacy in suppressing tumor growth in athymic mice (p <0.001). We conclude that this therapeutic complex could specifically and efficiently deliver SURVIVIN-siRNA to target cells and suppressed tumor growth in vivo, which indicates its potential to be used as a new strategy in prostate cancer therapy PMID:26954374

  3. DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer.

    PubMed

    Huang, Lin; Chen, Keng; Cai, Zhao-Peng; Chen, Fu-Chao; Shen, Hui-Yong; Zhao, Wei-Hua; Yang, Song-Jie; Chen, Xu-Biao; Tang, Guo-Xue; Lin, Xi

    2017-08-26

    DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development.

    PubMed

    Wang, Qian; Tiffen, Jessamy; Bailey, Charles G; Lehman, Melanie L; Ritchie, William; Fazli, Ladan; Metierre, Cynthia; Feng, Yue Julie; Li, Estelle; Gleave, Martin; Buchanan, Grant; Nelson, Colleen C; Rasko, John E J; Holst, Jeff

    2013-10-02

    L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4-7 months of neoadjuvant hormone therapy (4-7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

  5. Transcriptional regulation of CXCR4 in prostate tumor cells: Significance of TMPRSS2-ERG fusions.¶

    PubMed Central

    Singareddy, Rajareddy; Semaan, Louie; Conley-LaComb, M. Katie; St. John, Jason; Powell, Katelyn; Iyer, Matthew; Smith, Daryn; Heilbrun, Lance K.; Shi, Dongping; Sakr, Wael; Cher, Michael L.; Chinni, Sreenivasa R.

    2013-01-01

    CXCR4 is a chemokine receptor that mediates invasion and metastasis. CXCR4 expression is transcriptionally regulated in cancer cells and is associated with aggressive phenotypes of prostate cancer. Previously, we and others have shown that the ERG transcription factor regulates CXCR4 expression in prostate cancer cells. We further showed that androgens regulate CXCR4 expression via increasing ERG transcription factor expression. Herein, we investigated molecular mechanisms of ERG-mediated CXCR4 promoter activation, phosphorylation of ERG by intracellular kinases and subsequent CXCR4 expression, as well as expression of ERG and CXCR4 in human prostate tumor tissues. Using multiple molecular strategies, we demonstrate that: (a) ERG expressed in TMPRSS2-ERG fusion positive VCaP cells selectively binds with specific ERG/Ets bindings sites in the CXCR4 promoter; (b) distal binding sites mediate promoter activation; (c) exogenously expressed ERG promotes CXCR4 expression; (d) ERG is phosphorylated at Serine 81 and 215, both IKK and Akt kinases induce serine phosphorylation, and Akt mediates CXCR4 expression; (e) ERG-induced CXCR4 drives CXCL12-dependent adhesion to fibronectin; (f) ERG and CXCR4 were co-expressed in human prostate tumor tissues, consistent with ERG-mediated transcriptional activation of CXCR4. These data demonstrates that ERG factor activates CXCR4 expression by binding to the specific ERG/Ets responsive elements and intracellular kinases phosphorylate at ERG at serine residues to induce CXCR4 expression. These findings may provide a mechanistic link between TMPRSS2-ERG translocations and intracellular kinase mediated phosphorylation of ERG on enhanced metastasis of tumor cells via CXCR4 expression and function in prostate cancer cells. PMID:23918819

  6. Recombinant disintegrin domain of human ADAM9 inhibits migration and invasion of DU145 prostate tumor cells

    PubMed Central

    Martin, Ana Carolina Baptista Moreno; Cardoso, Ana Carolina Ferreira; Selistre-de-Araujo, Heloisa Sobreiro; Cominetti, Márcia Regina

    2015-01-01

    One of the most important features of malignant cells is their capacity to invade adjacent tissues and metastasize to distant organs. This process involves the creation, by tumor and stroma cells, of a specific microenvironment, suitable for proliferation, migration and invasion of tumor cells. The ADAM family of proteins has been involved in these processes. This work aimed to investigate the role of the recombinant disintegrin domain of the human ADAM9 (rADAM9D) on the adhesive and mobility properties of DU145 prostate tumor cells. rADAM9D was able to support DU145 cell adhesion, inhibit the migration of DU145 cells, as well as the invasion of this cell line through matrigel in vitro. Overall this work demonstrates that rADAM9D induces specific cellular migratory properties when compared with different constructs having additional domains, specially those of metalloproteinase and cysteine-rich domains. Furthermore, we showed that rADAM9D was able to inhibit cell adhesion, migration and invasion mainly through interacting with α6β1 in DU145 tumor cell line. These results may contribute to the development of new therapeutic strategies for prostate cancer. PMID:26211476

  7. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer.

    PubMed

    Cann, Gordon M; Gulzar, Zulfiqar G; Cooper, Samantha; Li, Robin; Luo, Shujun; Tat, Mai; Stuart, Sarah; Schroth, Gary; Srinivas, Sandhya; Ronaghi, Mostafa; Brooks, James D; Talasaz, Amirali H

    2012-01-01

    Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  8. Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis.

    PubMed

    Heidegger, Isabel; Kern, Johann; Ofer, Philipp; Klocker, Helmut; Massoner, Petra

    2014-05-15

    We scrutinized the effect of insulin receptor (INSR) in addition to IGF1R in PCa using in vitro and in vivo models. In-vitro overexpression of IGF1R and INSRA, but not INSRB increased cell proliferation, colony formation, migration, invasion and resistance to apoptosis in prostate cancer cells (DU145, LNCaP, PC3). Opposite effects were induced by downregulation of IGF1R and total INSR, but not INSRB. In contrast to tumor cells, non-cancerous epithelial cells of the prostate (EP156T, RWPE-1) were inhibited on overexpression and stimulated by knockdown of receptors. In-vivo analyses using the chicken allantoic membrane assay confirmed the tumorigenic effects of IGF1R and INSR. Apart of promoting tumor growth, IGF1R and INSR overexpression also enhanced angiogenesis indicated by higher vessel density and increased number of desmin-immunoreactive pericytes. Our study underscores the oncogenic impact of IGF1R including significant effects on tumor growth, cell migration, sensitivity to apoptotic/chemotherapeutic agents and angiogenesis, and characterizes the INSR, in particular the isoform INSRA, as additional cancer-promoting receptor in prostate cancer. Both, the insulin-like growth factor receptor 1 and the insulin receptor exert oncogenic functions, thus proposing that both receptors need to be considered in therapeutic settings.

  9. Obesity inhibits lymphangiogenesis in prostate tumors.

    PubMed

    Moreira, Ângela; Pereira, Sofia S; Machado, Christiane L; Morais, Tiago; Costa, Madalena; Monteiro, Mariana P

    2014-01-01

    Lymphangiogenesis is the process that leads to new lymphatic vessels formation from preexisting blood vessels in the presence of appropriate inducing signals, which in pathologic conditions such as cancer, may contribute to tumor cells dissemination. The aim of the present study was to study the role of obesity, leptin and insulin in tumor lymphangiogenesis. For that, we have quantified the lymphatic vessels in prostate tumors through their immunohistochemistry staining by Lyve-1 in RM1 prostate tumors induced in different obese mice models (ob/ob, db/db and diet induced obese (DIO) and in normal weight C57BL/6J mice (control). Lymph vessels density was determined by Lyve-1 immunohistochemistry of prostate adenocarcinomas, while the percentage of the Lyve-1 stained area and lymphatic vessels number were obtained using a morphometric computerized tool. Obese ob/ob and DIO mice presented prostate tumors that were significantly larger (p<0.001) than controls, while tumors of db/db mice were significantly smaller (p=0.047). Lyve-1 expression was significantly higher in prostate tumors of DIO mice compared to tumors of db/db mice (p<0.05); furthermore Lyve-1 expression was negatively correlated with the percentage of the epididymal fat and body weight (p<0.01). No significantly correlations were found between Lyve-1 expression and tumor weight and leptin or insulin plasma levels. Our results suggest that obesity may have a protective effect against prostate cancer dissemination by inhibiting lymphangiogenesis through a still unidentified mechanism that appears not to involve leptin or insulin.

  10. Dissociated Primary Human Prostate Cancer Cells Coinjected with the Immortalized Hs5 Bone Marrow Stromal Cells Generate Undifferentiated Tumors in NOD/SCID-γ Mice

    PubMed Central

    Chen, Xin; Liu, Bigang; Li, Qiuhui; Honorio, Sofia; Liu, Xin; Liu, Can; Multani, Asha S.; Calhoun-Davis, Tammy; Tang, Dean G.

    2013-01-01

    Reconstitution of tumor development in immunodeficient mice from disaggregated primary human tumor cells is always challenging. The main goal of the present study is to establish a reliable assay system that would allow us to reproducibly reconstitute human prostate tumor regeneration in mice using patient tumor-derived single cells. Using many of the 114 untreated primary human prostate cancer (HPCa) samples we have worked on, here we show that: 1) the subcutaneum represents the most sensitive site that allows the grafting of the implanted HPCa pieces; 2) primary HPCa cells by themselves fail to regenerate tumors in immunodeficient hosts; 3) when coinjected in Matrigel with rUGM (rat urogenital sinus mesenchyme), CAF (carcinoma-associated fibroblasts), or Hs5 (immortalized bone marrow derived stromal) cells, primary HPCa cells fail to initiate serially transplantable tumors in NOD/SCID mice; and 4) however, HPCa cells coinjected with the Hs5 cells into more immunodeficient NOD/SCID-IL2Rγ−/− (NSG) mice readily regenerate serially transplantable tumors. The HPCa/Hs5 reconstituted ‘prostate’ tumors present an overall epithelial morphology, are of the human origin, and contain cells positive for AR, CK8, and racemase. Cytogenetic analysis provides further evidence for the presence of karyotypically abnormal HPCa cells in the HPCa/Hs5 tumors. Of importance, HPCa/Hs5 xenograft tumors contain EpCAM+ cells that are both clonogenic and tumorigenic. Surprisingly, all HPCa/Hs5 reconstituted tumors are undifferentiated, even for HPCa cells derived from Gleason 7 tumors. Our results indicate that primary HPCa cells coinjected with the immortalized Hs5 stromal cells generate undifferentiated tumors in NSG mice and we provide evidence that undifferentiated HPCa cells might be the cells that possessed tumorigenic potential and regenerated HPCa/Hs5 xenograft tumors. PMID:23451107

  11. Controlling RECK miR21 Promotes Tumor Cell Invasion and Is Related to Biochemical Recurrence in Prostate Cancer

    PubMed Central

    Leite, Katia R. M.; Reis, Sabrina T.; Viana, Nayara; Morais, Denis R.; Moura, Caio M.; Silva, Iran A.; Pontes, José; Katz, Betina; Srougi, Miguel

    2015-01-01

    The search for biomarkers to characterize prostate cancer aggressiveness has been the objective for the majority of researchers involved with the most prevalent tumor in men. MiRNAs are important for the control of many cellular functions and their deregulation is involved with tumor development and progression. To find miRNAs differentially expressed in prostate cancer and their relation to prognostic factors and biochemical recurrence we studied 53 surgical specimens from men who underwent radical prostatectomy, through a microarray analysis using the microarray platform (GeneChip® miRNA Array - Affymetrix) with more than 46,000 probes and 847 mature human miRNAs and transcripts. We defined different as an expression level greater or less than 1.1 with p<0.05. The validation study using qRT-PCR had confirmed miR21 as overexpressed in tumor that have recurred with a risk of 2.5. Transfection of miR-21 using lipid based assay in DU145 cell line, showed decrease in expression of RECK resulting in increase in expression of MMP9. Invasion assay with Matrigel showed increase in tumor cell invasion after miR-21 transfection. We conclude that miR-21 overexpression is related to increased biochemical recurrence after surgical treatment of prostate cancer. And the negative control of RECK results in overexpression of MMP9 promotes increasing tumor cell invasion supporting miR-21 as an oncomiR related to aggressiveness in prostate cancer. PMID:25663948

  12. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    DTIC Science & Technology

    2014-07-01

    treatment with hormonal therapy . We have shown that this novel assay can effectively measure AR activity levels in CTCs, and that CTC AR activity at baseline...and after therapy may be correlated with treatment outcomes in prostate cancer. In addition, we have made progress in single CTC digital gene...castration-resistant prostate cancer cells that have acquired resistance to AR targeting therapies . Finally, this Award has enabled the protection of

  13. Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling.

    PubMed

    Qu, Yi; Oyan, Anne Margrete; Liu, Runhui; Hua, Yaping; Zhang, Jigang; Hovland, Randi; Popa, Mihaela; Liu, Xiaojun; Brokstad, Karl A; Simon, Ronald; Molven, Anders; Lin, Biaoyang; Zhang, Wei-dong; McCormack, Emmet; Kalland, Karl-Henning; Ke, Xi-Song

    2013-12-01

    How prostate cancer is initiated remains a topic of debate. In an effort to establish a human model of prostate carcinogenesis, we adapted premalignant human prostate EPT2-D5 cells to protein-free medium to generate numerous tight prostate spheres (D5HS) in monolayer culture. In contrast to EPT2-D5 cells, the newly generated D5HS efficiently formed large subcutaneous tumors and subsequent metastases in vivo, showing the tumorigenicity of D5HS spheres. A striking production of interleukin (IL)-6 mRNA and protein was found in D5HS cells. The essential roles of IL-6 and the downstream STAT3 signaling in D5HS tumor sphere formation were confirmed by neutralizing antibody, chemical inhibitors, and fluorescent pathway reporter. In addition, elevated reactive oxygen species (ROS) produced upon protein depletion was required for the activation of IL-6/STAT3 in D5HS. Importantly, a positive feedback loop was found between ROS and IL-6 during tumor sphere formation. The association of ROS/IL-6/STAT3 to the carcinogenesis of human prostate cells was further examined in xenograft tumors and verified by limiting dilution implantations. Collectively, we have for the first time established human prostate tumor-initiating cells based on physiologic adaption. The intrinsic association of ROS and IL-6/STAT3 signaling in human prostate carcinogenesis shed new light on this relationship and define therapeutic targets in this setting.

  14. Enhancement of Tumor Immunotherapy by Blockade of a Prostate Tumor Derived Immunosuppressive Factor

    DTIC Science & Technology

    2006-08-01

    suppresses the growth of human prostate tumor Du145, fibrosarcoma HT1080 and epidermoid tumor A431 cells in an anchorage independent way. Further...of Slit2 had any effect on tumor development. Human fibrosarcoma HT1080 , prostate tumor Du145, and epidermoid tumor line A431 do not express Slit2...lung metastasis in animal models. REPROTABLE OUTCOMES Three stable Slit2 transfectants of human tumor cell lines , HT1080 , Du145 and A431 have

  15. Human Prostate Tumor Antigen-Specific CD8+ Regulatory T Cells are Inhibited by CTLA-4 or IL-35 Blockade

    PubMed Central

    Olson, Brian M.; Jankowska-Gan, Ewa; Becker, Jordan T.; Vignali, Dario A.A.; Burlingham, William J.; McNeel, Douglas G.

    2012-01-01

    Regulatory T cells play important roles in cancer development and progression by limiting the generation of innate and adaptive anti-tumor immunity. We hypothesized that in addition to natural CD4+CD25+ Tregs and myeloid-derived suppressor cells, tumor antigen-specific regulatory T cells interfere with the detection of anti-tumor immunity following immunotherapy. Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses following immunization was prevented by the activity of PAP-specific regulatory cells. These regulatory cells were CD8+CTLA-4+, and their suppression was relieved by blockade of CTLA-4, but not IL-10 or TGF-β. Moreover, antigen-specific CD8+ regulatory T cells were detected prior to immunization in the absence of PAP-specific effector responses. These PAP-specific CD8+CTLA-4+ suppressor T cells expressed IL-35, which was decreased following blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8+CTLA-4+ T cells also suppressed T-cell proliferation in an IL-35-dependent, contact-independent fashion. Taken together, these findings suggest a novel population of CD8+CTLA-4+ IL-35-secreting tumor antigen-specific regulatory T cells arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of antigen-specific effector responses by an IL-35-dependent mechanism. PMID:23152566

  16. Combinatorial Targeting of Prostate Carcinoma Cells and Tumor Associated Pericytes with Antibody-Based Immunotherapy and Metronomic Chemotherapy

    DTIC Science & Technology

    2011-03-01

    4 ( CSPG4 ). This antigen has a restricted distribution in normal tissues, but has high expression in malignant lesions with limited inter-and intra...mesothelioma, melanoma and sarcoma. Relevant to this proposal AN-2 and CSPG4 are expressed in mouse and human prostate cancer cell lines, respectively...Fig. 1). Furthermore AN-2 and CSPG4 expression is upregulated on activated pericytes in the tumor microenvironment (Fig.2). As to the function of

  17. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer.

    PubMed

    Xu, Jingying; Escamilla, Jemima; Mok, Stephen; David, John; Priceman, Saul; West, Brian; Bollag, Gideon; McBride, William; Wu, Lily

    2013-05-01

    Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)(+)F4/80 (EMR1)+ tumor-associated macrophages (TAM), and CD11b(+)Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling, and immunosuppression. In this report, we used a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated, we observed a systemic increase of MDSCs in spleen, lung, lymph nodes, and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by two-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than irradiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs that can limit the efficacy of radiotherapy. Furthermore, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.

  18. Stem Cells in Prostate

    DTIC Science & Technology

    2005-03-01

    disease upon aging, specifically prostate cancer and benign prostatic hyperplasia . In order to study the cell differentiation lineage associated with...specifically prostate cancer and benign prostatic hyperplasia . In order to study the cell differentiation lineage associated with normal and diseased prostate

  19. Effects of freezing on membranes and proteins in LNCaP prostate tumor cells

    PubMed Central

    Wolkers, Willem F.; Balasubramanian, Saravana K.; Ongstad, Emily L.; Zec, Helena C.; Bischof, John C.

    2007-01-01

    Fourier transform infrared spectroscopy (FTIR) and cryomicroscopy were used to define the process of cellular injury during freezing in LNCaP prostate tumor cells, at the molecular level. Cell pellets were monitored during cooling at 2°C/min while the ice nucleation temperature was varied between −3 and −10°C. We show that the cells tend to dehydrate precipitously after nucleation unless intracellular ice formation occurs. The predicted incidence of intracellular ice formation rapidly increases at ice nucleation temperatures below −4°C and cell survival exhibits an optimum at a nucleation temperature of −6°C. The ice nucleation temperature was found to have a great effect on the membrane phase behavior of the cells. The onset of the liquid crystalline to gel phase transition coincided with the ice nucleation temperature. In addition, nucleation at −3°C resulted in a much more co-operative phase transition and a concomitantly lower residual conformational disorder of the membranes in the frozen state compared to samples that nucleated at −10°C. These observations were explained by the effect of the nucleation temperature on the extent of cellular dehydration and intracellular ice formation. Amide-III band analysis revealed that proteins are relatively stable during freezing and that heat-induced protein denaturation coincides with an abrupt decrease in α-helical structures and a concomitant increase in β-sheet structures starting at an onset temperature of approximately 48°C. PMID:17239814

  20. Optical Strategies for Studying Metastatic Mechanisms, Tumor Cell Detection and Treatment of Prostate Cancer

    DTIC Science & Technology

    2006-10-01

    task 1(a) to test the adhesion of PDT treated MLL cells to the extracellular matrix protein collagen IV. MLL cells were treated with 140 nM BPD for 1 h...cancer cells it is a reliable marker for the detection of circulating prostate cancer cells. We have tested the expression of PSMA in LNCaP and MLL cells...Licha, editors. Molecular Imaging: An Essential Tool in Preclinical Research, Diagnostic Imaging, and Therapy. Heidelberg: Springer-Verlag, 2005

  1. A convenient and effective strategy for the enrichment of tumor-initiating cell properties in prostate cancer cells.

    PubMed

    Zhang, Yiming; Huang, Yiqiang; Jin, Zhong; Li, Xiezhao; Li, Bingkun; Xu, Peng; Huang, Peng; Liu, Chunxiao

    2016-09-01

    Stem-like prostate cancer (PrCa) cells, also called PrCa stem cells (PrCSCs) or PrCa tumor-initiating cells (PrTICs), are considered to be involved in the mediation of tumor metastasis and may be responsible for the poor prognosis of PrCa patients. Currently, the methods for PrTIC sorting are mainly based on cell surface marker or side population (SP). However, the rarity of these sorted cells limits the investigation of the molecular mechanisms and therapeutic strategies targeting PrTICs. For PrTIC enrichment, we induced cancer stem cell (CSC) properties in PrCa cells by transducing three defined factors (OCT3/4, SOX2, and KLF4), followed by culture with conventional serum-containing medium. The CSC properties in the transduced cells were evaluated by proliferation, cell cycle, SP assay, drug sensitivity technology, in vivo tumorigenicity, and molecular marker analysis of PrCSCs compared with parental cells and spheroids. After culture with serum-containing medium for 8 days, the PrCa cells transduced with the three factors showed significantly enhanced CSC properties in terms of marker gene expression, sphere formation, chemoresistance to docetaxel, and tumorigenicity. The percentage of CD133(+)/CD44(+) cells was ninefold higher in the transduced cell population than in the adherent PC3 cell population (2.25 ± 0.62 vs. 0.25 ± 0.12 %, respectively), and the SP increased to 1.22 ± 0.18 % in the transduced cell population, but was undetectable in the adherent population. This method can be used to obtain abundant PrTIC material and enables a complete understanding of PrTIC biology and development of novel therapeutic agents targeting PrTICs.

  2. Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth.

    PubMed

    Ahmad, Gulzar; El Sadda, Rana; Botchkina, Galina; Ojima, Iwao; Egan, James; Amiji, Mansoor

    2017-10-10

    The main aim of this study was to evaluate the therapeutic efficacy of an oil-in-water nanoemulsion formulation encapsulating DHA-SBT-1214, a novel omega-3 fatty acid conjugated taxoid prodrug, against prostate cancer stem cells. Nanoemulsions of DHA-SBT-1214 (NE-DHA-SBT-1214) were prepared and characterized. In vitro delivery efficiency and cytotoxicity of NE-DHA-SBT-1214 was compared with solution formulation in PPT2 cells. In vivo studies included analysis of comparative efficacy of NE-DHA-SBT-1214 with Abraxane(®) and placebo nanoemulsions as well as post-treatment alternations in clonogenic and sphere-forming capabilities of the tumor cells. Qualitative intracellular uptake studies of dye encapsulated NEs by confocal imaging showed uptake by both monolayer and spheroid cultured PPT2 cells. Treatment of PPT2 cells with NE DHA-SBT-1214 (1nM-1μM for monolayer culture of cells grown on collagen-coated dishes for 48 h) induced complete cell death, showing higher efficacy as compared to the drug solution. This nanoemulsion (10nM-10μM) also showed toxicity in 3D culture of floating spheroids. Weekly intravenous administration of the NE-DHA-SBT-1214 to NOD/SCID mice bearing subcutaneous PPT2 tumor xenografts led to dramatic suppression of tumor growth compared to Abraxane(®) and placebo nanoemulsion formulation. Viable cells that survived from this in vivo treatment regimen were no longer able to induce floating spheroids and holoclones, whereas control and Abraxane(®) treated tumor cells induced a large number of both. The results show that NE-DHA-SBT-1214 possesses significant activity against prostate CD133(high)/CD44+/(high) tumor-initiating cells both in vitro and in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Myeloid cell leukemia-1 is a key molecular target for mithramycin A-induced apoptosis in androgen-independent prostate cancer cells and a tumor xenograft animal model.

    PubMed

    Choi, Eun-Sun; Jung, Ji-Youn; Lee, Jin-Seok; Park, Jong-Hwan; Cho, Nam-Pyo; Cho, Sung-Dae

    2013-01-01

    Mithramycin A (Mith) is a natural polyketide that has been used in multiple areas of research including apoptosis of various cancer cells. Here, we examined the critical role of Mith in apoptosis and its molecular mechanism in DU145 and PC3 prostate cancer cells and tumor xenografts. Mith decreased cell growth and induced apoptosis in DU145 and PC-3 cells. Myeloid cell leukemia-1 (Mcl-1) was over-expressed in both cell lines compared to RWPE1 cells. Mith inhibited Mcl-1 protein expression in both cells, but only altered Mcl-1 mRNA levels in PC-3 cells. We also found that Mith reduced Mcl-1 protein levels through both proteasome-dependent protein degradation and the inhibition of protein synthesis in DU145 cells. Studies using siRNA confirmed that the knockdown of Mcl-1 induced apoptosis. Mith significantly suppressed TPA-induced neoplastic cell transformation through the down-regulation of the Mcl-1 protein in JB6 cells, and suppressed the transforming activity of both cell types. Mith also inhibited tumor growth and Mcl-1 levels, in addition to inducing apoptosis, in athymic nude mice bearing DU145 cell xenografts without affecting five normal organs. Therefore, Mith inhibits cell growth and induces apoptosis by suppressing Mcl-1 in both prostate cancer cells and xenograft tumors, and thus is a potent anticancer drug candidate for prostate cancer.

  4. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in normal prostate epithelial cells.

    PubMed

    Nesterov, Alexandre; Ivashchenko, Yuri; Kraft, Andrew S

    2002-02-07

    TRAIL is a pro-apoptotic cytokine believed to selectively kill cancer cells without harming normal ones. However, we found that in normal human prostate epithelial cells (PrEC) TRAIL is capable of inducing apoptosis as efficiently as in some tumor cell lines. At the same time, TRAIL did not cause apoptosis in several other human primary cell lines: aorta smooth muscle cells, foreskin fibroblasts, and umbilical vein endothelial cells. Compared to these primary cells, PrEC were found to contain significantly fewer TRAIL receptors DcR1 and DcR2 which are not capable of conducting the apoptotic signal. This result suggests that the unusual sensitivity of PrEC to TRAIL may result from their deficiency in anti-apoptotic decoy receptors. The protein synthesis inhibitor cycloheximide significantly enhanced TRAIL toxicity toward PrEC as measured by tetrazolium conversion but had little or no effect on other TRAIL-induced apoptotic responses. Although cycloheximide did not further accelerate the processing of caspases 3 and 8, it significantly enhanced cleavage of the caspase 3 substrate gelsolin, indicating that in PrEC a protein(s) with a short half-life may inhibit the activity of the executioner caspases toward specific substrates. As the majority of prostate cancers are derived from epithelial cells, our data suggest the possibility that TRAIL could be a useful treatment for the early stages of prostate cancer.

  5. β4 Integrin signaling induces expansion of prostate tumor progenitors

    PubMed Central

    Yoshioka, Toshiaki; Otero, Javier; Chen, Yu; Kim, Young-Mi; Koutcher, Jason A.; Satagopan, Jaya; Reuter, Victor; Carver, Brett; de Stanchina, Elisa; Enomoto, Katsuhiko; Greenberg, Norman M.; Scardino, Peter T.; Scher, Howard I.; Sawyers, Charles L.; Giancotti, Filippo G.

    2013-01-01

    The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells. PMID:23348745

  6. 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.

  7. ANX7, a candidate tumor suppressor gene for prostate cancer

    PubMed Central

    Srivastava, Meera; Bubendorf, Lukas; Srikantan, Vasantha; Fossom, Linda; Nolan, Lisa; Glasman, Mirta; Leighton, Ximena; Fehrle, Wilfred; Pittaluga, Stefania; Raffeld, Mark; Koivisto, Pasi; Willi, Niels; Gasser, Thomas C.; Kononen, Juha; Sauter, Guido; Kallioniemi, Olli P.; Srivastava, Shiv; Pollard, Harvey B.

    2001-01-01

    The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression. PMID:11287641

  8. A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands

    PubMed Central

    Qin, Tai; Barron, Lindsey; Xia, Lu; Huang, Haojie; Villarreal, Maria M.; Zwaagstra, John; Collins, Cathy; Yang, Junhua; Zwieb, Christian; Kodali, Ravindra; Hinck, Cynthia S.; Kim, Sun Kyung; Reddick, Robert L.; Shu, Chang; O’Connor-McCourt, Maureen D.; Hinck, Andrew P.; Sun, Lu-Zhe

    2016-01-01

    The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer. PMID:27863384

  9. A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.

    PubMed

    Qin, Tai; Barron, Lindsey; Xia, Lu; Huang, Haojie; Villarreal, Maria M; Zwaagstra, John; Collins, Cathy; Yang, Junhua; Zwieb, Christian; Kodali, Ravindra; Hinck, Cynthia S; Kim, Sun Kyung; Reddick, Robert L; Shu, Chang; O'Connor-McCourt, Maureen D; Hinck, Andrew P; Sun, Lu-Zhe

    2016-12-27

    The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.

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

    DTIC Science & Technology

    2013-10-01

    4. Dayyani F, Gallick GE, Logothetis CJ, Corn PG. Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 103:1665-75...analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 2009;347(1–2):70–78. 30. Hurt EM, Kawasaki BT

  11. A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T-cell epitope delays tumor growth in a murine model of prostate cancer.

    PubMed

    Klyushnenkova, Elena N; Kouiavskaia, Diana V; Parkins, Christopher J; Caposio, Patrizia; Botto, Sara; Alexander, Richard B; Jarvis, Michael A

    2012-06-01

    Cytomegalovirus (CMV) is a highly immunogenic virus that results in a persistent, life-long infection in the host typically with no ill effects. Certain unique features of CMV, including its capacity to actively replicate in the presence of strong host CMV-specific immunity, may give CMV an advantage compared with other virus-based vaccine delivery platforms. In the present study, we tested the utility of mouse CMV (mCMV)-based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in double-transgenic mice expressing PSA and HLA-DRB1*1501 (DR2bxPSA F1 mice). We assessed the capacity of 2 mCMV-based vectors to induce PSA-specific CD8 T-cell responses and affect the growth of PSA-expressing Transgenic Adenocarcinoma of the Mouse Prostate tumors (TRAMP-PSA). In the absence of tumor challenge, immunization with mCMV vectors expressing either a H2-D(b)-restricted epitope PSA(65-73) (mCMV/PSA(65-73)) or the full-length gene for PSA (mCMV/PSA(FL)) induced comparable levels of CD8 T-cell responses that increased (inflated) with time. Upon challenge with TRAMP-PSA tumor cells, animals immunized with mCMV/PSA(65-73) had delay of tumor growth and increased PSA-specific CD8 T-cell responses, whereas animals immunized with mCMV/PSA(FL) showed progressive tumor growth and no increase in number of splenic PSA(65-73)-specific T cells. The data show that a prototype CMV-based prostate cancer vaccine can induce an effective antitumor immune response in a "humanized" double-transgenic mouse model. The observation that mCMV/PSA(FL) is not effective against TRAMP-PSA is consistent with our previous findings that HLA-DRB1*1501-restricted immune responses to PSA are associated with suppression of effective CD8 T-cell responses to TRAMP-PSA tumors.

  12. DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo.

    PubMed

    Mendonca, Marc S; Turchan, William T; Alpuche, Melanie E; Watson, Christopher N; Estabrook, Neil C; Chin-Sinex, Helen; Shapiro, Jeremy B; Imasuen-Williams, Imade E; Rangel, Gabriel; Gilley, David P; Huda, Nazmul; Crooks, Peter A; Shapiro, Ronald H

    2017-11-01

    Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent.

    PubMed

    Lin, Hsiang-Yu; Kuo, Yi-Chiu; Weng, Yu-I; Lai, I-Lu; Huang, Tim H-M; Lin, Shuan-Pei; Niu, Dau-Ming; Chen, Ching-Shih

    2012-12-01

    Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation. Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-à-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5. CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes. These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy. Copyright © 2012 Wiley Periodicals

  14. 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.

  15. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

    PubMed

    Armstrong, Andrew J; Marengo, Matthew S; Oltean, Sebastian; Kemeny, Gabor; Bitting, Rhonda L; Turnbull, James D; Herold, Christina I; Marcom, Paul K; George, Daniel J; Garcia-Blanco, Mariano A

    2011-08-01

    During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

  16. Prostate tumor grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

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

  17. Prostate tumor grown in NASA Bioreactor

    NASA Technical Reports Server (NTRS)

    2001-01-01

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

  18. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

    PubMed Central

    Li, Jianneng; Alyamani, Mohammad; Zhang, Ao; Chang, Kai-Hsiung; Berk, Michael; Li, Zhenfei; Zhu, Ziqi; Petro, Marianne; Magi-Galluzzi, Cristina; Taplin, Mary-Ellen; Garcia, Jorge A; Courtney, Kevin; Klein, Eric A; Sharifi, Nima

    2017-01-01

    Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation. DOI: http://dx.doi.org/10.7554/eLife.20183.001 PMID:28191869

  19. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer.

    PubMed

    Li, Jianneng; Alyamani, Mohammad; Zhang, Ao; Chang, Kai-Hsiung; Berk, Michael; Li, Zhenfei; Zhu, Ziqi; Petro, Marianne; Magi-Galluzzi, Cristina; Taplin, Mary-Ellen; Garcia, Jorge A; Courtney, Kevin; Klein, Eric A; Sharifi, Nima

    2017-02-13

    Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

  20. Loss of Keap1 Function in Prostate Cancer Cells Causes Chemo- and Radio-resistance and Promotes Tumor Growth

    PubMed Central

    Zhang, Ping; Singh, Anju; Yegnasubramanian, Srinivasan; Esopi, David; Kombairaju, Ponvijay; Bodas, Manish; Wu, Hailong; Bova, G. Steven; Biswal, Shyam

    2010-01-01

    Loss-of-function mutations in the nuclear factor erythroid-2 related factor-2 (Nrf2) inhibitor, Kelch-like-ECH-associated protein (Keap1), result in increased Nrf2 activity in non–small-cell lung cancer (NSCLC) and confer therapeutic resistance. We detected point mutations in Keap1 gene leading to non-conservative amino acid substitutions in prostate cancer cells. We found novel transcriptional and post-transcriptional mechanisms of Keap1 inactivation such as promoter CpG island hypermethylation and aberrant splicing of Keap1 in DU-145 cells. Very low levels of Keap1 mRNA were detected in DU-145 cells, which significantly increased by treatment with DNA methyltransferase inhibitor 5-aza-cytidine. The loss of Keap1 function led to an enhanced activity of Nrf2 and its downstream electrophile/drug detoxification pathway. Inhibition of Nrf2 expression in DU-145 cells by RNAi attenuated the expression of glutathione, thioredoxin, and the drug efflux pathways involved in counteracting electrophiles, oxidative stress, and detoxification of a broad spectrum of drugs. DU-145 cells expressing Nrf2-shRNA had lower levels of total glutathione and higher levels of intracellular reactive oxygen species. Attenuation of Nrf2 function in DU-145 cells enhanced sensitivity to chemotherapeutic drugs and radiation-induced cell death. In addition, Inhibition of Nrf2 greatly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells. Thus, targeting Nrf2 pathway in prostate cancer cells may provide a novel strategy to enhance chemo- and radio-therapy responsiveness and ameliorate the growth and tumorigenecity leading to improved clinical outcomes. PMID:20124447

  1. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    PubMed Central

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  2. Defining the Recruitment of Reactive Stroma Progenitor Cells to the Tumor Microenvironment of Human Prostate Cancer

    DTIC Science & Technology

    2009-02-01

    AD Award Number: W81XWH-08-1-0059 TITLE: Defining the Recruitment of Reactive Stroma Progenitor Cells to the Tumor Microenvironment of Human...2008 - 6 Jan 2009 4. TITLE AND SUBTITLE Defining the Recruitment of Reactive Stroma Progenitor Cells to the Tumor Microenvironment of Human...Symposium on Stem Cells , Cancer, and Aging in Singapore RESEARCH EXPERIENCE 2001 Baylor College of Medicine, Department of Pulmonary and Critical

  3. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    SciTech Connect

    Guo, Jia; Liu, Xiuheng Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  4. Cell density in prostate histopathology images as a measure of tumor distribution

    NASA Astrophysics Data System (ADS)

    Reynolds, Hayley M.; Williams, Scott; Zhang, Alan M.; Ong, Cheng Soon; Rawlinson, David; Chakravorty, Rajib; Mitchell, Catherine; Haworth, Annette

    2014-03-01

    We have developed an automatic technique to measure cell density in high resolution histopathology images of the prostate, allowing for quantification of differences between tumour and benign regions of tissue. Haemotoxylin and Eosin (H&E) stained histopathology slides from five patients were scanned at 20x magnification and annotated by an expert pathologist. Colour deconvolution and a radial symmetry transform were used to detect cell nuclei in the images, which were processed as a set of small tiles and combined to produce global maps of cell density. Kolmogorov-Smirnov tests showed a significant difference in cell density distribution between tumour and benign regions of tissue for all images analyzed (p < 0.05), suggesting that cell density may be a useful feature for segmenting tumour in un-annotated histopathology images. ROC curves quantified the potential utility of cell density measurements in terms of specificity and sensitivity and threshold values were investigated for their classification accuracy. Motivation for this work derives from a larger study in which we aim to correlate ground truth histopathology with in-vivo multiparametric MRI (mpMRI) to validate tumour location and tumour characteristics. Specifically, cell density maps will be registered with T2-weighted MRI and ADC maps from diffusion-weighted MRI. The validated mpMRI data will then be used to parameterise a radiobiological model for designing focal radiotherapy treatment plans for prostate cancer patients.

  5. Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development.

    PubMed

    Pedrosa, Ana-Rita; Graça, José L; Carvalho, Sandra; Peleteiro, Maria C; Duarte, António; Trindade, Alexandre

    2016-01-01

    The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. © 2015 Wiley Periodicals, Inc.

  6. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer.

    PubMed

    Futakuchi, Mitsuru; Fukamachi, Katsumi; Suzui, Masumi

    2016-04-01

    Bone is the most common target organ of metastasis of prostate and breast cancers. This produces considerable morbidity due to skeletal-related events, SREs, including bone pain, hypercalcemia, pathologic fracture, and compression of the spinal cord. The mechanism of bone metastasis is complex and involves cooperative reciprocal interaction among tumor cells, osteoblasts, osteoclasts, and the mineralized bone matrix. The interaction between the metastatic tumor and bone stromal cells has been commonly referred to as the "vicious cycle". Tumor cells stimulate osteoblasts, which in turn stimulate osteoclasts through the secretion of cytokines such as the TNF family member receptor activator of nuclear κB ligand (RANKL). Activated osteoclasts degrade the bone matrix by producing strong acid and proteinases. Bone degradation by osteoclasts releases TGFβ and other growth factors stored in the bone matrix, that further stimulate tumor cells. Bone modifying agents, targeting osteoclast activity, such as bisphosphonate and RANKL antibodies are considered as the standard of care for reducing SREs of patients with bone metastatic diseases. These agents decrease osteoclast activity and delay worsening of skeletal pain and aggravation of bone metastatic diseases. While the management of SREs by these agents may improve patients' lives, this treatment does not address the specific issues of the patients with bone metastasis such as tumor dormancy, drug resistance, or improvement of survival. Here, we review the mechanisms of bone metastasis formation, tumor heterogeneity in the bone microenvironment, and conventional therapy for bone metastatic diseases and discuss the potential development of new therapies targeting tumor heterogeneity in the bone microenvironment.

  7. Targeting TARP, a novel breast and prostate tumor-associated antigen, with T cell receptor-like human recombinant antibodies.

    PubMed

    Epel, Malka; Carmi, Irit; Soueid-Baumgarten, Sharon; Oh, Sang Kon; Bera, Tapan; Pastan, Ira; Berzofsky, Jay; Reiter, Yoram

    2008-06-01

    MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptide-specific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRgamma alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes.

  8. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1

    PubMed Central

    Li, Xin; Fan, Shengjun; Pan, Xueyang; Xiaokaiti, Yilixiati; Duan, Jianhui; Shi, Yundi; Pan, Yan; Tie, Lu; Wang, Xin; Li, Yuhua; Li, Xuejun

    2016-01-01

    Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer. PMID:27863391

  9. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1.

    PubMed

    Li, Xin; Fan, Shengjun; Pan, Xueyang; Xiaokaiti, Yilixiati; Duan, Jianhui; Shi, Yundi; Pan, Yan; Tie, Lu; Wang, Xin; Li, Yuhua; Li, Xuejun

    2016-12-27

    Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.

  10. Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases.

    PubMed

    Chen, Jie-Fu; Ho, Hao; Lichterman, Jake; Lu, Yi-Tsung; Zhang, Yang; Garcia, Mitch A; Chen, Shang-Fu; Liang, An-Jou; Hodara, Elisabeth; Zhau, Haiyen E; Hou, Shuang; Ahmed, Rafi S; Luthringer, Daniel J; Huang, Jiaoti; Li, Ker-Chau; Chung, Leland W K; Ke, Zunfu; Tseng, Hsian-Rong; Posadas, Edwin M

    2015-09-15

    Although enumeration of circulating tumor cells (CTCs) has shown some clinical value, the pool of CTCs contains a mixture of cells that contains additional information that can be extracted. The authors subclassified CTCs by shape features focusing on nuclear size and related this with clinical information. A total of 148 blood samples were obtained from 57 patients with prostate cancer across the spectrum of metastatic states: no metastasis, nonvisceral metastasis, and visceral metastasis. CTCs captured and enumerated on NanoVelcro Chips (CytoLumina, Los Angeles, Calif) were subjected to pathologic review including nuclear size. The distribution of nuclear size was analyzed using a Gaussian mixture model. Correlations were made between CTC subpopulations and metastatic status. Statistical modeling of nuclear size distribution revealed 3 distinct subpopulations: large nuclear CTCs, small nuclear CTCs, and very small nuclear CTCs (vsnCTCs). Small nuclear CTCs and vsnCTC identified those patients with metastatic disease. However, vsnCTC counts alone were found to be elevated in patients with visceral metastases when compared with those without (0.36 ± 0.69 vs 1.95 ± 3.77 cells/mL blood; P<.001). Serial enumeration studies suggested the emergence of vsnCTCs occurred before the detection of visceral metastases. There are morphologic subsets of CTCs that can be identified by fundamental pathologic approaches, such as nuclear size measurement. The results of this observational study strongly suggest that CTCs contain relevant information regarding disease status. In particular, the detection of vsnCTCs was found to be correlated with the presence of visceral metastases and should be formally explored as a putative blood-borne biomarker to identify patients at risk of developing this clinical evolution of prostate cancer. © 2015 American Cancer Society.

  11. ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models.

    PubMed

    Parray, Aijaz; Siddique, Hifzur R; Kuriger, Jacquelyn K; Mishra, Shrawan K; Rhim, Johng S; Nelson, Heather H; Aburatani, Hiroyuki; Konety, Badrinath R; Koochekpour, Shahriar; Saleem, Mohammad

    2014-12-01

    High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/β-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans.

  12. ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: Study in African-American and Caucasian prostate cancer models

    PubMed Central

    Parray, Aijaz; Siddique, Hifzur R.; Kuriger, Jacquelyn K.; Mishra, Shrawan K.; Rhim, Johng S.; Nelson, Heather H.; Aburatani, Hiroyuki; Konety, Badrinath R.; Koochekpour, Shahriar; Saleem, Mohammad

    2015-01-01

    High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/β-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans. PMID:24752651

  13. Inhibition of vimentin or B1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

    SciTech Connect

    Zhang, Xueping; Fournier, Marcia V; Ware, Joy L; Bissell, Mina J; Yacoub, Adly; Zehner, Zendra E

    2008-06-12

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin, or {alpha}6 and {beta}1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of {alpha}6 and {beta}1 integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and {beta}1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis. [Mol Cancer Ther 2009;8(3):499-508].

  14. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    DTIC Science & Technology

    2016-07-01

    treatment response in prostate cancer. Nat Rev Clin Oncol 2014; 11: 401-12. 6. Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, et...U S A 2010; 107: 18392-7. 10. Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10...J. Morris, S. Larson, G. Heller, Nat . Rev . Clin. Oncol. 10, 225–234 (2013). 4. D. Robinson et al., Cell 161, 1215–1228 (2015). 5. D. T. Miyamoto et

  15. The Mechanosensitive Ca2+ Channel as a Central Regular of Prostate Tumor Cell Migration and Invasiveness

    DTIC Science & Technology

    2011-04-01

    Gadolinium blocks a variety of MS channels (e.g., MscCa, MscK, MscL, and MscS), several TRP channels (e.g., TRPC-1, TRPC-4, TRPC-5, and TRPV1 ), various...Vlachova V (2004) Gadolinium activates and sensitizes the vanilloid receptor TRPV1 through the external protonation sites. Mol Cell Neurosci 30:207...M. J., Prieto, J. C., and Diaz‐Laviada, I. I. (2005). Expression of the transient receptor potential vanilliod 1 ( TRPV1 ) in LNCaP and PC‐3 prostate

  16. Adenovirus E2F1 Overexpression Sensitizes LNCaP and PC3 Prostate Tumor Cells to Radiation In Vivo

    SciTech Connect

    Udayakumar, Thirupandiyur S.; Stoyanova, Radka; Hachem, Paul; Ahmed, Mansoor M.; Pollack, Alan

    2011-02-01

    Purpose: We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in vitro. Here, we demonstrate the radiosensitization efficacy of adenovirus (Ad)-E2F1 infection in growing (orthotopic) LNCaP and (subcutaneous) PC3 nude mice xenograft tumors. Methods and Materials: Ad-E2F1 was injected intratumorally in LNCaP (3 x 10{sup 8} plaque-forming units [PFU]) and PC3 (5 x 10{sup 8} PFU) tumors treated with or without radiation. LNCaP tumor volumes (TV) were measured by magnetic resonance imaging, caliper were used to measure PC3 tumors, and serum prostate-specific antigen (PSA) levels were determined by enzyme-linked immunosorbent assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, and key proteins involved in cell death signaling were analyzed by Western blotting. Results: Intracellular overexpression of Ad-E2F1 had a significant effect on the regression of TV and reduction of PSA levels relative to that of adenoviral luciferase (Ad-Luc)-infected control. The in vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA, 34 ng/ml; TV, 142 mm{sup 3}) compared to that of Ad-Luc control (PSA, 59 ng/ml; TV, 218 mm{sup 3}; p <0.05). This effect was significantly enhanced by radiation therapy (compare: Ad-E2F1+RT/PSA, 16 ng/ml, and TV, 55 mm{sup 3} to Ad-Luc+RT/PSA, 42 ng/ml, and TV, 174 mm{sup 3}, respectively; p <0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 infection alone; there was little or no effect when radiotherapy (RT) was combined. However, addition of RT enhanced the level of in situ apoptosis in PC3 tumors. Molecularly, addition of Ad-E2F1 in a combination treatment abrogated radiation-induced BCL-2 protein expression and was associated with an increase in activated BAX, and together they caused a potent radiosensitizing effect, irrespective of p53 and androgen receptor functional status. Conclusions: We show here for the first time that

  17. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Muniyan, Sakthivel; D’Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G.; Bu, Xiu R.; Batra, Surinder K.; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  18. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    PubMed

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  19. 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.

  20. Bicalutamide demonstrates biologic effectiveness in prostate cancer cell lines and tumor primary cultures irrespective of Her2/neu expression levels.

    PubMed

    Gravina, Giovanni Luca; Festuccia, Claudio; Millimaggi, Danilo; Tombolini, Vincenzo; Dolo, Vincenza; Vicentini, Carlo; Bologna, Mauro

    2009-08-01

    To evaluate the role of Her2/neu as a molecular marker predictive of the treatment response to bicalutamide in prostate cancer (PCa). Four PCa cell lines with graded Her2/neu expression levels and 63 primary tumor cultures derived from men with PCa and selected according to Her2/neu tumor levels were used. Primary tumor cultures and PCa cell lines were treated with bicalutamide (0.1-10 microM) in the presence of dehydrotestosterone (10(-12) M) for 4 days. The presence of a significant correlation between Her2/nue expression and drug efficacy was used to define the role of Her2/neu as molecular predictor of bicalutamide effectiveness. As an indicator of drug effectiveness we used the concentration that inhibits 50% values determined after bicalutamide treatment. After bicalutamide treatment, no significant differences in the concentration that inhibits 50% were found among the different tumor cell lines (P = .081). In this experimental model, the correlation analysis suggested that the effectiveness of this drug was not influenced by Her2/neu levels (r = 0.053, P = .823). In primary cultures with high Her2/neu levels (43 tumor cultures), the mean value of the concentration that inhibits 50% for bicalutamide was 0.43 +/- 0.13 microM, and in cultures with low Her2/neu levels (20 tumor cultures), the same parameter was 0.5 +/- 0.16 microM (P = .14). The correlation analysis suggested that the effectiveness of this drug was not influenced by Her2/neu levels (r = 0.33, P = .101). Our biologic data seem to indicate that the antitumor effect of bicalutamide is independent of Her2/neu levels in preclinical models of PCa. Bicalutamide could be configured as a pharmacologic option to treat patients with high or low levels of Her2/neu.

  1. Targeting prostate cancer stem cells.

    PubMed

    Crea, Francesco; Mathews, Lesley A; Farrar, William L; Hurt, Elaine M

    2009-12-01

    Cancer stem cells are the sub-population of cells present within tumors responsible for tumorigenesis. These cells have unique biological properties including self-renewal and the ability to differentiate. Furthermore, it is thought that these cells are more resistant to conventional chemotherapy and, as a result, are responsible for patient relapse. We will discuss the identification of prostate cancer stem cells, their unique properties and how these cells may be targeted for more efficacious therapies.

  2. Glycan Stimulation Enables Purification of Prostate Cancer Circulating Tumor Cells on PEDOT NanoVelcro Chips for RNA Biomarker Detection.

    PubMed

    Shen, Mo-Yuan; Chen, Jie-Fu; Luo, Chun-Hao; Lee, Sangjun; Li, Cheng-Hsuan; Yang, Yung-Ling; Tsai, Yu-Han; Ho, Bo-Cheng; Bao, Li-Rong; Lee, Tien-Jung; Jan, Yu Jen; Zhu, Ya-Zhen; Cheng, Shirley; Feng, Felix Y; Chen, Peilin; Hou, Shuang; Agopian, Vatche; Hsiao, Yu-Sheng; Tseng, Hsian-Rong; Posadas, Edwin M; Yu, Hsiao-Hua

    2017-09-11

    A glycan-stimulated and poly(3,4-ethylene-dioxythiophene)s (PEDOT)-based nanomaterial platform is fabricated to purify circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This new platform, phenylboronic acid (PBA)-grafted PEDOT NanoVelcro, combines the 3D PEDOT nanosubstrate, which greatly enhances CTC capturing efficiency, with a poly(EDOT-PBA-co-EDOT-EG3) interfacial layer, which not only provides high specificity for CTC capture upon antibody conjugation but also enables competitive binding of sorbitol to gently release the captured cells. CTCs purified by this PEDOT NanoVelcro chip provide well-preserved RNA transcripts for the analysis of the expression level of several PCa-specific RNA biomarkers, which may provide clinical insights into the disease. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Detection of circulating prostate tumor cells: alternative spliced variant of PSM induced false-positive result.

    PubMed

    Hisatomi, Hisashi; Nagao, Kumi; Kawakita, Mutsuji; Matsuda, Tadashi; Hirata, Hiroyuki; Yamamoto, Shigeki; Nakamoto, Takaaki; Harasawa, Hiroshi; Kaneko, Noboru; Hikiji, Kazumasa; Tsukada, Yutaka

    2002-11-01

    RT-nested PCR has been introduced as a highly specific and sensitive assay method to detect the prostate-specific membrane antigen (PSM) mRNA in peripheral blood. However, appreciable percentages of false-positive cases have been reported. Additionally, primer sets reported previously could not discriminate between PSM and PSM', an alternatively spliced variant, mRNA. These isoforms can be produced from a single gene. Switches in alternative splicing patterns are often controlled with strict cell-type or developmental-stage specificity. Therefore, it is most important to discriminate between PSM mRNA and PSM' mRNA. Using our highly specific primer sets, PSM mRNA was detected in 3 of 24 peripheral blood samples of normal male volunteers (12.5%) and was not detected in peripheral blood of 11 normal female volunteers. PSM' mRNA was detected in 5 of 24 peripheral blood samples of normal male volunteers (20.8%) and in 4 of 11 of normal female volunteers (36.4%). PSM' mRNA induced false-positive results, it is important for genetic diagnosis of prostate cancer to discriminate between PSM and PSM' using our primer sets with high specificity. The advances in the uniquely designed primer sets may allow researchers to detect a real PSM mRNA without PSM' mRNA.

  4. Loss of Somatostatin Receptor Subtype 2 in Prostate Cancer Is Linked to an Aggressive Cancer Phenotype, High Tumor Cell Proliferation and Predicts Early Metastatic and Biochemical Relapse

    PubMed Central

    Hennigs, Jan K.; Müller, Julia; Adam, Matti; Spin, Joshua M.; Riedel, Emilia; Graefen, Markus; Bokemeyer, Carsten; Sauter, Guido; Huland, Hartwig; Schlomm, Thorsten; Minner, Sarah

    2014-01-01

    Somatostatin receptor subtype 2 (SSTR2) is the most frequently expressed SSTR subtype in normal human tissues. SSTR2 expression is differentially regulated in various tumor types and therapeutic somatostatin analogs binding to SSTR2 are in clinical use. In prostate cancers highly contradictory results in terms of SSTR2 expression and its consequences have been published over the past years. The aim of this study was to clarify prevalence and clinical significance of SSTR2 expression in prostate cancer. Therefore, quantitative immunohistochemistry (IHC) using a tissue microarray containing samples from 3,261 prostate cancer patients with extensive clinical and molecular cancer characteristics and oncological follow-up data was performed. IHC data was compared to publicly available Gene Expression Omnibus datasets of human prostate cancer gene expression arrays. While membranous SSTR2 staining was always seen in normal prostate epithelium, SSTR2 staining was absent in more than half (56.1%) of 2,195 interpretable prostate cancer samples. About 13% of all analyzed prostate cancers showed moderate to strong cytoplasmic and membranous SSTR2 staining. Staining intensities were inversely correlated with high Gleason grade, advanced pT category, high tumor cell proliferation (p<0.0001 each), high pre-operative PSA levels, (p = 0.0011) and positive surgical margins (p = 0.006). In silico analysis confirmed lower SSTR2 gene expression in prostate cancers vs. normal adjacent tissue (p = 0.0424), prostate cancer metastases vs. primary cancers (p = 0.0011) and recurrent vs. non-recurrent prostate cancers (p = 0.0438). PSA-free survival gradually declined with SSTR2 staining intensity (p<0.0001). SSTR2-negative cancers were more likely to develop metastases over time (p<0.05). In conclusion, most prostate cancers are indeed SSTR2-negative and loss of SSTR2 strongly predicts an unfavorable tumor phenotype and poor prognosis. Therefore, SSTR2 expression seems

  5. Peptide Agonists of Vasopressin V2 Receptor Reduce Expression of Neuroendocrine Markers and Tumor Growth in Human Lung and Prostate Tumor Cells

    PubMed Central

    Pifano, Marina; Garona, Juan; Capobianco, Carla S.; Gonzalez, Nazareno; Alonso, Daniel F.; Ripoll, Giselle V.

    2017-01-01

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that express neuropeptides as synaptophysin, chromogranin A (CgA), and specific neuronal enolase (NSE), among others. Vasopressin (AVP) is a neuropeptide with an endocrine, paracrine, and autocrine effect in normal and pathological tissues. AVP receptors are present in human lung, breast, pancreatic, colorectal, and gastrointestinal tumors. While AVP V1 receptors are associated with stimulation of cellular proliferation, AVP V2 receptor (V2r) is related to antiproliferative effects. Desmopressin (dDAVP) is a synthetic analog of AVP that acts as a selective agonist for the V2r, which shows antitumor properties in breast and colorectal cancer models. Recently, we developed a derivative of dDAVP named [V4Q5]dDAVP, which presents higher antitumor effects in a breast cancer model compared to the parental compound. The goal of present work was to explore the antitumor properties of the V2r agonist dDAVP and its novel analog [V4Q5]dDAVP on aggressive human lung (NCI-H82) and prostate cancer (PC-3) cell lines with neuroendocrine (NE) characteristics. We study the presence of specific NE markers (CgA and NSE) and V2r expression in NCI-H82 and PC-3. Both cell lines express high levels of NE markers NSE and CgA but then incubation with dDAVP diminished expression levels of both markers. DDAVP and [V4Q5]dDAVP significantly reduced proliferation, doubling time, and migration in both tumor cell cultures. [V4Q5]dDAVP analog showed a higher cytostatic effect than dDAVP, on cellular proliferation in the NCI-H82 cell line. Silencing of V2r using small interfering RNA significantly attenuated the inhibitory effects of [V4Q5]dDAVP on NCI-H82 cell proliferation. We, preliminarily, explored the in vivo effect of dDAVP and [V4Q5]dDAVP on NCI-H82 small cell lung cancer xenografts. Treated tumors (0.3 μg kg−1, thrice a week) grew slower in comparison to vehicle-treated animals. In this work, we demonstrated

  6. RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway

    PubMed Central

    James, Michael A.; Lu, Yan; Liu, Yan; Vikis, Haris G.; You, Ming

    2009-01-01

    We have identified RGS17 as a commonly induced gene in lung and prostate tumors. Through microarray and gene expression analysis, we show that expression of RGS17 is up-regulated in 80% of lung tumors, and also up-regulated in prostate tumors. Through knockdown and overexpression of RGS17 in tumor cells, we show that RGS17 confers a proliferative phenotype and is required for the maintenance of the proliferative potential of tumor cells. We show through exon microarray, transcript analysis, and functional assays that RGS17 promotes cyclic AMP (cAMP)-responsive element binding protein (CREB)-responsive gene expression, increases cAMP levels, and enhances forskolin-mediated cAMP production. Furthermore, inhibition of cAMP-dependent kinase prevents tumor cell proliferation, and proliferation is partially rescued by RGS17 overexpression. In the present study, we show a role for RGS17 in the maintenance of tumor cell proliferation through induction of cAMP signaling and CREB phosphorylation. The prevalence of the induction of RGS17 in tumor tissues of various types further implicates its importance in the maintenance of tumor growth. PMID:19244110

  7. Diagnosis of a Gastrointestinal Stromal Tumor Presenting as a Prostatic Mass: A Case Report

    PubMed Central

    Huh, Jung-Sik; Park, Kyung Kgi; Kim, Young Joo

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are an unusual and heterogeneous group of spindle cell tumors that can also appear on the exterior of the gastrointestinal tract (extra-GISTs). Despite the fact that extra-GISTs or large rectal GISTs can lead to the clinical impression of a prostatic mass, these tumors are, in general, excluded in the differential diagnosis of spindle cell tumors observed on prostate needle biopsy. Here, we present, in detail, a case of an extra-GIST identified on prostatic biopsy; the tumor was previously believed to be a primary prostatic stromal sarcoma in the differential diagnosis. Every investigator should check for KIT (CD117) in immunohistochemical staining to rule out an extra-GIST prior to diagnosing a solitary prostatic tumor, specialized prostatic stromal tumor, or leiomyosarcoma on prostate needle biopsy. PMID:25606568

  8. Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.

    PubMed

    Caley, Matthew P; King, Helen; Shah, Neel; Wang, Kai; Rodriguez-Teja, Mercedes; Gronau, Julian H; Waxman, Jonathan; Sturge, Justin

    2016-02-01

    The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.

  9. A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer

    PubMed Central

    Chen, Jie-Fu; Lin, Millicent; Li, Fuqiang; Wu, Kui; Wu, Hanjie; Lichterman, Jake; Wan, Haolei; Lu, Chia-Lun; OuYang, William; Ni, Ming; Wang, Linlin; Li, Guibo; Lee, Tom; Zhang, Xiuqing; Yang, Jonathan; Rettig, Matthew; Chung, Leland W.K.; Yang, Huanming; Li, Ker-Chau; Hou, Yong; Tseng, Hsian-Rong; Hou, Shuang; Xu, Xun; Wang, Jun; Posadas, Edwin M.

    2015-01-01

    Previous studies have demonstrated focal but limited molecular similarities between circulating tumor cells (CTCs) and biopsies using isolated genetic assays. We hypothesized that molecular similarity between CTCs and tissue exists at the single cell level when characterized by whole genome sequencing (WGS). By combining the NanoVelcro CTC Chip with laser capture microdissection (LCM), we developed a platform for single-CTC WGS. We performed this procedure on CTCs and tissue samples from a patient with advanced prostate cancer who had serial biopsies over the course of his clinical history. We achieved 30X depth and ≥ 95% coverage. Twenty-nine percent of the somatic single nucleotide variations (SSNVs) identified were founder mutations that were also identified in CTCs. In addition, 86% of the clonal mutations identified in CTCs could be traced back to either the primary or metastatic tumors. In this patient, we identified structural variations (SVs) including an intrachromosomal rearrangement in chr3 and an interchromosomal rearrangement between chr13 and chr15. These rearrangements were shared between tumor tissues and CTCs. At the same time, highly heterogeneous short structural variants were discovered in PTEN, RB1, and BRCA2 in all tumor and CTC samples. Using high-quality WGS on single-CTCs, we identified the shared genomic alterations between CTCs and tumor tissues. This approach yielded insight into the heterogeneity of the mutational landscape of SSNVs and SVs. It may be possible to use this approach to study heterogeneity and characterize the biological evolution of a cancer during the course of its natural history. PMID:26575023

  10. The p202 Gene as a Tumor Suppressor in Prostate Cancer Cells

    DTIC Science & Technology

    2005-06-01

    prostate for advanced prostate cancer patients after hormone cancer, but this study points out that finasteride also increases the deprivation. A growing...prostate outcome may have resulted from the fact that finasteride reduced cancer phenotype. Notably, androgen receptor (AR) not only ntraprostatic... finasteride survival of C3(1)/SV40 transgenic mice in vivo. Emodin as a preventive agent due to the potential high risk for treatment resulted in

  11. Regulation of Prostate Cancer Progression by the Tumor Microenvironment

    PubMed Central

    Shiao, Stephen L.; Chu, Gina Chia-Yi; Chung, Leland W. K.

    2016-01-01

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease . Experimental data has uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  12. Regulation of prostate cancer progression by the tumor microenvironment.

    PubMed

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts

    PubMed Central

    Huang, Guangcun; Osmulski, Pawel A.; Bouamar, Hakim; Mahalingam, Devalingam; Lin, Chun-Lin; Liss, Michael A.; Kumar, Addanki Pratap; Chen, Chun-Liang; Thompson, Ian M.; Sun, Lu-Zhe; Gaczynska, Maria E.; Huang, Tim H.-M.

    2016-01-01

    Activation of TGF-β signaling is known to promote epithelial-mesenchymal transition (EMT) for the development of metastatic castration-resistant prostate cancer (mCRPC). To determine whether targeting TGF-β signaling alone is sufficient to mitigate mCRPC, we used the CRISPR/Cas9 genome-editing approach to generate a dominant-negative mutation of the cognate receptor TGFBRII that attenuated TGF-β signaling in mCRPC cells. As a result, the delicate balance of oncogenic homeostasis is perturbed, profoundly uncoupling proliferative and metastatic potential of TGFBRII-edited tumor xenografts. This signaling disturbance triggered feedback rewiring by enhancing ERK signaling known to promote EMT-driven metastasis. Circulating tumor cells displaying upregulated EMT genes had elevated biophysical deformity and an increase in interactions with chaperone macrophages for facilitating metastatic extravasation. Treatment with an ERK inhibitor resulted in decreased aggressive features of CRPC cells in vitro. Therefore, combined targeting of TGF-β and its backup partner ERK represents an attractive strategy for treating mCRPC patients. PMID:27780930

  14. Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer.

    PubMed

    Ward-Kavanagh, Lindsay K; Zhu, Junjia; Cooper, Timothy K; Schell, Todd D

    2014-08-01

    Adoptive immunotherapy has demonstrated efficacy in a subset of clinical and preclinical studies, but the T cells used for therapy often are rendered rapidly nonfunctional in tumor-bearing hosts. Recent evidence indicates that prostate cancer can be susceptible to immunotherapy, but most studies using autochthonous tumor models demonstrate only short-lived T-cell responses in the tolerogenic prostate microenvironment. Here, we assessed the efficacy of sublethal whole-body irradiation (WBI) to enhance the magnitude and duration of adoptively transferred CD8(+) T cells in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We demonstrate that WBI promoted high-level accumulation of granzyme B (GzB, Gzmb)-expressing donor T cells both in lymphoid organs and in the prostate of TRAMP mice. Donor T cells remained responsive to vaccination in irradiated recipients, but a single round of WBI-enhanced adoptive immunotherapy failed to affect significantly the existing disease. Addition of a second round of immunotherapy promoted regression of established disease in half of the treated mice, with no progression observed. Regression was associated with long-term persistence of effector/memory phenotype CD8(+) donor cells. Administration of the second round of adoptive immunotherapy led to reacquisition of GzB expression by persistent T cells from the first transfer. These results indicate that WBI conditioning amplifies tumor-specific T cells in the TRAMP prostate and lymphoid tissue, and suggest that the initial treatment alters the tolerogenic microenvironment to increase antitumor activity by a second wave of donor cells.

  15. Circulating Tumor Cells in a Phase 3 Study of Docetaxel and Prednisone with or without Lenalidomide in Metastatic Castration-resistant Prostate Cancer.

    PubMed

    Vogelzang, Nicholas J; Fizazi, Karim; Burke, John M; De Wit, Ronald; Bellmunt, Joaquim; Hutson, Thomas E; Crane, Edward; Berry, William R; Doner, Kevin; Hainsworth, John D; Wiechno, Pawel J; Liu, Kejian; Waldman, Michelle F; Gandhi, Anita; Barton, Debora; Jungnelius, Ulf; Fandi, Abderrahim; Sternberg, Cora N; Petrylak, Daniel P

    2017-02-01

    Elevated circulating tumor cell (CTC) blood levels (≥5 cells/7.5ml) convey a negative prognosis in metastatic castration-resistant prostate cancer but their prognostic significance in patients receiving chemotherapy is uncertain. The association between CTC counts (at baseline or after treatment), overall survival (OS), and response to docetaxel with lenalidomide was evaluated in a 208-patient subset from the MAINSAIL trial, which compared docetaxel-prednisone-lenalidomide and docetaxel-prednisone-placebo in metastatic castration-resistant prostate cancer patients. Baseline CTCs were <5 cells/7.5ml blood in 87 (42%) patients and ≥5 cells/7.5ml in 121 (58%) patients. Neither tumor response nor prostate-specific antigen response correlated with baseline CTCs. However, CTC count ≥5 cells/7.5ml was significantly associated with lower OS (hazard ratio: 3.23, p = 0.0028). Increases in CTCs from <5 cells/7.5ml to ≥5 cells/7.5ml after three cycles were associated with significantly shorter OS (hazard ratio: 5.24, p=0.025), whereas CTC reductions from ≥5 cells/7.5ml to <5 cells/7.5ml were associated with the best prognosis (p=0.003). Our study in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy, with or without lenalidomide, showed that patient survival was best predicted by circulating tumor cell count at the start of treatment. A rising circulating tumor cell count after three cycles of therapy predicted poor survival, while a decline predicted good survival. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  16. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    DTIC Science & Technology

    2013-07-01

    4 , Sridhar Ramaswamy 1 , 4 , Mehmet Toner 2 , 5 , Shyamala Maheswaran 1 , 5 , and Daniel A. Haber 1 , 4 , 8 Authors’ Affi liations: 1...4 Shyamala Maheswaran,2,7 Ravi Kapur,1 Daniel A. Haber,2,5,6 Mehmet Toner1,7† o n A pr il 21 , 2 01 3 ag .o rgCirculating tumor cells (CTCs) are

  17. Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue.

    PubMed

    Ai, Jianzhong; Tai, Phillip W L; Lu, Yi; Li, Jia; Ma, Hong; Su, Qin; Wei, Qiang; Li, Hong; Gao, Guangping

    2017-09-01

    Prostate diseases are common in males worldwide with high morbidity. Gene therapy is an attractive therapeutic strategy for prostate diseases, however, it is currently underdeveloped. As well known, adeno virus (Ad) is the most widely used gene therapy vector. The aims of this study are to explore transduction efficiency of Ad in prostate cancer cells and normal prostate tissue, thus further providing guidance for future prostate pathophysiological studies and therapeutic development of prostate diseases. We produced Ad expressing enhanced green fluorescence protein (EGFP), and characterized the transduction efficiency of Ad in both human and mouse prostate cancer cell lines in vitro, as well as prostate tumor xenograft, and wild-type mouse prostate tissue in vivo. Ad transduction efficiency was determined by EGFP fluorescence using microscopy and flow cytometry. Cell type-specific transduction was examined by immunofluorescence staining of cell markers. Our data showed that Ad efficiently transduced human and mouse prostate cancer cells in vitro in a dose dependent manner. Following intratumoral and intraprostate injection, Ad could efficiently transduce prostate tumor xenograft and the major prostatic cell types in vivo, respectively. Our findings suggest that Ad can efficiently transduce prostate tumor cells in vitro as well as xenograft and normal prostate tissue in vivo, and further indicate that Ad could be a potentially powerful toolbox for future gene therapy of prostate diseases. © 2017 Wiley Periodicals, Inc.

  18. Enhancement of Tumor Immunotherapy by Blockade of a Prostate Tumor Derived Immunosuppressive Factor

    DTIC Science & Technology

    2005-02-01

    human fibrosarcoma cell line HT1080 which, like Du145, originally did not express Slit2 but the receptor Robo4 (Fig...tumors suppresses the growth of human prostate tumor Du145, fibrosarcoma HT1080 and epidermoid tumor A431 cells in an anchorage independent way. Further...animal models. REPROTABLE OUTCOMES Two stable Slit2 transfectants of human tumor cell lines , HT1080 and Du145 have been established. 9

  19. Acidosis-Induced Changes in Proteome Patterns of the Prostate Cancer-Derived Tumor Cell Line AT-1.

    PubMed

    Ihling, Angelika; Ihling, Christian H; Sinz, Andrea; Gekle, Michael

    2015-09-04

    Under various pathological conditions, such as inflammation, ischemia and in solid tumors, physiological parameters (local oxygen tension or extracellular pH) show distinct tissue abnormalities (hypoxia and acidosis). For tumors, the prevailing microenvironment exerts a strong influence on the phenotype with respect to proliferation, invasion, and metastasis formation and therefore influences prognosis. In this study, we investigate the impact of extracellular metabolic acidosis (pH 7.4 versus 6.6) on the proteome patterns of a prostate cancer-derived tumor cell type (AT-1) using isobaric labeling and LC-MS/MS analysis. In total, 2710 proteins were identified and quantified across four biological replicates, of which seven were significantly affected with changes >50% and used for validation. Glucose transporter 1 and farnesyl pyrophosphatase were found to be down-regulated after 48 h of acidic treatment, and metallothionein 2A was reduced after 24 h and returned to control values after 48 h. After 24 and 48 h at pH 6.6, glutathione S transferase A3 and NAD(P)H dehydrogenase 1, cellular retinoic acid-binding protein 2, and Na-bicarbonate transporter 3 levels were found to be increased. The changes in protein levels were confirmed by transcriptome and functional analyses. In addition to the experimental in-depth investigation of proteins with changes >50%, functional profiling (statistical enrichment analysis) including proteins with changes >20% revealed that acidosis upregulates GSH metabolic processes, citric acid cycle, and respiratory electron transport. Metabolism of lipids and cholesterol biosynthesis were downregulated. Our data comprise the first comprehensive report on acidosis-induced changes in proteome patterns of a tumor cell line.

  20. A Novel Class of Hsp90 C-Terminal Modulators Have Pre-Clinical Efficacy in Prostate Tumor Cells Without Induction of a Heat Shock Response.

    PubMed

    Armstrong, Heather K; Koay, Yen Chin; Irani, Swati; Das, Rajdeep; Nassar, Zeyad D; Selth, Luke A; Centenera, Margaret M; McAlpine, Shelli R; Butler, Lisa M

    2016-12-01

    While there is compelling rationale to use heat shock protein 90 (Hsp90) inhibitors for treatment of advanced prostate cancer, agents that target the N-terminal ATP-binding site of Hsp90 have shown little clinical benefit. These N-terminal binding agents induce a heat shock response that activates compensatory heat shock proteins, which is believed to contribute in part to the agents' lack of efficacy. Here, we describe the functional characterization of two novel agents, SM253 and SM258, that bind the N-middle linker region of Hsp90, resulting in reduced client protein activation and preventing C-terminal co-chaperones and client proteins from binding to Hsp90. Inhibition of Hsp90 activity in prostate cancer cells by SM253 and SM 258 was assessed by pull-down assays. Cell viability, proliferation and apoptosis were assayed in prostate cancer cell lines (LNCaP, 22Rv1, PC-3) cultured with N-terminal Hsp90 inhibitors (AUY922, 17-AAG), SM253 or SM258. Expression of HSR heat shock proteins, Hsp90 client proteins and co-chaperones was assessed by immunoblotting. Efficacy of the SM compounds was evaluated in human primary prostate tumors cultured ex vivo by immunohistochemical detection of Hsp70 and Ki67. SM253 and SM258 exhibit antiproliferative and pro-apoptotic activity in multiple prostate cancer cell lines (LNCaP, 22Rv1, and PC-3) at low micromolar concentrations. Unlike the N-terminal inhibitors AUY922 and 17-AAG, these SM agents do not induce expression of Hsp27, Hsp40, or Hsp70, proteins that are characteristic of the heat shock response, in any of the prostate cell lines analyzed. Notably, SM258 significantly reduced proliferation within 2 days in human primary prostate tumors cultured ex vivo, without the significant induction of Hsp70 that was caused by AUY922 in the tissues. Our findings provide the first evidence of efficacy of this class of C-terminal modulators of Hsp90 in human prostate tumors, and indicate that further evaluation of these promising new

  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. Prostate biopsy volume predicts final tumor volume.

    PubMed

    Zavaski, Michael E; Korus, Adam; Staff, Ilene; Champagne, Alison; Fish-Furhman, Jamie; Tortora, Joseph; Meraney, Anoop; Kesler, Stuart; Wagner, Joseph

    2014-03-01

    To assess the ability of prostate biopsy volume to effectively predict actual tumor volume, and whether increasing the number of prostate biopsy cores improves the ability to forecast actual tumor volume. 765 patients who underwent robotic radical prostatectomy (2009-2010) were identified. Of these, 663 had complete demographics, biopsy, and final pathology data available. The number ofbiopsy samples, biopsy tumor volume, and actual tumor volume were calculated from pathology reports. Data from 663 radical prostatectomy specimens indicated a positive linearrelationship between biopsy tumor volume and actual tumor volume (R=0.524, P< 0.0001). The number ofbiopsy samples collected (i.e., < or =6, 7-8, 9-10, 11-12, 13-14, or > or =15) did not affect the ability of biopsy tumor volume to predict final tumor volume. The routine collection of biopsy tumor volume may prove useful in predicting actual tumor volume and the construction of more effective preoperative nomograms.

  3. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  4. Heterogeneous PSMA expression on circulating tumor cells - a potential basis for stratification and monitoring of PSMA-directed therapies in prostate cancer

    PubMed Central

    Gorges, Tobias M.; Riethdorf, Sabine; von Ahsen, Oliver; Nastały, Paulina; Röck, Katharina; Boede, Marcel; Peine, Sven; Kuske, Andra; Schmid, Elke; Kneip, Christoph; König, Frank; Rudolph, Marion; Pantel, Klaus

    2016-01-01

    The prostate specific membrane antigen (PSMA) is the only clinically validated marker for therapeutic decisions in prostate cancer (PC). Characterization of circulating tumor cells (CTCs) obtained from the peripheral blood of PC patients might provide an alternative to tissue biopsies called “liquid biopsy”. The aim of this study was to develop a reliable assay for the determination of PSMA on CTCs. PSMA expression was analyzed on tissue samples (cohort one, n = 75) and CTCs from metastatic PC patients (cohort two, n = 29). Specific signals for the expression of PSMA could be seen for different prostate cancer cell line cells (PC3, LaPC4, 22Rv1, and LNCaP) by Western blot, immunohistochemistry (IHC), immunocytochemistry (ICC), and FACS. PSMA expression was found to be significantly increased in patients with higher Gleason grade (p = 0.0011) and metastases in lymph nodes (p = 0.0000085) or bone (p = 0.0020) (cohort one). In cohort two, CTCs were detectable in 20 out of 29 samples (69 %, range from 1 - 1000 cells). Twelve out of 20 CTC-positive patients showed PSMA-positive CTCs (67 %, score 1+ to 3+). We found intra-patient heterogeneity regarding the PSMA status between CTCs and the corresponding primary tumors. The results of our study could help to address the question whether treatment decisions based on CTC PSMA profiling will lead to a measurable benefit in clinical outcome for prostate cancer patients in the near future. PMID:27145459

  5. Latrunculin A and Its C-17-O-Carbamates Inhibit Prostate Tumor Cell Invasion and HIF-1 Activation in Breast Tumor Cells⊥

    PubMed Central

    El Sayed, Khalid A.; Shallal, Hassan M.; Khanfar, Mohammad A.; Muralidharan, A.; Awate, Bhushan; Youssef, Diaa T.A.; Liu, Yang; Zhou, Yu-Dong; Nagle, Dale G.; Shah, Girish

    2010-01-01

    The marine-derived macrolides latrunculins A (1) and B, from the Red Sea sponge Negombata magnifica, have been found to reversibly bind actin monomers, forming a 1:1 complex with G-actin and disrupting its polymerization. The microfilament protein actin is responsible for several essential functions within the cell such as cytokinesis and cell migration. One of the main binding pharmacophores of 1 to G-actin was identified as the C-17 lactol hydroxyl moiety that binds arginine 210 NH. Latrunculin A-17-O-carbamates 2–6 were prepared by reaction with the corresponding isocyanates. Latrunculin A (1) and carbamates 4–6 displayed potent anti-invasive activity against the human highly metastatic human prostate cancer PC-3M cells in a Matrigel™ assay at a concentration range of 50 nM-1 µM. Latrunculin A (1, 500 nM) decreased the disaggregation and cell migration of PC-3M-CT+ spheroids by three-fold. Carbamates 4 and 5 were two and half and five-fold more active than 1, respectively, in this assay with less actin binding affinity. Latrunculin A (1, IC50 6.7 µM) and its 17-O-[N-(benzyl)carbamate (6, IC50 29 µM) suppress hypoxia-induced HIF-1 activation in T47D breast tumor cells. PMID:18298079

  6. MicroRNA Regulation of CD44+ Prostate Tumor Stem/Progenitor Cells and Prostate Cancer Development/Metastasis

    DTIC Science & Technology

    2013-05-01

    Diehn M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Pera RA, Lao K, Clarke MF. Downregulation of miRNA- 200c links breast cancer stem cells with...renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010). 4. Yu, F. et al. let-7 regulates self-renewal and tumorigenicity of breast cancer ...cells. Cell 131, 1109–1123 (2007). 5. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138

  7. 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.

  8. Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells.

    PubMed

    Kondo, Miwako; MacKinnon, Shawna L; Craft, Cheryl C; Matchett, Michael D; Hurta, Robert A R; Neto, Catherine C

    2011-03-30

    Ursolic acid and its cis- and trans-3-O-p-hydroxycinnamoyl esters have been identified as constituents of American cranberries (Vaccinium macrocarpon), which inhibit tumor cell proliferation. Since the compounds may contribute to berry anticancer properties, their content in cranberries, selected cranberry products, and three other Vaccinium species (V. oxycoccus, V. vitis-idaea and V. angustifolium) was determined by liquid chromatography-mass spectroscopy. The ability of these compounds to inhibit growth in a panel of tumor cell lines and inhibit matrix metalloproteinase (MMP) activity associated with tumor invasion and metastasis was determined in DU145 prostate tumor cells. The highest content of ursolic acid and esters was found in V. macrocarpon berries (0.460-1.090 g ursolic acid and 0.040-0.160 g each ester kg(-1) fresh weight). V. vitis-idaea and V. angustifolium contained ursolic acid (0.230-0.260 g kg(-1) ), but the esters were not detected. V. oxycoccus was lowest (0.129 g ursolic acid and esters per kg). Ursolic acid content was highest in cranberry products prepared from whole fruit. Ursolic acid and its esters inhibited tumor cell growth at micromolar concentrations, and inhibited MMP-2 and MMP-9 activity at concentrations below those previously reported for cranberry polyphenolics. Cranberries (V. macrocarpon) were the best source of ursolic acid and its esters among the fruit and products tested. These compounds may limit prostate carcinogenesis through matrix metalloproteinase inhibition. Copyright © 2011 Society of Chemical Industry.

  9. Positron emission tomographic imaging of iodine 124 anti-prostate stem cell antigen-engineered antibody fragments in LAPC-9 tumor-bearing severe combined immunodeficiency mice.

    PubMed

    Fonge, Humphrey; Leyton, Jeffrey V

    2013-05-01

    The humanized antibody (hu1G8) has been shown to localize to prostate stem cell antigen (PSCA) and image PSCA-positive xenografts. We previously constructed hu1G8 anti-PSCA antibody fragments and tested them for tumor targeting and the ability to image prostate cancer at early and late time points postinjection by positron emission tomography (PET). We now then compare the PET imaging and the radioactivity accumulation properties in prostate cancer tumors and nontarget tissues to determine the superior 124I-labeled hu1G8 antibody format. 124I-labeled diabody, minibody, scFv-Fc, scFv-Fc double mutant (DM), and parental IgG were administered into severe combined immunodeficiency (SCID) mice bearing LAPC-9 xenografts and followed by whole-body PET imaging of mice at preselected time points. Regions of interest were manually drawn around tumor and nontarget tissues and evaluated for radioactivity accumulation. The 124I-hu1G8 IgG has its best time point for tumor high-contrast imaging at 168 hours postinjection. The 124I-hu1G8 minibody at 44 hours postinjection results in superior tumor high-contrast imaging compared to the other antibody formats. The 124I-hu1G8 minibody at 44 hours postinjection also has comparable percent tumor radioactivity compared to 124I-hu1G8 IgG at 168 hours postinjection. The 124I-hu1G8 minibody is the best engineered hu1G8 antibody format for imaging prostate cancer.

  10. Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes

    PubMed Central

    Yan, Lisa; Da Silva, Diane M.; Verma, Bhavna; Gray, Andrew; Brand, Heike E.; Skeate, Joseph G.; Porras, Tania B.; Kanodia, Shreya; Kast, W. Martin

    2014-01-01

    Background LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown in a virus induced tumor model to activate immune cells and result in tumor regression, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Methods Real Time PCR was used to evaluate expression of forced LIGHT and various other genes in prostate tumors samples. Adenovirus encoding murine LIGHT was injected intratumorally into TRAMP C2 prostate cancer cell tumor bearing mice for in vivo studies. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor specific lymphocytes were quantified via an ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. Results LIGHT expression peaked within 48 hours of infection, recruited effector T cells into the tumor microenvironment that recognized mouse prostate stem cell antigen (PSCA) and inhibited the infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. Conclusion Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated

  11. Solitary Fibrous Tumor of the Prostate Which Was Initially Misdiagnosed as Prostate Cancer

    PubMed Central

    Osamu, Soma; Murasawa, Hiromi; Yoneyama, Takahiro; Koie, Takuya; Ohyama, Chikara

    2017-01-01

    Solitary fibrous tumor (SFT) of the prostate is a very rare tumor. We report a case of 65-year-old man with SFT of the prostate which was initially misdiagnosed as prostate cancer. Finally, we performed total prostatectomy and the tumor was histologically diagnosed as SFT of the prostate. The patient's clinical course has progressed favorably with no obvious recurrence 18 months postoperatively.

  12. [Giant phyllodes tumor of the prostate].

    PubMed

    Kawamorita, Naoki; Inaba, Yasuo; Soma, Fumihiko; Katayama, Yousei; Mikami, Yoshiki

    2007-09-01

    A 55 year-old man complained dysuria and visited to our hospital. Physical examination showed firm large mass occupying whole abdomen. Computed tomography (CT) demonstrated a huge retroperitoneal tumor which compressed intestine, liver, kidney, and urinary bladder. We performed extirpation of the tumor (8.6 kg, largest diameter 60 cm) which was composed of myxoid stromal region associated with cystic pattern. Histological examination revealed that the epithelium of the cystic region was positive for prostate specific antigen (PSA) immunostaining. The tumor was diagnosed phyllodes tumor of the prostate (prostatic stromal proliferation of uncertain malignancy, PSTUMP). Serum PSA was declined 3.9 ng/ml to 0.9 ng/ml; however, magnetic resonance imaging (MRI) demonstrated a residual (recurrent?) tumor in the pelvis one month after the operation. We carried out total prostatectomy and residual tumor resection. Phyllodes tumor of the prostate is histologically characterized with biphasic pattern of hyperplastic epithelial cysts and variably cellular spindle stroma. The tumor is considered to have malignant potential and several histological factors including cellularity, atypia, etc. are utilized to assess it. However diagnostic criteria and subsequent treatment modalities are not established thus far. Previous reports showed efficacy of total surgical removal rather than partial resection and that we performed radical extirpation of the entire tumor. Close follow up is needed against this frequently recurrent disease.

  13. CXCR4 Expression in Prostate Cancer Progenitor Cells

    PubMed Central

    Dubrovska, Anna; Elliott, Jimmy; Salamone, Richard J.; Telegeev, Gennady D.; Stakhovsky, Alexander E.; Schepotin, Ihor B.; Yan, Feng; Wang, Yan; Bouchez, Laure C.; Kularatne, Sumith A.; Watson, James; Trussell, Christopher; Reddy, Venkateshwar A.; Cho, Charles Y.; Schultz, Peter G.

    2012-01-01

    Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44+/CD133+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy. PMID:22359577

  14. Disseminated Tumor Cells in Prostate Cancer Patients after Radical Prostatectomy and without Evidence of Disease Predicts Biochemical Recurrence

    PubMed Central

    Morgan, Todd M.; Lange, Paul H.; Porter, Michael P.; Lin, Daniel W.; Ellis, William J.; Gallaher, Ian S.; Vessella, Robert L.

    2011-01-01

    Purpose Men with apparently localized prostate cancer often relapse years after radical prostatectomy (RP). We sought to determine if epithelial-like cells identified from bone marrow (BM) in patients after RP (commonly called disseminated tumor cells, DTC) were associated with biochemical recurrence (BR). Experimental Design We obtained BM aspirates from 569 men prior to RP and from 34 healthy men with PSA<2.5 ng/ml to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients after RP with no evidence of disease (NED) was established to evaluate the relationship between DTC and BR. Epithelial cells in the BM were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. Results DTC were present in 72% (408/569) of patients prior to RP. There was no correlation with pathologic stage, Gleason grade, or pre-operative PSA. Three of 34 controls (8.8%) had DTC present. In patients NED post-RP, DTC were present in 56/98 (57%). DTC were detected in 12/14 (86%) NED patients post-RP who subsequently suffered BR. Presence of DTC in NED patients was an independent predictor of recurrence (HR 6.9, CI 1.03–45.9). Conclusions Approximately 70% of men undergoing RP had DTC detected in their BM prior to surgery, suggesting that these cells escape early in the disease. Though pre-operative DTC status does not correlate with pathologic risk factors, persistence of DTC after RP in NED patients was an independent predictor of recurrence. PMID:19147774

  15. Detection of Live Circulating Tumor Cells by a Class of Near-Infrared Heptamethine Carbocyanine Dyes in Patients with Localized and Metastatic Prostate Cancer

    PubMed Central

    Hu, Peizhen; Chu, Chia-Yi; Zhang, Lei; Bui, Matthew H. T.; Ng, Christopher S.; Josephson, David Y.; Knudsen, Beatrice; Tighiouart, Mourad; Kim, Hyung L.; Zhau, Haiyen E.; Chung, Leland W. K.; Wang, Ruoxiang; Posadas, Edwin M.

    2014-01-01

    Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR) heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs) from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR+) CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total) were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population. PMID:24551200

  16. Modulation of Adhesion Molecule Expression on Prostate Tumor Cells after Co-Culture with Eosinophilic Cell Lines

    DTIC Science & Technology

    2001-10-01

    and/or regulate eosinophil activity(8 ). Eosinophils have been traditionally known as anti- helminthic effector cells and inflammatory agents in...the monolayer assay. In order to quantitate the inhibitory activity observed in the monolayer assays, we utilized a Chemi- Imager 4000 (alpha Innotech...experiments, eosinophil:tumor cell clusters were observed. This thus- created high density values which were readily detected by the Chemi- Imager

  17. Regulation of Prostate Tumor Cell Line Proliferation and Tumorigenicity by ErbB4

    DTIC Science & Technology

    2005-02-01

    family of tyrosine kinases, which tumors of the thyroid , breast, and gastrointestinal tract (11- includes EGFR/ErbB1, ErbB2/HER2/Neu, and ErbB3/ 14...ErbB2 is observed medulloblastoma (one of the most common solid tumors of in many human malignancies. In contrast, the roles childhood), patients...Prognostic significance of HER2 and HER4 coexpression in resentative of three independent experiments, childhood medulloblastoma . Cancer Res., 57

  18. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    SciTech Connect

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  19. Quantitative [Fe]MRI of PSMA-targeted SPIONs specifically discriminates among prostate tumor cell types based on their PSMA expression levels

    PubMed Central

    Sillerud, Laurel O

    2016-01-01

    We report the development, experimental verification, and application of a general theory called [Fe]MRI (pronounced fem-ree) for the non-invasive, quantitative molecular magnetic resonance imaging (MRI) of added magnetic nanoparticles or other magnetic contrast agents in biological tissues and other sites. [Fe]MRI can easily be implemented on any MRI instrument, requiring only measurements of the background nuclear magnetic relaxation times (T1, T2) of the tissue of interest, injection of the magnetic particles, and the subsequent acquisition of a pair of T1-weighted and T2-weighted images. These images, converted into contrast images, are subtracted to yield a contrast difference image proportional to the absolute nanoparticle, iron concentration, ([Fe]) image. [Fe]MRI was validated with the samples of superparamagnetic iron oxide nanoparticles (SPIONs) both in agarose gels and bound to human prostate tumor cells. The [Fe]MRI measurement of the binding of anti-prostate specific membrane antigen (PSMA) conjugated SPIONs to PSMA-positive LNCaP and PSMA-negative DU145 cells in vitro allowed a facile discrimination among prostate tumor cell types based on their PSMA expression level. The low [Fe] detection limit of ~2 μM for SPIONs allows sensitive MRI of added iron at concentrations considerably below the US Food and Drug Administration’s human iron dosage guidelines (<90 μM, 5 mg/kg). PMID:26855574

  20. Prostate Cancer Stem Cells: Research Advances

    PubMed Central

    Jaworska, Dagmara; Król, Wojciech; Szliszka, Ewelina

    2015-01-01

    Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease. PMID:26593898

  1. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

    PubMed Central

    Alcayaga-Miranda, Francisca; González, Paz L.; Lopez-Verrilli, Alejandra; Varas-Godoy, Manuel; Aguila-Díaz, Carolina; Contreras, Luis; Khoury, Maroun

    2016-01-01

    Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies. PMID:27286448

  2. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species.

    PubMed

    Alcayaga-Miranda, Francisca; González, Paz L; Lopez-Verrilli, Alejandra; Varas-Godoy, Manuel; Aguila-Díaz, Carolina; Contreras, Luis; Khoury, Maroun

    2016-07-12

    Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies.

  3. MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.

    PubMed

    Wu, Jason Boyang; Yin, Lijuan; Shi, Changhong; Li, Qinlong; Duan, Peng; Huang, Jen-Ming; Liu, Chunyan; Wang, Fubo; Lewis, Michael; Wang, Yang; Lin, Tzu-Ping; Pan, Chin-Chen; Posadas, Edwin M; Zhau, Haiyen E; Chung, Leland W K

    2017-03-13

    Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

  4. Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer.

    PubMed

    Chang, Kun; Kong, Yun-Yi; Dai, Bo; Ye, Ding-Wei; Qu, Yuan-Yuan; Wang, Yue; Jia, Zhong-Wei; Li, Gao-Xiang

    2015-12-08

    Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial-mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow-up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC ≥5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene

  5. SD-208, a Novel Protein Kinase D Inhibitor, Blocks Prostate Cancer Cell Proliferation and Tumor Growth In Vivo by Inducing G2/M Cell Cycle Arrest

    PubMed Central

    Tandon, Manuj; Salamoun, Joseph M.; Carder, Evan J.; Farber, Elisa; Xu, Shuping; Deng, Fan; Tang, Hua; Wipf, Peter; Wang, Q. Jane

    2015-01-01

    Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment. PMID:25747583

  6. Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer.

    PubMed

    Marín-Aguilera, Mercedes; Reig, Òscar; Lozano, Juan José; Jiménez, Natalia; García-Recio, Susana; Erill, Nadina; Gaba, Lydia; Tagliapietra, Andrea; Ortega, Vanesa; Carrera, Gemma; Colomer, Anna; Gascón, Pedro; Mellado, Begoña

    2015-04-30

    The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression.

  7. Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer

    PubMed Central

    Marín-Aguilera, Mercedes; Reig, Òscar; Lozano, Juan José; Jiménez, Natalia; García-Recio, Susana; Erill, Nadina; Gaba, Lydia; Tagliapietra, Andrea; Ortega, Vanesa; Carrera, Gemma; Colomer, Anna; Gascón, Pedro; Mellado, Begoña

    2015-01-01

    The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression. PMID:25871394

  8. Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: perspectives for therapeutics.

    PubMed

    Zhou, Xiaoling; Yang, Xu-Yu; Popescu, Nicholas C

    2010-04-01

    Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and used successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers, including prostate and liver cancer, transduction of 22Rv1 and 7703K cells with an Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 microM) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to histone deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro

  9. Invariant NKT Cell Ligands for Prostate Cancer Vaccines

    DTIC Science & Technology

    2011-06-01

    NUMBER Invariant NKT Cell Ligands for Prostate Cancer Vaccines 5b. GRANT NUMBER W81XWH-09-1-0156 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...efficacy in tumor bearing mice. 15. SUBJECT TERMS prostate cancer , immunotherapy, NKT cells 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...proposal have shown that mice bearing prostate cancers in the TRAMP model ( prostate specific expression on SV40 T antigen, Tag, oncogene) do not respond

  10. Prostate cancer stem cells: from theory to practice.

    PubMed

    Adamowicz, Jan; Pakravan, Katayoon; Bakhshinejad, Babak; Drewa, Tomasz; Babashah, Sadegh

    2017-04-01

    None of the generally accepted theories on prostate cancer development can fully explain many distinguishing features of the disease, such as intratumoral heterogeneity, metastatic growth, drug resistance and tumor relapse. Prostate stem cells are a heterogeneous and small subpopulation of self-renewing cells which can actively proliferate in response to changes in the androgen level and give rise to all the cell lineages that build the prostate epithelium. According to the cancer stem cell hypothesis, prostate cancer could be a stem cell disease. Prostate cancer stem cells, which represent only a minimal percentage of the tumor mass, are characterized by a markedly increased clonogenicity and therapeutic resistance. These tumor-initiating cells reside in dynamic niches distributed within the prostate but at a higher concentration in proximal regions of the prostatic ducts. Several markers have been used to identify prostate cancer stem cells. Nevertheless, a definitive profile has not yet been established owing to specificity issues. As cancer stem cells play determining roles in the birth and burst of prostate malignancy, strategies that selectively target them have gained huge clinical attention. Unraveling the mechanisms underlying the physiological functions of cancer stem cells and gaining fundamental insights into their putative involvement in the pathogenesis of prostate tumors provide novel opportunities for the development of efficient and sophisticated therapeutic strategies in the future.

  11. The Mechanosensitive Ca2+ Channel as a Central Regulator of Prostate Tumor Cell Migration and Invasiveness

    DTIC Science & Technology

    2010-01-01

    nM for 2 hours), an agent reported to promote actin polymerization also did not alter MscCa transient gating in LNCaP cells. However, curcumin (60...channels. J Cell Sci 2008; 121: 496-503. 17. Holy J. Curcumin inhibits cell motility and alters microfilaments organization and function in

  12. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

    PubMed

    Demir, Ummuhan; Koehler, Andrea; Schneider, Rainer; Schweiger, Susann; Klocker, Helmut

    2014-01-31

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin.

  13. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    PubMed Central

    2014-01-01

    Background Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. Methods The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Results Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Conclusions Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin. PMID:24484909

  14. Zinc as an anti-tumor agent in prostate cancer and in other cancers

    PubMed Central

    Franklin, Renty B.; Costello, Leslie C.

    2007-01-01

    Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors. PMID:17400177

  15. Immunotherapy of Prostate Cancer With Genetically Enhanced Tumor-Specific T-Cell Precursors

    DTIC Science & Technology

    2011-06-01

    extrathymic locations. We adoptively transferred Pz1+ preT cells in B6 B6 syngeneic bone marrow transplantation recipients (BMT) recipients. Pz1...would lead to the development of an “off-the-shelf” cell-based therapy without the requirement of bone marrow transplantation . 6. REFERENCES 1

  16. The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells.

    PubMed

    Gravina, Giovanni Luca; Marampon, Francesco; Petini, Foteini; Biordi, Leda; Sherris, David; Jannini, Emmanuele A; Tombolini, Vincenzo; Festuccia, Claudio

    2011-08-01

    One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies.

  17. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression.

    PubMed

    Santoro, Stephen P; Kim, Soorin; Motz, Gregory T; Alatzoglou, Dimitrios; Li, Chunsheng; Irving, Melita; Powell, Daniel J; Coukos, George

    2015-01-01

    Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of protumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here, we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA(+) endothelial targets in vitro, regardless of the signaling domain. T cells bearing the third-generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA(+) vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide a strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA. Cancer Immunol Res; 3(1); 68-84. ©2014 AACR. ©2014 American Association for Cancer Research.

  18. Secondary Signet Ring Cell Carcinoma of Prostate

    PubMed Central

    Khan, Kalyan; Bandyopadhyay, Arghya; Gangopadhyay, Mimi; Chakraborty, Subrata; Bera, Pranati

    2012-01-01

    True metastases to prostate from solid tumors are reported only in 0.2% of all surgical prostatic specimens and 2.9% of all male postmortems. Clinical context, morphological features, and immunohistochemical localization of prostate specific antigen (PSA) are supposed to clarify the differential diagnosis between a secondary and a primary tumor. We report an unusual and rare case of secondary signet ring cell carcinoma (SRCC) of prostate in which the clinical data and signet ring cell morphology pointed toward the diagnosis of a primary SRCC. Immunohistochemistry (IHC) for PSA not only proved the case to be a secondary SRCC but also initiated the process for diagnosis of the occult primary malignancy in the patient′s stomach. PMID:24027389

  19. Somatic Single-hits Inactivate the X-linked Tumor Suppressor FOXP3 in the Prostate

    PubMed Central

    Wang, Lizhong; Liu, Runhua; Li, Weiquan; Chen, Chong; Katoh, Hiroto; Chen, Guo-Yun; McNally, Beth; Lin, Lin; Zhou, Penghui; Zuo, Tao; Cooney, Kathleen A.; Liu, Yang; Zheng, Pan

    2009-01-01

    Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis. PMID:19800578

  20. Tumor-suppressive microRNA-497 targets IKKβ to regulate NF-κB signaling pathway in human prostate cancer cells

    PubMed Central

    Kong, Xiang-Jie; Duan, Liu-Jian; Qian, Xiao-Qiang; Xu, Ding; Liu, Hai-Long; Zhu, Ying-Jian; Qi, Jun

    2015-01-01

    Background: Prostate cancer (PCa) is one of the most prevalent malignant tumors, PCa-related death is mainly due to the high probability of metastasis. MicroRNAs (miRNAs) play an important role in cancer initiation, progression and metastasis by regulating their target genes. Methods: real-time PCR was used to detected the expression of microRNA-497. The molecular biological function was investigated by using cell proliferation assays, cell cycle assay, and migration and invasion assay. We used several Algorithms and confirmed that IKKβ is directly regulated by miR-497. Results: Here, we found miR-497 is downregulated in human prostate cancer (PCa) and inhibites the proliferation activity, migration and invasion of PC3-AR cells. Subsequently, IKKβ is confi rmed as a target of miR-497. Furthermore, knockdown of IKKβ expression resulted in decreased proliferation activity, migration and invasion. Finally, similar results was found after treatment with a novel IKK-β inhibitor (IMD-0354) in PC3-AR cells. CDK8, MMP-9, and PSA were involved in all these process. Conclusion: Taken together, our results show evidence that miR-497 may function as a tumor suppressor genes by regulating IKK-β in PCa, and may provide a strategy for blocking PCa metastasis. PMID:26175947

  1. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth.

    PubMed

    Zhang, Ping; Singh, Anju; Yegnasubramanian, Srinivasan; Esopi, David; Kombairaju, Ponvijay; Bodas, Manish; Wu, Hailong; Bova, Steven G; Biswal, Shyam

    2010-02-01

    Loss-of-function mutations in the nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor Kelch-like ECH-associated protein 1 (Keap1) result in increased Nrf2 activity in non-small cell lung cancer and confer therapeutic resistance. We detected point mutations in Keap1 gene, leading to nonconservative amino acid substitutions in prostate cancer cells. We found novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation, such as promoter CpG island hypermethylation and aberrant splicing of Keap1, in DU-145 cells. Very low levels of Keap1 mRNA were detected in DU-145 cells, which significantly increased by treatment with DNA methyltransferase inhibitor 5-aza-deoxycytidine. The loss of Keap1 function led to an enhanced activity of Nrf2 and its downstream electrophile/drug detoxification pathway. Inhibition of Nrf2 expression in DU-145 cells by RNA interference attenuated the expression of glutathione, thioredoxin, and the drug efflux pathways involved in counteracting electrophiles, oxidative stress, and detoxification of a broad spectrum of drugs. DU-145 cells constitutively expressing Nrf2 short hairpin RNA had lower levels of total glutathione and higher levels of intracellular reactive oxygen species. Attenuation of Nrf2 function in DU-145 cells enhanced sensitivity to chemotherapeutic drugs and radiation-induced cell death. In addition, inhibition of Nrf2 greatly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells. Thus, targeting the Nrf2 pathway in prostate cancer cells may provide a novel strategy to enhance chemotherapy and radiotherapy responsiveness and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.

  2. On the relationship between tumor structure and complexity of the spatial distribution of cancer cell nuclei: a fractal geometrical model of prostate carcinoma.

    PubMed

    Waliszewski, Przemyslaw; Wagenlehner, Florian; Gattenlöhner, Stefan; Weidner, Wolfgang

    2015-03-01

    A risk of the prostate cancer patient is defined by both the objective and subjective criteria, that is, PSA concentration, Gleason score, and pTNM-stage. The subjectivity of tumor grading influences the risk assessment owing to a large inter- and intra-observer variability. Pathologists propose a central prostate pathology review as a remedy for this problem; yet, the review cannot eliminate the subjectivity from the diagnostic algorithm. The spatial distribution of cancer cell nuclei changes during tumor progression. It implies changes in complexity measured by the capacity dimension D0, the information dimension D1, and the correlation dimension D2. The cornerstone of the approach is a model of prostate carcinomas composed of the circular fractals CF(4), CF(6 + 0), and CF(6 + 1). This model is both geometrical and analytical, that is, its structure is well-defined, the capacity fractal dimension D0 can be calculated for the infinite circular fractals, and the dimensions D0, D1, D2 can be computed for their finite counterparts representing distribution of cell nuclei. The model enabled both the calibration of the software and the validation of the measurements in 124 prostate carcinomas. The ROC analysis defined the cut-off D0 values for seven classes of complexity. The Gleason classification matched in part with the classification based on the D0 values. The mean ROC sensitivity was 81.3% and the mean ROC specificity 75.2%. Prostate carcinomas were re-stratified into seven classes of complexity according to their D0 values. This increased both the mean ROC sensitivity and the mean ROC specificity to 100%. All homogeneous Gleason patterns were subordinated to the class C1, C4, or C7. D0 = 1.5820 was the cut-off D0 value between the complexity class C2 and C3 representing low-risk cancers and intermediate-risk cancers, respectively. The global fractal dimensions eliminate the subjectivity in the diagnostic algorithm of prostate cancer. Those complexity

  3. Tumor Specific Regulation of C-CAM Cell Adhesion Molecule in Prostate Cancer Carcinogenesis

    DTIC Science & Technology

    2002-08-01

    692 9. Graff, J. R., Herman, J. G., Lapidus, R. G., Chopra, H., Xu , R., Jarrard, D. F., Isaacs, W. B., Pitha, P. M., Davidson, N. E., and Baylin, S. B...2001) 115-123 www.elsevier.com/locate/mce Androgen regulation of the cell-cell adhesion molecule-1 (Ceacam i) gene Dillon Phan a, Xiaomei Sui b, Dung...Nature Medicine, 1: 686-692, 1995. 27 34. Graff, J. R., Herman, J. G., Lapidus, R. G., Chopra, H., Xu , R., Jarrard, D. F., Isaacs, W. B., Pitha, P. M

  4. Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer.

    PubMed

    Burdelski, Christoph; Reiswich, Viktor; Hube-Magg, Claudia; Kluth, Martina; Minner, Sarah; Koop, Christina; Graefen, Markus; Heinzer, Hans; Tsourlakis, Maria Christina; Wittmer, Corinna; Huland, Hartwig; Simon, Ronald; Schlomm, Thorsten; Sauter, Guido; Steurer, Stefan

    2015-08-01

    Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells. To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies. p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P = 0.0002), 3p13 (P = 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling. Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings. ©2015 American Association for Cancer Research.

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

    DTIC Science & Technology

    2014-10-01

    G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human...1, OCT3/4, Hedgehog (Hh), Wnt/β-catenin, Notch signaling, Hox gene family, PTEN/Akt pathway, efflux transporters such as ABCG markers of self...105-111 (2001). 50. Liu, S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer

  6. Targeting the Adipocyte-Tumor Cell Interaction in Prostate Cancer Treatment

    DTIC Science & Technology

    2014-10-01

    is required for IL-6 overproduction in p62-deficient fibroblasts. We observed a striking decrease in the reduced nicotinamide adenine dinucleotide...phosphate (NADPH)/ nicotinamide adenine dinucleotide phosphate (NADP) ratio in p62-deficient fibroblasts(F) Immunoblot analysis of KEAP1 in cell lysates...liquid organotypic culture cultures have been used extensively in skin (Gaggioli et al., 2007), esophageal (Okawa et al., 2007), pancreas (Coleman et

  7. BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone

    DTIC Science & Technology

    2013-07-01

    2. Polyak , K. and Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev...as abilities of self-renewal and differentiation in addition to their invasive capability (Pantel and Alix-Panabières, 2007; Polyak and Weinberg...must retain stem cell–like properties (Pantel and Alix-Panabières, 2007; Polyak and Weinberg, 2009). Therefore, we intended to examine the effect of

  8. The Mechanosensitive Ca2+ Channel as a Central Regular of Prostate Tumor Cell Migration and Invasiveness

    DTIC Science & Technology

    2009-01-01

    Toimil, M., Ronde, P., Takeda, K., and Baretz, A. (2000). Migration of human vascular smooth muscle cells involves serum‐dependent repeated cytosolic...TRPCs, the C-terminal coiled-coil domains and the N-terminal ankyrin repeats have the potential to mediate protein - CSK interactions. All TRP family...its C-terminus (Wes et al. 1995) that may allow for interaction with dystrophin – the major CSK protein in skeletal muscle – and this could pos

  9. Pulmonary tumor thrombotic microangiopathy caused by prostate carcinoma

    PubMed Central

    Kuriyama, Keiko; Kinoshita, Tatsuya; Nagai, Keisuke; Hongyo, Hidenari; Kishimoto, Kentaro; Inoue, Atsuo; Takamura, Manabu; Choi, Soomi

    2016-01-01

    Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal malignancy-related condition that involves rapidly progressing hypoxia and pulmonary hypertension. We report a case of PTTM caused by prostate carcinoma, which was diagnosed before autopsy in an 81-year-old man. Computed tomography showed diffuse ground-glass opacities, consolidation, and small nodules in the peripheral regions of the lung. Autopsy showed adenocarcinoma cells embolizing small pulmonary arteries with fibrocellular intimal proliferation, which was consistent with PTTM caused by prostate carcinoma. PMID:27635254

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

    DTIC Science & Technology

    2014-10-01

    12183433. 14. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self- renewal of...these interacting pathways are BMI-1, OCT3/4, Hedgehog (Hh), Wnt/β-catenin, Notch signaling, Hox gene family, PTEN/Akt pathway, efflux transporters...and cancer stem cells. Nature 414, 105-111 (2001). 50. Liu, S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant

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

    DTIC Science & Technology

    2014-10-01

    Res 62:4736-45, (2002). PMC: 12183433. 14. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1...Among these interacting pathways are BMI-1, OCT3/4, Hedgehog (Hh), Wnt/β-catenin, Notch signaling, Hox gene family, PTEN/Akt pathway, efflux...cancer, and cancer stem cells. Nature 414, 105-111 (2001). 50. Liu, S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and

  12. CK2 targeted RNAi therapeutic delivered via malignant cell-directed tenfibgen nanocapsule: dose and molecular mechanisms of response in xenograft prostate tumors

    PubMed Central

    Vogel, Rachel I.; Shaughnessy, Daniel P.; Nacusi, Lucas; Korman, Vicci L.; Li, Yingming; Dehm, Scott M.; Zimmerman, Cheryl L.; Niehans, Gloria A.; Unger, Gretchen M.; Trembley, Janeen H.

    2016-01-01

    CK2, a protein serine/threonine kinase, promotes cell proliferation and suppresses cell death. This essential-for-survival signal demonstrates elevated expression and activity in all cancers examined, and is considered an attractive target for cancer therapy. Here, we present data on the efficacy of a tenfibgen (TBG) coated nanocapsule which delivers its cargo of siRNA (siCK2) or single stranded RNA/DNA oligomers (RNAi-CK2) simultaneously targeting CK2α and α′ catalytic subunits. Intravenous administration of TBG-siCK2 or TBG-RNAi-CK2 resulted in significant xenograft tumor reduction at low doses in PC3-LN4 and 22Rv1 models of prostate cancer. Malignant cell uptake and specificity in vivo was verified by FACS analysis and immunofluorescent detection of nanocapsules and PCR detection of released oligomers. Dose response was concordant with CK2αα′ RNA transcript levels and the tumors demonstrated changes in CK2 protein and in markers of proliferation and cell death. Therapeutic response corresponded to expression levels for argonaute and GW proteins, which function in oligomer processing and translational repression. No toxicity was detected in non-tumor tissues or by serum chemistry. Tumor specific delivery of anti-CK2 RNAi via the TBG nanoencapsulation technology warrants further consideration of translational potential. PMID:27557516

  13. Necrosis in DU145 prostate cancer spheroids induces COX-2/mPGES-1-derived PGE2 to promote tumor growth and to inhibit T cell activation.

    PubMed

    Sha, Weixiao; Olesch, Catherine; Hanaka, Hiromi; Rådmark, Olof; Weigert, Andreas; Brüne, Bernhard

    2013-10-01

    Cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2 ) supports the growth of a spectrum of cancers. The potential benefit of COX-2-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) for cancer treatment is however limited by their well-known cardiovascular side-effects. Therefore, targeting microsomal PGE synthase 1 (mPGES-1), the downstream enzyme in the COX-2-dependent pathway of PGE2 production might be attractive, although conflicting data regarding a potential tumor-supporting function of mPGES-1 were reported. We determined the impact of mPGES-1 in human DU145 prostate cancer cell growth. Surprisingly, knockdown of mPGES-1 did not alter growth of DU145 monolayer cells, but efficiently inhibited the growth of DU145 multicellular tumor spheroids (MCTS). Opposed to MCTS, monolayer cells did not secrete PGE2 due to a lack of COX-2 expression, which was induced during spheroid formation. Pharmacological inhibition of COX-2 and mPGES-1 supported the crucial role of PGE2 for growth of MCTS. The functionality of spheroid-derived PGE2 was demonstrated by its ability to inhibit cytotoxic T cell activation. When investigating mechanisms of spheroid-induced COX-2 induction, we observed that among microenvironmental factors neither glucose deprivation, hypoxia nor tumor cell apoptosis enhanced COX-2 expression. Interestingly, interfering with apoptosis in spheroids triggered a shift towards necrosis, thus augmenting COX-2 expression. We went on to demonstrate that necrotic cells induced COX-2 mRNA expression and PGE2 secretion from live tumor cells. In conclusion, necrosis-dependent COX-2 upregulation in MCTS promoted PGE2 -dependent tumor growth and inhibited activated cytotoxic T cells. Hence, blocking mPGES-1 as a therapeutic option may be considered for COX-2/mPGES-1-positive solid cancers.

  14. HLA class II antigen presentation by prostate cancer cells.

    PubMed

    Younger, A R; Amria, S; Jeffrey, W A; Mahdy, A E M; Goldstein, O G; Norris, J S; Haque, A

    2008-01-01

    Prostate cancer is the second most commonly diagnosed cancer in men. Recent evidence suggests that reduced expression of target protein antigens and human leukocyte antigen (HLA) molecules is the predominant immune escape mechanism of malignant prostate tumor cells. The purpose of this study was to investigate the prospect of antigen specific immunotherapy against prostate cancer via the HLA class II pathway of immune recognition. Here, we show for the first time that prostate cancer cells express HLA class II proteins that are recognized by CD4+ T cells. Prostate tumor cells transduced with class II molecules efficiently presented tumor-associated antigens/peptides to CD4+ T cells. This data suggests that malignant prostate tumors can be targeted via the HLA class II pathway, and that class II-positive tumors could be employed for direct antigen presentation, and CD4+ T-cell mediated tumor immunotherapy.Prostate Cancer and Prostatic Diseases (2008) 11, 334-341; doi:10.1038/sj.pcan.4501021; published online 16 October 2007.

  15. Regulation of tumor suppressor EAF2 polyubiquitination by ELL1 and SIAH2 in prostate cancer cells.

    PubMed

    Yu, Xinpei; Ai, Junkui; Cai, Liquan; Jing, Yifeng; Wang, Dan; Dong, Jun; Pascal, Laura E; Zhang, Jian; Luo, Rongcheng; Wang, Zhou

    2016-05-17

    RNA Polymerase II Elongation Factor (ELL)-associated factor 2 (EAF2) is a tumor suppressor frequently down-regulated in human prostate cancer. We previously reported that its binding partner ELL1 can enhance EAF2 protein stability and activity. Here we show that EAF2 can be polyubiquitinated and its degradation blocked by proteasome inhibitor. Co-immunoprecipitation detected EAF2 binding to SIAH2, an E3 ligase, and SIAH2 overexpression enhanced polyubiquitination of EAF2. Co-transfection of EAF2 binding partner ELL1 blocked EAF2 ubiquitination, providing a mechanism for EAF2 stabilization. Finally, EAF2K81R mutant, which exhibits reduced polyubiquitination and increased stability, was more potent than wild-type EAF2 in apoptosis induction. These findings suggest that SIAH2 is an E3 ligase for EAF2 polyubiquitination and ELL1 can enhance EAF2 level and function by blocking its polyubiquitination.

  16. Regulation of tumor suppressor EAF2 polyubiquitination by ELL1 and SIAH2 in prostate cancer cells

    PubMed Central

    Yu, Xinpei; Ai, Junkui; Cai, Liquan; Jing, Yifeng; Wang, Dan; Dong, Jun; Pascal, Laura E.; Zhang, Jian; Luo, Rongcheng; Wang, Zhou

    2016-01-01

    RNA Polymerase II Elongation Factor (ELL)-associated factor 2 (EAF2) is a tumor suppressor frequently down-regulated in human prostate cancer. We previously reported that its binding partner ELL1 can enhance EAF2 protein stability and activity. Here we show that EAF2 can be polyubiquitinated and its degradation blocked by proteasome inhibitor. Co-immunoprecipitation detected EAF2 binding to SIAH2, an E3 ligase, and SIAH2 overexpression enhanced polyubiquitination of EAF2. Co-transfection of EAF2 binding partner ELL1 blocked EAF2 ubiquitination, providing a mechanism for EAF2 stabilization. Finally, EAF2K81R mutant, which exhibits reduced polyubiquitination and increased stability, was more potent than wild-type EAF2 in apoptosis induction. These findings suggest that SIAH2 is an E3 ligase for EAF2 polyubiquitination and ELL1 can enhance EAF2 level and function by blocking its polyubiquitination. PMID:27058417

  17. Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice

    PubMed Central

    Tuomela, Johanna M; Valta, Maija P; Väänänen, Kalervo; Härkönen, Pirkko L

    2008-01-01

    Background Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. Methods PC-3 cells (5 × 105) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. Results Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96–485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209–1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed. Conclusion Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by

  18. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2017-06-01

    Award  Number:    W81XWH-11-1-0260   TITLE:      Regulation  of  the  Prostate   Cancer  Tumor  Microenvironment PRINCIPAL  INVESTIGATOR:      Dr... Cancer Tumor Microenvironment 5a.  CONTRACT  NUMBER   5b.  GRANT  NUMBER  W81XWH--11--1-- 0260 5c.  PROGRAM  ELEMENT  NUMBER   6. AUTHOR(S) Arnold  I...immunity  in  prostate   cancer  tumorigenesis  is  unclear.  We  hypothesis  that  innate  immune  pathways   contribute  to  programming  the

  19. Prostate-Specific Antigen Modulates the Expression of Genes Involved in Prostate Tumor Growth1

    PubMed Central

    Bindukumar, B; Schwartz, Stanley A; Nair, Madhavan P N; Aalinkeel, Ravikumar; Kawinski, Elzbieta; Chadha, Kailash C

    2005-01-01

    Abstract Prostate-specific antigen (PSA) is a serine protease that is widely used as a surrogate marker in the early diagnosis and management of prostate cancer. The physiological relevance of tissue PSA levels and their role in prostate tumor growth and metastasis are not known. Free-PSA (f-PSA) was purified to homogeneity from human seminal plasma by column chromatography, eliminating hk2 and all known PSA complexes and retaining its protease activity. Confluent mono-layers of prostate cancer cell lines, PC-3M and LNCaP, were treated with f-PSA in a series of in vitro experiments to determine the changes in expression of various genes that are known to regulate tumor growth and metastasis. Gene array, quantitative polymerase chain reaction (QPCR), and enzyme-linked immunosorbent assay (ELISA) results show significant changes in the expression of various cancer-related genes in PC-3M and LNCaP cells treated with f-PSA. In a gene array analysis of PC-3M cells treated with 10 µM f-PSA, 136 genes were upregulated and 137 genes were downregulated. In LNCaP cells treated with an identical concentration of f-PSA, a total of 793 genes was regulated. QPCR analysis reveals that the genes for urokinase-type plasminogen activator (uPA), VEGF, and Pim-1 oncogene, known to promote tumor growth, were significantly downregulated, whereas IFN-γ, known to be a tumor-suppressor gene, was significantly upregulated in f-PSA-treated PC-3M cells. The effect of f-PSA on VEGF and IFN-γ gene expression and on protein release in PC-3M cells was distinctly dose-dependent. In vivo studies showed a significant reduction (P = .03) in tumor load when f-PSA was administered in the tumor vicinity of PC-3M tumor-bearing BALB/c nude mice. Our data support the hypothesis that f-PSA plays a significant role in prostate tumor growth by regulating various proangiogenic and antiangiogenic growth factors. PMID:15799824

  20. Nanomicellar TGX221 blocks xenograft tumor growth of prostate cancer in nude mice

    PubMed Central

    Chen, Ruibao; Zhao, Yunqi; Huang, Yan; Yang, Qiuhong; Zeng, Xing; Jiang, Wencong; Liu, Jihong; Thrasher, J. Brantley; Forrest, M. Laird; Li, Benyi

    2014-01-01

    Background Combination of androgen ablation along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men due to castration-resistant progression, suggesting that novel therapeutic agents are urgently needed for this life-threaten condition. Phosphatidylinositol 3-kinase p110β is a major cellular signaling molecule and has been identified as a critical factor in prostate cancer progression. In a recent report, we established a nanomicelle-based strategy to deliver p110β-specific inhibitor TGX221 to prostate cancer cells by conjugating the surface of nanomicelles with a RNA aptamer against prostate membrane specific antigen (PSMA) present in all clinical prostate cancers. In this study, we tested this nanomicellar TGX221 for its in vivo anti-tumor effect in mouse xenograft models. Methods Prostate cancer cell lines LAPC-4, LNCaP, C4-2 and 22RV1 were used to establish subcutaneous xenograft tumors in nude mice. Paraffin sections from xenograft tumor specimens were used in immunohistochemistry assays to detect AKT phosphorylation, cell proliferation marker Ki67 and PCNA, as well as BrdU incorporation. Quantitative PCR assay was conducted to determine PSA gene expression in xenograft tumors. Results Although systemic delivery of unconjugated TGX221 significantly reduced xenograft tumor growth in nude mice compared to solvent control, the nanomicellar TGX221 conjugates completely blocked tumor growth of xenografts derived from multiple prostate cancer cell lines. Further analyses revealed that AKT phosphorylation and cell proliferation indexes were dramatically reduced in xenograft tumors received nanomicellar TGX221 compared to xenograft tumors received unconjugated TGX221 treatment. There was no noticeable side effect by gross observation or at microscopic level of organ tissue section. Conclusion These data strongly suggest that prostate

  1. Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

    SciTech Connect

    Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D.; Marples, Brian

    2010-03-01

    Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing gammaH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2mug/mL], Trinovin [10mug/mL], and Prostate Rx [50 mug/mL]). However, both Trinovin (10mug/mL) and Prostate Rx (6mug/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

  2. The tumor suppressor ING1b is a novel corepressor for the androgen receptor and induces cellular senescence in prostate cancer cells.

    PubMed

    Esmaeili, Mohsen; Jennek, Susanne; Ludwig, Susann; Klitzsch, Alexandra; Kraft, Florian; Melle, Christian; Baniahmad, Aria

    2016-06-01

    The androgen receptor (AR) signaling is critical for prostate cancer (PCa) progression to the castration-resistant stage with poor clinical outcome. Altered function of AR-interacting factors may contribute to castration-resistant PCa (CRPCa). Inhibitor of growth 1 (ING1) is a tumor suppressor that regulates various cellular processes including cell proliferation. Interestingly, ING1 expression is upregulated in senescent primary human prostate cells; however, its role in AR signaling in PCa was unknown. Using a proteomic approach by surface-enhanced laser desorption ionization-mass spectrometry (SELDI-MS) combined with immunological techniques, we provide here evidence that ING1b interacts in vivo with the AR. The interaction was confirmed by co-immunoprecipitation, in vitro GST-pull-down, and quantitative intracellular colocalization analyses. Functionally, ING1b inhibits AR-responsive promoters and endogenous key AR target genes in the human PCa LNCaP cells. Conversely, ING1b knockout (KO) mouse embryonic fibroblasts (MEFs) exhibit enhanced AR activity, suggesting that the interaction with ING1b represses the AR-mediated transcription. Also, data suggest that ING1b expression is downregulated in CRPCa cells compared with androgen-dependent LNCaP cells. Interestingly, its ectopic expression induces cellular senescence and reduces cell migration in both androgen-dependent and CRPCa cells. Intriguingly, ING1b can also inhibit androgen-induced growth in LNCaP cells in a similar manner as AR antagonists. Moreover, ING1b upregulates different cell cycle inhibitors including p27(KIP1), which is a novel target for ING1b. Taken together, our findings reveal a novel corepressor function of ING1b on various AR functions, thereby inhibiting PCa cell growth. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  3. Transcriptome analyses in normal prostate epithelial cells exposed to low-dose cadmium: oncogenic and immunomodulations involving the action of tumor necrosis factor.

    PubMed

    Bakshi, Shlomo; Zhang, Xiang; Godoy-Tundidor, Sonia; Cheng, Robert Yuk Sing; Sartor, Maureen A; Medvedovic, Mario; Ho, Shuk-Mei

    2008-06-01

    Cadmium is implicated in prostate carcinogenesis, but its oncogenic action remains unclear. In this study we aimed to decipher changes in cell growth and the transcriptome in an immortalized human normal prostate epithelial cell line (NPrEC) following exposure to low-dose Cd. Synchronized NPrEC cells were exposed to different doses of Cd and assayed for cell viability and cell-cycle progression. We investigated changes in transcriptome by global profiling and used Ingenuity Pathways Analysis software to develop propositions about functional connections among differentially expressed genes. A neutralizing antibody was used to negate the effect of Cd-induced up-regulation of tumor necrosis factor (TNF) in NPrEC cells. Exposure of NPrEC to 2.5 microM Cd enhanced cell viability and accelerated cell-cycle progression. Global expression profiling identified 48 genes that exhibited >or= 1.5-fold changes in expression after 4, 8, 16, and 32 hr of Cd treatment. Pathway analyses inferred a functional connection among 35 of these genes in one major network, with TNF as the most prominent node. Fourteen of the 35 genes are related to TNF, and 11 exhibited an average of >2-fold changes in gene expression. Real-time reverse transcriptase-polymerase chain reaction confirmed the up-regulation of 7 of the 11 genes (ADAM8, EDN1, IL8, IL24, IL13RA2, COX2/PTGS2, and SERPINB2) and uncovered a 28-fold transient increase in TNF expression in Cd-treated NPrEC cells. A TNF-neutralizing antibody effectively blocked Cd-induced elevations in the expression of these genes. Noncytotoxic, low-dose Cd has growth-promoting effects on NPrEC cells and induces transient overexpression of TNF, leading to up-regulation of genes with oncogenic and immunomodulation functions.

  4. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    SciTech Connect

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, Andre; Gnanasekar, Munirathinam

    2012-01-27

    Highlights: Black-Right-Pointing-Pointer Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. Black-Right-Pointing-Pointer Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. Black-Right-Pointing-Pointer Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. Black-Right-Pointing-Pointer Knock down of RAGE abrogates prostate tumor growth in vivo. Black-Right-Pointing-Pointer Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  5. Preliminary experience on the use of the Adnatest® system for detection of circulating tumor cells in prostate cancer patients.

    PubMed

    Todenhöfer, Tilman; Hennenlotter, Jörg; Feyerabend, Susan; Aufderklamm, Stefan; Mischinger, Johannes; Kühs, Ursula; Gerber, Valentina; Fetisch, Jasmin; Schilling, David; Hauch, Siegfried; Stenzl, Arnulf; Schwentner, Christian

    2012-08-01

    The Adnatest® system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest® in patients with castration-resistant PC receiving docetaxel chemotherapy. CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements. Before chemotherapy, 11 patients were Adnatest®-positive whereas five patients were Adnatest®-positive before cycle three. A positive Adnatest® correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03). In this preliminary study, the Adnatest® detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response.

  6. Periprostatic adipose tissue from obese prostate cancer patients promotes tumor and endothelial cell proliferation: a functional and MR imaging pilot study.

    PubMed

    Venkatasubramanian, Palamadai N; Brendler, Charles B; Plunkett, Beth A; Crawford, Susan E; Fitchev, Philip S; Morgan, Gina; Cornwell, Mona L; McGuire, Michael S; Wyrwicz, Alice M; Doll, Jennifer A

    2014-02-01

    Obesity, particularly visceral adiposity, confers a worse prognosis for prostate cancer (PCa) patients, and increasing periprostatic adipose (PPA) tissue thickness or density is positively associated with more aggressive disease. However, the cellular mechanism of this activity remains unclear. Therefore, in this pilot study, we assessed the functional activity of PPA tissue secretions and established a biochemical profile of PPA as compared to subcutaneous adipose (SQA) tissues from lean, overweight and obese PCa patients. Adipose tissues were collected from PCa patients undergoing surgical prostate removal. Tissues were analyzed by histologic and magnetic resonance (MR) techniques. Explant tissue culture secretions were used in proliferation assays on PCa and endothelial cells. PPA secretions obtained from obese patients were significantly more pro-proliferative in both PCa and endothelial cells as compared to PPA obtained from lean or overweight men and SQA tissues. Consistent with this, PPA microvessel density was increased, and the T2 relaxation time was decreased, compared to SQA tissues, and we observed a modest, inverse correlation between the T2 and tumor stage. Moreover, the ratio of unsaturated to saturated fatty acids, obtained using MR spectroscopy, showed a modest, inverse correlation with Gleason score. These pilot data show that PPA stimulates PCa cell proliferation and angiogenesis and that obesity intensifies this activity, thus generating a mechanistic hypothesis to explain the worse prognosis observed in obese PCa patients. Our pilot study also shows that MR technology may be useful in further elucidating the relationship between obesity and PCa progression.

  7. Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

    PubMed

    Sonnemann, Jürgen; Gekeler, Volker; Sagrauske, Antje; Müller, Cornelia; Hofmann, Hans-Peter; Beck, James F

    2004-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL.

  8. Use of macrophages to target therapeutic adenovirus to human prostate tumors.

    PubMed

    Muthana, Munitta; Giannoudis, Athina; Scott, Simon D; Fang, Hsin-Yu; Coffelt, Seth B; Morrow, Fiona J; Murdoch, Craig; Burton, Julian; Cross, Neil; Burke, Bernard; Mistry, Roshna; Hamdy, Freddie; Brown, Nicola J; Georgopoulos, Lindsay; Hoskin, Peter; Essand, Magnus; Lewis, Claire E; Maitland, Norman J

    2011-03-01

    New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells.

  9. Maspin expression in prostate tumor elicits host anti-tumor immunity

    PubMed Central

    Dzinic, Sijana H.; Chen, Kang; Thakur, Archana; Kaplun, Alexander; Daniel Bonfil, R.; Li, Xiaohua; Liu, Jason; Margarida Bernardo, M.; Saliganan, Allen; Back, Jessica B.; Yano, Hiroshi; Schalk, Dana L.; Tomaszewski, Elyse N.; Beydoun, Ahmed S.; Dyson, Gregory; Mujagic, Adelina; Krass, David; Dean, Ivory; Mi, Qing-Sheng; Heath, Elisabeth; Sakr, Wael; Lum, Lawrence G.; Sheng, Shijie

    2014-01-01

    The goal of the current study is to examine the biological effects of epithelial-specific tumor suppressor maspin on tumor host immune response. Accumulated evidence demonstrates an anti-tumor effect of maspin on tumor growth, invasion and metastasis. The molecular mechanism underlying these biological functions of maspin is thought to be through histone deacetylase inhibition, key to the maintenance of differentiated epithelial phenotype. Since tumor-driven stromal reactivities co-evolve in tumor progression and metastasis, it is not surprising that maspin expression in tumor cells inhibits extracellular matrix degradation, increases fibrosis and blocks hypoxia-induced angiogenesis. Using the athymic nude mouse model capable of supporting the growth and progression of xenogeneic human prostate cancer cells, we further demonstrate that maspin expression in tumor cells elicits neutrophil- and B cells-dependent host tumor immunogenicity. Specifically, mice bearing maspin-expressing tumors exhibited increased systemic and intratumoral neutrophil maturation, activation and antibody-dependent cytotoxicity, and decreased peritumoral lymphangiogenesis. These results reveal a novel biological function of maspin in directing host immunity towards tumor elimination that helps explain the significant reduction of xenograft tumor incidence in vivo and the clinical correlation of maspin with better prognosis of several types of cancer. Taken together, our data raised the possibility for novel maspin-based cancer immunotherapies. PMID:25373490

  10. Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

    PubMed Central

    Tian, Suyan; Suárez-Fariñas, Mayte; Parveen, Salina; Blachère, Nathalie E.; Morris, Michael J.; Slovin, Susan; Scher, Howard I.; Albert, Matthew L.; Darnell, Robert B.

    2010-01-01

    Background Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine. Methods and Findings We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination. Conclusions An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number NCT00289341). Trial Registration ClinicalTrials.gov NCT00289341 PMID:20824184

  11. Spatial distribution of elements in the spheroids by prostate tumor cells using synchrotron radiation x-ray fluorescence

    SciTech Connect

    Leitao, Roberta G.; Santos, Carlos Antonio N.; Junior, Antonio Palumbo; Souza, Pedro A. V. R.; Canellas, Catarine G. L.; Anjos, Marcelino J.; Nasciutti, Luiz E.; Lopes, Ricardo T.

    2012-05-17

    The formation of three-dimensional cell microspheres such as spheroids has attracted attention as a useful culture technique. In this study, we investigated the trace elemental distribution (mapping) in spheroids derived from tissue prostate cancer (PCa). The measurements were performed in standard geometry of 45 deg. incidence, exciting with a white beam and using an optical capillary with 20 {mu}m diameter collimation in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The results showed that most elements analyzed presented non-uniform distribution. P, S and Cl showed similar elemental distribution in all the samples analyzed. K, Ca, Fe, and Cu showed different elemental distribution for the spheroids analyzed. Zinc presented more intense distributions in the spheroid central region for all spheroids analyzed.

  12. Basal cell carcinoma of the prostate: unusual subtype of prostatic carcinoma.

    PubMed

    Komura, Kazumasa; Inamoto, Teruo; Tsuji, Motomu; Ibuki, Naokazu; Koyama, Kohei; Ubai, Takanobu; Azuma, Haruhito; Katsuoka, Yoji

    2010-12-01

    Basal cell carcinoma of the prostate, which has been generally considered to be indolent, is an unusual histological type of prostatic carcinoma and is extremely rare. This tumor has been classified according to the prevalent pattern of growth as adenoid cystic carcinoma or basaloid cell carcinoma (BCC), with the former growth pattern being considered to be the main feature of this entity. A 67-year-old Japanese man was admitted to a general hospital with obstructive urinary symptoms. His prostate was slightly enlarged, stony hard, and with a rough surface on digital rectal examination, while serum prostate-specific antigen and prostatic acid phosphatase concentrations were within the normal ranges (0.007 and 0.9 ng/mL, respectively). 2-Fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) exhibited multiple accumulations suspicious for cancer metastases. Specimens obtained by prostatic needle biopsy showed immunohistochemical reactivity for cytokeratin 34βE12 and P63, findings that were identical to those seen in basal cell carcinoma. Basal cell carcinoma of the prostate is a rare tumor, reported in 56 cases so far, and among all these, the pure form of BCC is extremely rare. Immunohistochemistry is indispensable to distinguish this neoplasm from other unusual histological types of prostatic carcinomas. Our findings reveal that tumors with a basaloid cell-predominant pattern have significant potential for a poor prognosis, in contrast with the conventional understanding regarding this neoplasm.

  13. Masticadienonic and 3α-OH Masticadienoic Acids Induce Apoptosis and Inhibit Cell Proliferation and Tumor Growth in Prostate Cancer Xenografts in Vivo.

    PubMed

    Sánchez-Monroy, Ma Beatriz; Jacobo-Herrera, Nadia J; Zentella-Dehesa, Alejandro; Hernández-Téllez, Beatriz; Martínez-Vázquez, Mariano

    2017-09-06

    The triterpenes have been constituted as a group of interesting molecules as possible antitumor agents. Despite several of them not presenting a potent cytotoxic activity in vitro against cancer cells, in vivo in xenotransplant tumors studies, they show promising results. Based on the above considerations, we investigated the antitumor activity of both masticadienonic (MDA) and 3α-OH masticadienoic (3α-OH MDA) acids in a mouse prostate cancer xenograft model. Immunohistochemical assays were used to evaluate the decrease in the expression of the Proliferating Cell Nuclear Antigen (PCNA) and the Ki-67 induced by MDA and 3α-OH MDA. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to demonstrate the fragmentation of DNA. Our results showed that the two triterpenes inhibited tumor growth, had anti-proliferative effect in vivo and induced cell death by apoptosis. Collectively, our data suggested that the antitumor mechanism of MDA and 3α-OH MDA involves several molecular targets related to cell proliferation and apoptosis.

  14. Circulating tumor cells

    PubMed Central

    Raimondi, Cristina; Nicolazzo, Chiara; Gradilone, Angela; Giannini, Giuseppe; De Falco, Elena; Chimenti, Isotta; Varriale, Elisa; Hauch, Siegfried; Plappert, Linda; Cortesi, Enrico; Gazzaniga, Paola

    2014-01-01

    The hypothesis of the “liquid biopsy” using circulating tumor cells (CTCs) emerged as a minimally invasive alternative to traditional tissue biopsy to determine cancer therapy. Discordance for biomarkers expression between primary tumor tissue and circulating tumor cells (CTCs) has been widely reported, thus rendering the biological characterization of CTCs an attractive tool for biomarkers assessment and treatment selection. Studies performed in metastatic colorectal cancer (mCRC) patients using CellSearch, the only FDA-cleared test for CTCs assessment, demonstrated a much lower yield of CTCs in this tumor type compared with breast and prostate cancer, both at baseline and during the course of treatment. Thus, although attractive, the possibility to use CTCs as therapy-related biomarker for colorectal cancer patients is still limited by a number of technical issues mainly due to the low sensitivity of the CellSearch method. In the present study we found a significant discordance between CellSearch and AdnaTest in the detection of CTCs from mCRC patients. We then investigated KRAS pathway activating mutations in CTCs and determined the degree of heterogeneity for KRAS oncogenic mutations between CTCs and tumor tissues. Whether KRAS gene amplification may represent an alternative pathway responsible for KRAS activation was further explored. KRAS gene amplification emerged as a functionally equivalent and mutually exclusive mechanism of KRAS pathway activation in CTCs, possibly related to transcriptional activation. The serial assessment of CTCs may represent an early biomarker of treatment response, able to overcome the intrinsic limit of current molecular biomarkers represented by intratumor heterogeneity. PMID:24521660

  15. Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor β.

    PubMed

    Sharma, Vikas; Verma, Vikas; Lal, Nand; Yadav, Santosh K; Sarkar, Saumya; Mandalapu, Dhanaraju; Porwal, Konica; Rawat, Tara; Maikhuri, J P; Rajender, Singh; Sharma, V L; Gupta, Gopal

    2016-11-01

    Estrogen Receptor-β (ER-β), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA-methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT-inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT-inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-β. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-β (mRNA/protein). Bisulfite-sequencing of ER-β promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-β promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-β expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-β through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  16. Osteopontin is a tumor autoantigen in prostate cancer patients.

    PubMed

    Tilli, Tatiana M; Silva, Eloísio A; Matos, Lívia C; Faget, Douglas V; Dias, Bianca F P; Vasconcelos, Juliana S P; Yokosaki, Yasuyuki; Gimba, Etel R P

    2011-01-01

    Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN.

  17. Osteopontin is a tumor autoantigen in prostate cancer patients

    PubMed Central

    TILLI, TATIANA M.; SILVA, ELOÍSIO A.; MATOS, LÍVIA C.; FAGET, DOUGLAS V.; DIAS, BIANCA F.P.; VASCONCELOS, JULIANA S.P.; YOKOSAKI, YASUYUKI; GIMBA, ETEL R.P.

    2011-01-01

    Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN. PMID:22870138

  18. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    SciTech Connect

    Cai, Liquan; Wang, Dan; Fisher, Alfred L.; Wang, Zhou

    2014-05-02

    Highlights: • RNAi screen identified genetic enhancers for the C. elegans homolog of EAF2. • EAF2 and RBBP4 proteins physically bind to each other and alter transcription. • Overexpression of EAF2 and RBBP4 induces the cell death in prostate cancer cells. - Abstract: The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in

  19. Energy Restriction-mimetic Agents Induce Apoptosis in Prostate Cancer Cells in Part through Epigenetic Activation of KLF6 Tumor Suppressor Gene Expression*

    PubMed Central

    Chen, Chun-Han; Huang, Po-Hsien; Chu, Po-Chen; Chen, Mei-Chuan; Chou, Chih-Chien; Wang, Dasheng; Kulp, Samuel K.; Teng, Che-Ming; Wang, Qianben; Chen, Ching-Shih

    2011-01-01

    Although energy restriction has been recognized as an important target for cancer prevention, the mechanism by which energy restriction-mimetic agents (ERMAs) mediate apoptosis remains unclear. By using a novel thiazolidinedione-derived ERMA, CG-12 (Wei, S., Kulp, S. K., and Chen, C. S. (2010) J. Biol. Chem. 285, 9780–9791), vis-à-vis 2-deoxyglucose and glucose deprivation, we obtain evidence that epigenetic activation of the tumor suppressor gene Kruppel-like factor 6 (KLF6) plays a role in ERMA-induced apoptosis in LNCaP prostate cancer cells. KLF6 regulates the expression of many proapoptotic genes, and shRNA-mediated KLF6 knockdown abrogated the ability of ERMAs to induce apoptosis. Chromatin immunoprecipitation analysis indicates that this KLF6 transcriptional activation was associated with increased histone H3 acetylation and histone H3 lysine 4 trimethylation occupancy at the promoter region. Several lines of evidence demonstrate that the enhancing effect of ERMAs on these active histone marks was mediated through transcriptional repression of histone deacetylases and H3 lysine 4 demethylases by down-regulating Sp1 expression. First, putative Sp1-binding elements are present in the promoters of the affected histone-modifying enzymes, and luciferase reporter assays indicate that site-directed mutagenesis of these Sp1 binding sites significantly diminished the promoter activities. Second, shRNA-mediated knockdown of Sp1 mimicked the repressive effect of energy restriction on these histone-modifying enzymes. Third, ectopic Sp1 expression protected cells from the repressive effect of CG-12 on these histone-modifying enzymes, thereby abolishing the activation of KLF6 expression. Together, these findings underscore the intricate relationship between energy restriction and epigenetic regulation of tumor suppressor gene expression, which has therapeutic relevance to foster novel strategies for prostate cancer therapy. PMID:21282102

  20. Energy restriction-mimetic agents induce apoptosis in prostate cancer cells in part through epigenetic activation of KLF6 tumor suppressor gene expression.

    PubMed

    Chen, Chun-Han; Huang, Po-Hsien; Chu, Po-Chen; Chen, Mei-Chuan; Chou, Chih-Chien; Wang, Dasheng; Kulp, Samuel K; Teng, Che-Ming; Wang, Qianben; Chen, Ching-Shih

    2011-03-25

    Although energy restriction has been recognized as an important target for cancer prevention, the mechanism by which energy restriction-mimetic agents (ERMAs) mediate apoptosis remains unclear. By using a novel thiazolidinedione-derived ERMA, CG-12 (Wei, S., Kulp, S. K., and Chen, C. S. (2010) J. Biol. Chem. 285, 9780-9791), vis-à-vis 2-deoxyglucose and glucose deprivation, we obtain evidence that epigenetic activation of the tumor suppressor gene Kruppel-like factor 6 (KLF6) plays a role in ERMA-induced apoptosis in LNCaP prostate cancer cells. KLF6 regulates the expression of many proapoptotic genes, and shRNA-mediated KLF6 knockdown abrogated the ability of ERMAs to induce apoptosis. Chromatin immunoprecipitation analysis indicates that this KLF6 transcriptional activation was associated with increased histone H3 acetylation and histone H3 lysine 4 trimethylation occupancy at the promoter region. Several lines of evidence demonstrate that the enhancing effect of ERMAs on these active histone marks was mediated through transcriptional repression of histone deacetylases and H3 lysine 4 demethylases by down-regulating Sp1 expression. First, putative Sp1-binding elements are present in the promoters of the affected histone-modifying enzymes, and luciferase reporter assays indicate that site-directed mutagenesis of these Sp1 binding sites significantly diminished the promoter activities. Second, shRNA-mediated knockdown of Sp1 mimicked the repressive effect of energy restriction on these histone-modifying enzymes. Third, ectopic Sp1 expression protected cells from the repressive effect of CG-12 on these histone-modifying enzymes, thereby abolishing the activation of KLF6 expression. Together, these findings underscore the intricate relationship between energy restriction and epigenetic regulation of tumor suppressor gene expression, which has therapeutic relevance to foster novel strategies for prostate cancer therapy.

  1. Deformability of Tumor Cells versus Blood Cells

    PubMed Central

    Shaw Bagnall, Josephine; Byun, Sangwon; Begum, Shahinoor; Miyamoto, David T.; Hecht, Vivian C.; Maheswaran, Shyamala; Stott, Shannon L.; Toner, Mehmet; Hynes, Richard O.; Manalis, Scott R.

    2015-01-01

    The potential for circulating tumor cells (CTCs) to elucidate the process of cancer metastasis and inform clinical decision-making has made their isolation of great importance. However, CTCs are rare in the blood, and universal properties with which to identify them remain elusive. As technological advancements have made single-cell deformability measurements increasingly routine, the assessment of physical distinctions between tumor cells and blood cells may provide insight into the feasibility of deformability-based methods for identifying CTCs in patient blood. To this end, we present an initial study assessing deformability differences between tumor cells and blood cells, indicated by the length of time required for them to pass through a microfluidic constriction. Here, we demonstrate that deformability changes in tumor cells that have undergone phenotypic shifts are small compared to differences between tumor cell lines and blood cells. Additionally, in a syngeneic mouse tumor model, cells that are able to exit a tumor and enter circulation are not required to be more deformable than the cells that were first injected into the mouse. However, a limited study of metastatic prostate cancer patients provides evidence that some CTCs may be more mechanically similar to blood cells than to typical tumor cell lines. PMID:26679988

  2. Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo.

    PubMed

    Hu, Hongbo; Lee, Hyo-Jeong; Jiang, Cheng; Zhang, Jinhui; Wang, Lei; Zhao, Yan; Xiang, Qiu; Lee, Eun-Ok; Kim, Sung-Hoon; Lü, Junxuan

    2008-09-01

    Penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG) is a naturally occurring gallotannin from some Oriental herbs. Several cell culture studies suggested a potential for PGG as a novel agent for the chemoprevention and treatment of cancer. Here, we investigated the cell death signaling mechanisms induced by PGG in human prostate cancer cells of different p53 functional status. We observed the induction of G(1)- and S-phase arrests and caspase-mediated apoptosis in the androgen-dependent human LNCaP cells, which express wild-type p53, and in the androgen-independent, p53-mutant DU145 cells. In LNCaP cells, caspase-mediated apoptosis induction by PGG was associated with and mediated in major part by activation of p53 as established through small interfering RNA knockdown and dominant-negative mutant approaches. Intracellular reactive oxygen species production by PGG was found to be crucial for these molecular and cellular actions. In DU145 cells, which harbor constitutively active signal transducer and activator of transcription 3 (STAT3), caspase-mediated apoptosis induction by PGG was associated with an inhibition of STAT3 Tyr705 phosphorylation and the down-regulation of STAT3 transcriptional targets Bcl-XL and Mcl-1. Overexpression of Bcl-XL or knockdown of its binding partner Bak attenuated apoptosis induction. Furthermore, we provide, for the first time, in vivo data that PGG significantly inhibited DU145 xenograft growth in an athymic nude mouse model in association with an inhibition of pSTAT3. Our data support PGG as a multitargeting agent for chemoprevention and therapy of prostate cancer by activating the p53 tumor suppressor pathway and by inhibiting STAT3 oncogenic signaling.

  3. Transformation of prostatic adenocarcinoma to well-differentiated neuroendocrine tumor after hormonal treatment.

    PubMed

    Gilani, Syed; Guo, Charles C; Li-Ning, Elsa M; Pettaway, Curtis; Troncoso, Patricia

    2017-06-01

    Carcinoid tumor of the prostate is extremely rare. Here we report a unique case of prostate cancer that underwent complete transformation from conventional adenocarcinoma to carcinoid-like tumor shortly after androgen-deprivation treatment (ADT). The patient was a 59-year-old man who presented with lower urinary tract symptoms. His biopsy specimen demonstrated a high-grade prostatic adenocarcinoma with mixed acinar and ductal features. After ADT for 6months, the patient underwent radical prostatectomy. The post-ADT tumor showed monotonous neoplastic cells with fine granular chromatin forming rosette-like structures, resembling a carcinoid tumor. No residual conventional adenocarcinoma was present. On immunostain, the tumor cells were diffusely positive for synaptophysin and chromogranin and negative for prostate-specific antigen and prostein. Thus, the carcinoid-like tumor represented complete transformation from prostatic adenocarcinoma to well-differentiated neuroendocrine tumor after ADT. This unique case highlights the important role of ADT in neuroendocrine differentiation of prostate cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

    SciTech Connect

    Zhang, Jing; Shen, Chengwu; Wang, Lin; Ma, Quanping; Xia, Pingtian; Qi, Mei; Yang, Muyi; Han, Bo

    2014-09-26

    Highlights: • Metformin inhibits TGF-β-induced EMT in prostate cancer (PCa) cells. • Metformin upregulates tumor suppressor miR30a and downregulates SOX4 in PCa cells. • SOX4 is a target gene of miR30a. - Abstract: Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial–mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p = 0.013), Vimentin (p = 0.002) and the decrease of E-cadherin (p = 0.0023) and β-catenin (p = 0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P < 0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.

  5. Prostate cancer stem/progenitor cells: identification, characterization, and implications.

    PubMed

    Tang, Dean G; Patrawala, Lubna; Calhoun, Tammy; Bhatia, Bobby; Choy, Grace; Schneider-Broussard, Robin; Jeter, Collene

    2007-01-01

    Several solid tumors have now been shown to contain stem cell-like cells called cancer stem cells (CSC). These cells, although generally rare, appear to be highly tumorigenic and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. In this Perspective, we first provide our insight on how a CSC should be defined. We then summarize our current knowledge of stem/progenitor cells in the normal human prostate (NHP), an organ highly susceptible to hyperproliferative diseases such as benign prostate hyperplasia (BPH) and prostate cancer (PCa). We further review the evidence that cultured PCa cells, xenograft prostate tumors, and patient tumors may contain stem/progenitor cells. Along with our discussion, we present several methodologies that can be potentially used to identify putative tumor-reinitiating CSC. Finally, we present a hypothetical model for the hierarchical organization of human PCa cells and discuss the implications of this model in helping understand prostate carcinogenesis and design novel diagnostic, prognostic, and therapeutic approaches.

  6. Immunohistological analysis of ABCD3 expression in Caucasian and African American prostate tumors.

    PubMed

    Reams, R Renee; Jones-Triche, Jacqueline; Chan, Owen T M; Hernandez, Brenda Y; Soliman, Karam F A; Yates, Clayton

    2015-01-01

    In a previously published study, we showed that expression of the ABCD3 gene increased with increasing metastatic potential in a panel of prostate cancer cell lines derived from African American and Caucasian American men. Given importance of identifying biomarker(s) that can distinguish indolent versus aggressive prostate tumors, we conducted an immunohistochemical analysis of ABCD3 expression Caucasian and African American prostate tumors. ABCD3 expression in each patient population was compared with clinicopathologic characteristics, Gleason score, and age. ABCD3 expression increased with increasing Gleason score (P = 0.0094), age (P = 0.0014), and pathology grade (P = 0.0007) in Caucasian patients. Interestingly, in the AA patients, ABCD3 expression highly increased to the same degree in both low and high Gleason score tumors. Similarly, ABCD3 expression was elevated to the same degree in BPH derived from AA. Our findings demonstrate that increased ABCD3 expression correlates with Gleason Score in CA prostate tumors. However, in AA prostate tumors, ABCD3 expression was higher and was sustained in both low Gleason and high Gleason AA tumors. While the functional role of ABCD3 in prostate cancer is not completely elucidated, this gene warrants further study as a potential biomarker for aggressive prostate.

  7. Differential Expression of Matrix Metalloproteinase-2 Expression in Disseminated Tumor Cells and Micrometastasis in Bone Marrow of Patients with Nonmetastatic and Metastatic Prostate Cancer: Theoretical Considerations and Clinical Implications—An Immunocytochemical Study

    PubMed Central

    Murray, Nigel P.; Reyes, Eduardo; Tapia, Pablo; Badínez, Leonardo; Orellana, Nelson

    2012-01-01

    Matrix metalloproteinase-2 (MMP-2) is important in the dissemination and invasion of tumor cells and activates angiogenesis. We present an immunocytochemical study of MMP-2 expression in circulating prostate cells (CPCs), disseminated tumor cells (DTCs), and micrometastasis (mM) in bone marrow of men with prostate cancer. Methods and Patients. Tumor cells were identified with anti-PSA immunocytochemistry. Positive samples underwent processing with anti-MMP-2, its expression was compared with Gleason score, concordance of expression, and metastatic and nonmetastatic disease. Results. 215 men participated, CPCs were detected in 62.7%, DTCs in 62.2%, and mM in 71.4% in nonmetastatic cancer; in metastatic cancer all had CPCs, DTCs, and mM detected. All CPCs and DTCs expressed MMP-2; in mM MMP-2 expression was positively associated with increasing Gleason score. MMP-2 expression in CPCs and DTCs showed concordance. In low grade tumors, mM and surrounding stromal cells were MMP-2 negative, with variable expression in high grade tumors; in metastatic disease, both mM and stromal cells were MMP-2 positive. Conclusions. CPCs and DTCs are different from mM, with inhibition of MMP-2 expression in mM of low grade tumors. With disease progression, MMP-2 expression increases in both mM and surrounding stromal cells, with implications for the use of bisphosphonates or MMP-2 inhibitors. PMID:23227342

  8. New gene expressed in prostate: a potential target for T cell-mediated prostate cancer immunotherapy.

    PubMed

    Cereda, Vittore; Poole, Diane J; Palena, Claudia; Das, Sudipto; Bera, Tapan K; Remondo, Cinzia; Gulley, James L; Arlen, Philip M; Yokokawa, Junko; Pastan, Ira; Schlom, Jeffrey; Tsang, Kwong Y

    2010-01-01

    New gene expressed in prostate (NGEP) is a prostate-specific gene encoding either a small cytoplasmic protein (NGEP-S) or a larger polytopic membrane protein (NGEP-L). NGEP-L expression is detectable only in prostate cancer, benign prostatic hyperplasia and normal prostate. We have identified an HLA-A2 binding NGEP epitope (designated P703) which was used to generate T cell lines from several patients with localized and metastatic prostate cancer. These T cell lines were able to specifically lyse HLA-A2 and NGEP-expressing human tumor cells. NGEP-P703 tetramer binding assays demonstrated that metastatic prostate cancer patients had a higher frequency of NGEP-specific T cells when compared with healthy donors. Moreover, an increased frequency of NGEP-specific T cells was detected in the peripheral blood mononuclear cells of prostate cancer patients post-vaccination with a PSA-based vaccine, further indicating the immunogenicity of NGEP. These studies thus identify NGEP as a potential target for T cell-mediated immunotherapy of prostate cancer.

  9. Endothelial Caveolin-1 regulates the radiation response of epithelial prostate tumors

    PubMed Central

    Klein, D; Schmitz, T; Verhelst, V; Panic, A; Schenck, M; Reis, H; Drab, M; Sak, A; Herskind, C; Maier, P; Jendrossek, V

    2015-01-01

    The membrane protein caveolin-1 (Cav1) recently emerged as a novel oncogene involved in prostate cancer progression with opposed regulation in epithelial tumor cells and the tumor stroma. Here we examined the role of stromal Cav1 for growth and radiation response of MPR31-4 prostate cancer xenograft tumors using Cav1-deficient C57Bl/6 mice. Syngeneic MPR31-4 tumors grew faster when implanted into Cav1-deficient mice. Increased tumor growth on Cav1-deficient mice was linked to decreased integration of smooth muscle cells into the wall of newly formed blood vessels and thus with a less stabilized vessel phenotype compared with tumors from Cav1 wild-type animals. However, tumor growth delay of MPR31-4 tumors grown on Cav1 knockout mice to a single high-dose irradiation with 20 Gray was more pronounced compared with tumors grown on wild-type mice. Increased radiation-induced tumor growth delay in Cav1-deficient mice was associated with an increased endothelial cell apoptosis. In vitro studies using cultured endothelial cells (ECs) confirmed that the loss of Cav1 expression increases sensitivity of ECs to radiation-induced apoptosis and reduces their clonogenic survival after irradiation. Immunohistochemical analysis of human tissue specimen further revealed that although Cav1 expression is mostly reduced in the tumor stroma of advanced and metastatic prostate cancer, the vascular compartment still expresses high levels of Cav1. In conclusion, the radiation response of MPR31-4 prostate tumors is critically regulated by Cav1 expression in the tumor vasculature. Thus, Cav1 might be a promising therapeutic target for combinatorial therapies to counteract radiation resistance of prostate cancer at the level of the tumor vasculature. PMID:25985209

  10. Tumor clone dynamics in lethal prostate cancer.

    PubMed

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. Copyright © 2014, American Association for the Advancement of Science.

  11. Tumor clone dynamics in lethal prostate cancer

    PubMed Central

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; de Bono, Johann S.; Demichelis, Francesca; Attard, Gerhardt

    2015-01-01

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. PMID:25232177

  12. Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo.

    PubMed

    Saha, Achinto; Blando, Jorge; Fernandez, Irina; Kiguchi, Kaoru; DiGiovanni, John

    2016-05-03

    A cell line was established from ventral prostate (VP) tumors of one-year-old Hi-Myc mice. These cells, called HMVP2 cells, are LinnegSca-1highCD49fhigh with high CD44 and CD29 expression and express CK14, Sca-1 and CD49f (but not CK8), suggesting basal-epithelial characteristics. Furthermore, HMVP2 cells form spheroids and both the cells and spheroids produce tumors in syngeneic mice. After four days of culture, HMVP2 spheroids underwent a gradual transition from LinnegSca-1highCD49fhigh expression to LinnegSca-1lowCD49flow while a subpopulation of the cells retained the original LinnegSca-1highCD49fhigh expression pattern. Additional cell subpopulations expressing Lin positive markers were also present suggesting further differentiation of HMVP2 spheroids. Two additional highly tumorigenic cell lines (HMVP2A1 and HMVP2A2) were isolated from HMVP2 cells after subsequent tumor formation in FVB/N mice. Concurrently, we also established cell lines from the VP of 6 months old Hi-Myc mice (named as HMVP1) and FVB/N mice (called NMVP) having less aggressive growth properties compared to the other three cell lines. AR expression was reduced in HMVP2 cells compared to NMVP and HMVP1 cells and almost absent in HMVP2A1 and HMVP2A2 cells. These cell lines will provide valuable tools for further mechanistic studies as well as preclinical studies to evaluate preventive and/or therapeutic agents for prostate cancer.

  13. Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo

    PubMed Central

    Fernandez, Irina; Kiguchi, Kaoru; DiGiovanni, John

    2016-01-01

    A cell line was established from ventral prostate (VP) tumors of one-year-old Hi-Myc mice. These cells, called HMVP2 cells, are LinnegSca-1highCD49fhigh with high CD44 and CD29 expression and express CK14, Sca-1 and CD49f (but not CK8), suggesting basal-epithelial characteristics. Furthermore, HMVP2 cells form spheroids and both the cells and spheroids produce tumors in syngeneic mice. After four days of culture, HMVP2 spheroids underwent a gradual transition from LinnegSca-1highCD49fhigh expression to LinnegSca-1lowCD49flow while a subpopulation of the cells retained the original LinnegSca-1highCD49fhigh expression pattern. Additional cell subpopulations expressing Lin positive markers were also present suggesting further differentiation of HMVP2 spheroids. Two additional highly tumorigenic cell lines (HMVP2A1 and HMVP2A2) were isolated from HMVP2 cells after subsequent tumor formation in FVB/N mice. Concurrently, we also established cell lines from the VP of 6 months old Hi-Myc mice (named as HMVP1) and FVB/N mice (called NMVP) having less aggressive growth properties compared to the other three cell lines. AR expression was reduced in HMVP2 cells compared to NMVP and HMVP1 cells and almost absent in HMVP2A1 and HMVP2A2 cells. These cell lines will provide valuable tools for further mechanistic studies as well as preclinical studies to evaluate preventive and/or therapeutic agents for prostate cancer. PMID:26910370

  14. Malignant phyllodes tumor of the prostate: retrospective review of specimens obtained by sequential transurethral resection.

    PubMed

    Watanabe, Masatoshi; Yamada, Yasushi; Kato, Hiroya; Imai, Hiroshi; Nakano, Hiroshi; Araki, Tomio; Shiraishi, Taizo

    2002-12-01

    A case of malignant phyllodes tumor of the prostate in a 67-year-old man is reported. The patient was referred to a hospital for urinary retention. From material taken at three transurethral resections of the prostate (TURP), a histological diagnosis of benign prostatic hyperplasia was made. However, at the fourth TURP, phyllodes tumor was diagnosed due to the presence of elongated epithelial ducts and proliferating cellular stroma with mitosis and nuclear atypia. Two months later, total cystoprostatectomy was performed. Histologically, the tumor was composed of dysplastic stromal cells and irregularly elongated epithelial ducts. Five months later the patient developed multiple lung and pelvic lymph node metastases and died. This report documents progression to a higher histological grade of prostatic phyllodes tumor documented with sequential pathological findings obtained from four TURP and surgical specimens over about 3 years.

  15. Personalized ex vivo multiple peptide enrichment and detection of T cells reactive to multiple tumor-associated antigens in prostate cancer patients.

    PubMed

    Taborska, Pavla; Stakheev, Dmitry; Strizova, Zuzana; Vavrova, Katerina; Podrazil, Michal; Bartunkova, Jirina; Smrz, Daniel

    2017-09-02

    Personalized peptide vaccination is a promising immunotherapeutic approach in prostate cancer (PCa). We therefore examined whether an approach, utilizing personalized multiple peptide-mediated ex vivo enrichment with effector T cells reactive to multiple tumor-associated antigens (TAAs), could be employed as a basis for the development of T cell immunotherapy of PCa. In this study, we used the non-adherent fraction (lymphocytes) of cryopreserved peripheral blood mononuclear cells from a leukapheretic product of biochemically recurrent (BR, n = 14) and metastatic hormone-refractory (HR, n = 12) PCa patients. The lymphocytes were primed with a pool of mixed overlapping peptides derived from 6 PCa TAAs-PSA, PAP, NY-ESO-1, MAGE-A1, MAGE-A3 and MAGE-A4. After 2 weeks of culture, the cells were stimulated with the peptides and T cell reactivity determined by externalization of CD107a. No TAAs-reactive effector T cells were detected in the patient's lymphocytes after their reconstitution. However, following their priming with the TAAs-derived peptides and 2-week culturing, the lymphocytes became enriched with polyclonal TAAs-reactive effector CD8(+) T cells in 8 out of 14 BR and 5 out of 12 HR patients. No such reactive CD8(+) T cells were detected in cultured lymphocytes without the peptide priming. Stimulation of the responding cultures with peptides derived from individual TAAs revealed a unique repertoire of the reactive CD8(+) T cells. Our strategy revealed that the personalized multiple peptide-mediated ex vivo enrichment with multiple TAAs-reactive T cells in the PCa patient's lymphocytes is a viable approach for development of T cell immunotherapy of PCa.

  16. Origin and Properties of Prostatic Stem Cells

    DTIC Science & Technology

    2006-02-01

    treating prostate cancer and benign prostatic hyperplasia . prostate 6 integrin Bcl-2 S tem cell biology and tumorigenesis may be closely linked...In addition to being a source of carcinomas, stem cells may also give rise to benign prostatic hyperplasia (7). The isolation and characterization of...expression may contribute to the etiology of prostatic diseases such as benign prostatic hyperplasia (48), proliferative inflam- matory atrophy, which

  17. Cell Lineage Analysis of Mouse Prostate Carcinogenesis

    DTIC Science & Technology

    2015-09-01

    are derived from luminal or basal epithelial cells using genetic lineage tracing of prostate carcinogenesis in PSA-CreERT2;R26RmT/mG;EAF2-/-;PTEN...derived from luminal epithelial cells in the prostate, because a hallmark of prostate cancer is the loss of basal epithelial cells and prostate...publications [2, 3]. This project will determine whether prostate cancer cells are derived from luminal or basal epithelial cells in an EAF2-/- mouse

  18. Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

    PubMed Central

    Alhusban, Ahmed; Al-Azayzih, Ahmad; Goc, Anna; Gao, Fei; Fagan, Susan C.

    2014-01-01

    Angiotensin II receptor type 1 blockers (ARBs), widely used antihypertensive drugs, have also been investigated for their anticancer effects. The effect of ARBs on prostate cancer in experimental models compared with meta-analysis data from clinical trials is conflicting. Whereas this discrepancy might be due to the use of supratherapeutic doses of ARBs in cellular and animal models as compared with the clinical doses used in human trials, further investigation of the effects of clinical doses of ARBs on prostate cancer in experimental models is warranted. In the current study, we sought to determine the effects of candesartan on prostate cancer cellular function in vitro and tumor growth in vivo, and characterize the underlying mechanisms. Our analysis indicated that clinically relevant doses of candesartan significantly inhibited growth of PC3 cell tumor xenografts in mice. Interestingly, the same concentrations of candesartan actually promoted prostate cancer cellular function in vitro, through a modest but significant inhibition in apoptosis. Inhibition of tumor growth by candesartan was associated with a decrease in vascular endothelial growth factor (VEGF) expression in tumors and inhibition of tumor angiogenesis, but normalization of tumor vasculature. Although candesartan did not impair PC3 cell viability, it inhibited endothelial-barrier disruption by tumor-derived factors. Furthermore, candesartan significantly inhibited expression of VEGF in PC3 and DU145 cell lines independent of angiotensin II type 2 receptor, but potentially via angiotensin II type 1 receptor inhibition. Our findings clearly demonstrate the therapeutic potential of candesartan for prostate cancer and establish a link between ARBs, VEGF expression, and prostate tumor angiogenesis. PMID:24990940

  19. Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

    PubMed Central

    Okegawa, Takatsugu; Itaya, Naoshi; Hara, Hidehiko; Tambo, Mitsuhiro; Nutahara, Kikuo

    2016-01-01

    Objective: We examined whether epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184). There were 37 patients (61.7%) who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3%) with <5 CTCs (p < 0.001). A total of 15 patients (40.5%, 15/37) with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS) (5.5 months) than patients with EGFR-negative CTCs (20.0 months). CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP) were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively). Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome. PMID:27916908

  20. The Steroid Receptor Coactivator-3 Is Required for Developing Neuroendocrine Tumor in the Mouse Prostate

    PubMed Central

    Tien, Jean Ching-Yi; Liao, Lan; Liu, Yonghong; Liu, Zhaoliang; Lee, Dong-Kee; Wang, Fen; Xu, Jianming

    2014-01-01

    Neuroendocrine tumor cells (NETCs) are commonly observed in prostate cancer. Their presence is associated with castration resistance, metastasis and poor prognosis. Cellular and molecular mechanisms for NETC initiation and growth are unknown. TRAMP mice develop heterogeneous adenocarcinomas induced by expression of the SV40-T/t oncogene in prostate epithelial cells. Here, we demonstrate prostate tumors in TRAMP mice with a mixed genetic background are characterized mostly by atypical hyperplasia (AH) containing steroid receptor coactiator-3-positive, androgen receptor-positive and synaptophysin-negative (SRC-3+/AR+/Syp-) cells. Few SRC-3+/AR-/Syp+ NETCs are present in their prostates. We generated TRAMP mice in which SRC-3 was specifically ablated in AR+/Syp- prostatic epithelial cells (termed PE3KOT mice). In these animals, we observed a substantial reduction in SRC-3-/AR+/Syp- AH tumor growth. There was a corresponding increase in SRC-3-/AR+/Syp- phyllodes lesions, suggesting SRC-3 knockout can convert aggressive AH tumors with mostly epithelial tumor cells into less aggressive phyllodes lesions with mostly stromal tissue. Surprisingly, PE3KOT mice developed many more SRC-3+/AR-/Syp+ NETCs versus control TRAMP mice, indicating SRC-3 expression was retained in NETCs. In contrast, TRAMP mice with global SRC-3 knockout did not develop any NETC, indicating SRC-3 is required for developing NETC. Analysis of cell-differentiating markers revealed that these NETCs might not be derived from the mature AR-/Syp+ neuroendocrine cells or the AR+/Syp- luminal epithelial tumor cells. Instead, these NETCs might originate from the SV40-T/t-transformed intermediate/progenitor epithelial cells. In summary, SRC-3 is required for both AR+/Syp- AH tumor growth and AR-/Syp+ NETC development, suggesting SRC-3 is a target for inhibiting aggressive prostate cancer containing NETCs. PMID:25332686

  1. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism

    PubMed Central

    Tomkova, Veronika; Korenkova, Vlasta; Langerova, Lucie; Simonova, Ekaterina; Zjablovskaja, Polina; Alberich-Jorda, Meritxell; Neuzil, Jiri; Truksa, Jaroslav

    2017-01-01

    The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy. PMID:28031527

  2. 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.

  3. 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

  4. Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses.

    PubMed

    Ahmed, Maryam; Cramer, Scott D; Lyles, Douglas S

    2004-12-05

    Because of its potent ability to induce apoptosis, vesicular stomatitis virus (VSV) is an attractive candidate as an oncolytic virus for tumor therapy. Previous studies have suggested that VSV selectively infects tumor cells due to defects in their antiviral responses making them more susceptible to VSV infection than normal cells. We tested this hypothesis in the prostate tumor system by comparing LNCaP and PC-3 prostate tumor cells to benign human prostatic epithelial cells from patient prostatectomy specimens. We compared the cell killing ability of a recombinant virus containing a wild-type (wt) M protein (rwt) and an isogenic M protein mutant virus (rM51R-M) that induces interferon (IFN) in infected cells and should display a greater selectivity for tumor cells. Our results showed that in single-cycle infection experiments, LNCaP cells were sensitive to killing by both wt and mutant viruses, while PC-3 cells were highly resistant to VSV-induced cell killing. LNCaP and benign prostate cells were similarly susceptible to both viruses, indicating that normal prostate cells are not inherently resistant to killing by VSV. In each of the cell lines, the rM51R-M virus induced similar levels of apoptosis to rwt virus, showing that the M protein does not play a significant role in apoptosis induction by VSV in these cells. In multiple-cycle infection experiments, LNCaP cells were more sensitive than benign prostatic epithelial cells to virus-induced cell killing by rM51R-M virus, but not rwt virus. Both viruses were equally effective at reducing LNCaP tumor volume in vivo following intratumoral and intravenous inoculation in nude mice, while PC-3 tumors were resistant to VSV treatment. None of the mice treated with rM51R-M virus died as a result of virus infection, while 50-71% of mice treated with rwt virus succumbed to virus infection. Similarly, when inoculated by the more sensitive intranasal route, the rM51R-M virus was less pathogenic than the rwt virus from

  5. 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

  6. Stromal prostatic sarcoma: a rare tumor with rare clinical and imaging presentation

    PubMed Central

    Rojas-Jiménez, Anamaría; Otero-Garcia, Milagros; Mateos-Martin, Alejandro

    2013-01-01

    Adult prostatic stromal sarcoma is a rare malignant tumor. The main presenting symptom is urinary retention secondary to bladder outlet obstruction. Prostatic Specific Antigen level can be normal. Imaging features show a prostate mass with or without pelvic organ invasion depending on the aggressiveness of the tumor. We present a patient with prostatic stromal sarcoma who debuted with urinary obstruction, leukocytosis and neutrophilia, prostate enlargement, and hypodense prostate areas on CT images, simulating prostatitis with abscess formation. PMID:24421945

  7. An immune-inflammation gene expression signature in prostate tumors of smokers

    PubMed Central

    Yi, Ming; Tang, Wei; Luo, Jun; Dorsey, Tiffany H.; Stagliano, Katherine E.; Gillespie, John W.; Hudson, Robert S.; Terunuma, Atsushi; Shoe, Jennifer L.; Haines, Diana C.; Yfantis, Harris G.; Han, Misop; Martin, Damali N.; Jordan, Symone V.; Borin, James F.; Naslund, Michael J.; Alexander, Richard B.; Stephens, Robert M.; Loffredo, Christopher A.; Lee, Dong H.; Putluri, Nagireddy; Sreekumar, Arun; Hurwitz, Arthur A.; Ambs, Stefan

    2016-01-01

    Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggested that nicotine was sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. PMID:26719530

  8. An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers.

    PubMed

    Prueitt, Robyn L; Wallace, Tiffany A; Glynn, Sharon A; Yi, Ming; Tang, Wei; Luo, Jun; Dorsey, Tiffany H; Stagliano, Katherine E; Gillespie, John W; Hudson, Robert S; Terunuma, Atsushi; Shoe, Jennifer L; Haines, Diana C; Yfantis, Harris G; Han, Misop; Martin, Damali N; Jordan, Symone V; Borin, James F; Naslund, Michael J; Alexander, Richard B; Stephens, Robert M; Loffredo, Christopher A; Lee, Dong H; Putluri, Nagireddy; Sreekumar, Arun; Hurwitz, Arthur A; Ambs, Stefan

    2016-03-01

    Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. ©2015 American Association for Cancer Research.

  9. Ultrasound molecular imaging of VEGFR2 in a rat prostate tumor model using BR55.

    PubMed

    Tardy, Isabelle; Pochon, Sibylle; Theraulaz, Martine; Emmel, Patricia; Passantino, Lisa; Tranquart, François; Schneider, Michel

    2010-10-01

    To evaluate BR55, a new VEGFR2-specific ultrasound contrast agent, for imaging prostate tumors in an orthotopic model in the rat. Rat prostate adenocarcinoma were established by injection of G Dunning R-3327 tumor cells in one lobe of the prostate of Copenhagen rats. Imaging experiments were performed with BR55, SonoVue, and streptavidin-functionalized microbubbles coupled with an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody using a clinical ultrasound scanner. Contrast enhancement in the tumor and healthy prostate was followed over time by intermittent imaging at low acoustic power. Signal quantification and statistical analysis were performed in the tumor and healthy tissue to compare the behavior of the 3 contrast agents. Immunohistochemistry was performed on the prostate and tumor specimen to determine the expression of VEGFR2. Comparable contrast enhancement was observed in tumors at peak intensity for BR55 and SonoVue. Then, once unbound microbubbles had cleared from the circulation, a strong enhancement of the tumor was obtained with BR55, whereas no significant microbubble accumulation was detected in the healthy prostate tissue. SonoVue microbubbles were rapidly eliminated, and no significant binding was observed in the tumor. The tumor to prostate ratio calculated after signal quantification was about 20 for the 3 doses of BR55 tested. The enhancement obtained with BR55 in the tumor was not significantly different from the one observed with antibody-coupled streptavidin microbubbles. Intense staining for VEGFR2 was detected in the tumor vessels by immunohistochemistry. This study showed that BR55 binding to prostate tumors resulted in a strong enhancement of the lesions as early as a few minutes after contrast injection, whereas minimal nonspecific accumulation occurred in the healthy part of the gland. BR55, like SonoVue, provide information on tissue perfusion during the early vascular phase, but BR55 binding to the tumoral

  10. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells.

    PubMed

    Cai, Liquan; Wang, Dan; Fisher, Alfred L; Wang, Zhou

    2014-05-02

    The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in controlling the growth and survival of prostate cancer cells. Together these findings identify a novel physical and functional interaction between EAF2 and the Rb pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. A dual-reporter, diagnostic vector for prostate cancer detection and tumor imaging.

    PubMed

    Richter, J R; Mahoney, M; Warram, J M; Samuel, S; Zinn, K R

    2014-10-01

    Detection of prostate-specific antigen (PSA) as a screening strategy for prostate cancer is limited by the inability of the PSA test to differentiate between malignant cancer and benign hyperplasia. Here, we report the use of a cancer-specific promoter, inhibition of differentiation-1 (Id1), to drive a dual-reporter system (Ad5/3-Id1-SEAP-Id1-mCherry) designed for detection of prostate cancer using a blood-based reporter-secreted embryonic alkaline phosphatase (SEAP) and tumor visualization using a fluorescent reporter protein, mCherry. In human prostate tumors, Id1 levels are correlated with increased Gleason grade and disease progression. To evaluate the performance of the dual-reporter system, a prostate cell panel with varying aggressive phenotypes was tested. Following infection with the Ad5/3-Id1-SEAP-Id1-mCherry vector, expression of the SEAP and mCherry reporters was shown to increase with increasing levels of cellular Id1. No correlation was observed between Id1 and PSA. To evaluate in vivo performance, flank tumors were grown in athymic male mice using three prostate cancer cell lines. Following intra-tumoral injection of the vector, tumors formed by cells with high Id1 had the greatest reporter expression. Interestingly, tumors with the lowest levels of Id1 and reporter expression produced the greatest amounts of PSA. These data support the use of Ad5/3-Id1-SEAP-Id1-mCherry as a predictor of prostate cancer malignancy and as a strategy for tumor localization.

  12. A Dual-Reporter, Diagnostic Vector for Prostate Cancer Detection and Tumor Imaging

    PubMed Central

    Richter, Jillian R.; Mahoney, Marshall; Warram, Jason M.; Samuel, Sharon; Zinn, Kurt R.

    2014-01-01

    Detection of prostate-specific antigen (PSA) as a screening strategy for prostate cancer is limited by the inability of the PSA test to differentiate between malignant cancer and benign hyperplasia. Here, we report the use of a cancer-specific promoter, inhibition of differentiation-1 (Id1), to drive a dual-reporter system (Ad5/3-Id1-SEAP-Id1-mCherry) designed for detection of prostate cancer using a blood-based reporter SEAP (secreted embryonic alkaline phosphatase) and tumor visualization using a fluorescent reporter protein, mCherry. In human prostate tumors, Id1 levels correlate with increased Gleason grade and disease progression. To evaluate the performance of the dual-reporter system, a prostate cell panel with varying aggressive phenotypes was tested. Following infection with the Ad5/3-Id1-SEAP-Id1-mCherry vector, expression of the SEAP and mCherry reporters was shown to increase with increasing levels of cellular Id1. No correlation was observed between Id1 and PSA. To evaluate in vivo performance, flank tumors were grown in athymic male mice using three prostate cancer cell lines. Following intra-tumoral injection of the vector, tumors formed by cells with high Id1 had the greatest reporter expression. Interestingly, tumors with the lowest levels of Id1 and reporter expression produced the greatest amounts of PSA. These data support the use of Ad5/3-Id1-SEAP-Id1-mCherry as a predictor of prostate cancer malignancy and a strategy for tumor localization. PMID:25056609

  13. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation

    PubMed Central

    Diedrich, Jonathan D.; Rajagurubandara, Erandi; Herroon, Mackenzie K.; Mahapatra, Gargi; Hüttemann, Maik; Podgorski, Izabela

    2016-01-01

    Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche. PMID:27588494

  14. Epithelial-to-mesenchymal transition leads to disease-stage differences in circulating tumor cell detection and metastasis in pre-clinical models of prostate cancer

    PubMed Central

    Lowes, Lori E.; Goodale, David; Xia, Ying; Postenka, Carl; Piaseczny, Matthew M.; Paczkowski, Freeman; Allan, Alison L.

    2016-01-01

    Metastasis is the cause of most prostate cancer (PCa) deaths and has been associated with circulating tumor cells (CTCs). The presence of ≥5 CTCs/7.5mL of blood is a poor prognosis indicator in metastatic PCa when assessed by the CellSearch® system, the “gold standard” clinical platform. However, ~35% of metastatic PCa patients assessed by CellSearch® have undetectable CTCs. We hypothesize that this is due to epithelial-to-mesenchymal transition (EMT) and subsequent loss of necessary CTC detection markers, with important implications for PCa metastasis. Two pre-clinical assays were developed to assess human CTCs in xenograft models; one comparable to CellSearch® (EpCAM-based) and one detecting CTCs semi-independent of EMT status via combined staining with EpCAM/HLA (human leukocyte antigen). In vivo differences in CTC generation, kinetics, metastasis and EMT status were determined using 4 PCa models with progressive epithelial (LNCaP, LNCaP-C42B) to mesenchymal (PC-3, PC-3M) phenotypes. Assay validation demonstrated that the CellSearch®-based assay failed to detect a significant number (~40-50%) of mesenchymal CTCs. In vivo, PCa with an increasingly mesenchymal phenotype shed greater numbers of CTCs more quickly and with greater metastatic capacity than PCa with an epithelial phenotype. Notably, the CellSearch®-based assay captured the majority of CTCs shed during early-stage disease in vivo, and only after establishment of metastases were a significant number of undetectable CTCs present. This study provides important insight into the influence of EMT on CTC generation and subsequent metastasis, and highlights that novel technologies aimed at capturing mesenchymal CTCs may only be useful in the setting of advanced metastatic disease. PMID:27764810

  15. Transcriptomic alterations in human prostate cancer cell LNCaP tumor xenograft modulated by dietary phenethyl isothiocyanate

    USDA-ARS?s Scientific Manuscript database

    Temporal growth of tumor xenografts in mice on a control diet was compared to mice supplemented daily with 3 µmol/g of the cancer preventive compound phenethyl isothiocyanate. Phenethyl isothiocyanate decreased the rate of tumor growth. The effects of phenethyl isothiocyanate on tumor growth were ex...

  16. Prostate Cancer Stem-Like Cells | Center for Cancer Research

    Cancer.gov

    Prostate cancer is the third leading cause of cancer-related death among men, killing an estimated 27,000 men each year in the United States. Men with advanced prostate cancer often become resistant to conventional therapies. Many researchers speculate that the emergence of resistance is due to the presence of cancer stem cells, which are believed to be a small subpopulation of tumor cells that can self-renew and give rise to more differentiated tumor cells. It is thought that these stem cells survive initial therapies (such as chemotherapy and hormone therapy) and then generate new tumor cells that are resistant to these standard treatments. If prostate cancer stem cells could be identified and characterized, it might be possible to design treatments that prevent resistance.

  17. Circulating tumor cells in germ cell tumors: are those biomarkers of real prognostic value? A review

    PubMed Central

    CEBOTARU, CRISTINA LIGIA; OLTEANU, ELENA DIANA; ANTONE, NICOLETA ZENOVIA; BUIGA, RARES; NAGY, VIORICA

    2016-01-01

    Analysis of circulating tumor cells from patients with different types of cancer is nowadays a fascinating new tool of research and their number is proven to be useful as a prognostic factor in metastatic breast, colon and prostate cancer patients. Studies are going beyond enumeration, exploring the circulating tumor cells to better understand the mechanisms of tumorigenesis, invasion and metastasis and their value for characterization, prognosis and tailoring of treatment. Few studies investigated the prognostic significance of circulating tumor cells in germ cell tumors. In this review, we examine the possible significance of the detection of circulating tumor cells in this setting. PMID:27152069

  18. Cross-Presentation of the Oncofetal Tumor Antigen 5T4 from Irradiated Prostate Cancer Cells--A Key Role for Heat-Shock Protein 70 and Receptor CD91.

    PubMed

    Salimu, Josephine; Spary, Lisa K; Al-Taei, Saly; Clayton, Aled; Mason, Malcolm D; Staffurth, John; Tabi, Zsuzsanna

    2015-06-01

    Immune responses contribute to the success of radiotherapy of solid tumors; however, the mechanism of triggering CD8(+) T-cell responses is poorly understood. Antigen cross-presentation from tumor cells by dendritic cells (DC) is a likely dominant mechanism to achieve CD8(+) T-cell stimulation. We established a cross-presentation model in which DCs present a naturally expressed oncofetal tumor antigen (5T4) from irradiated DU145 prostate cancer cells to 5T4-specific T cells. The aim was to establish which immunogenic signals are important in radiation-induced cross-presentation. Radiation (12 Gy) caused G2-M cell-cycle arrest and cell death, increased cellular 5T4 levels, high-mobility protein group-B1 (HMGB1) release, and surface calreticulin and heat-shock protein-70 (Hsp70) expression in DU145 cells. DCs phagocytosed irradiated tumor cells efficiently, followed by upregulation of CD86 on phagocytic DCs. CD8(+) 5T4-specific T cells, stimulated with these DCs, proliferated and produced IFNγ. Inhibition of HMGB1 or the TRIF/MyD88 pathway only had a partial effect on T-cell stimulation. Unlike previous investigators, we found no evidence that DCs carrying Asp299Gly Toll-like receptor-4 (TLR4) single-nucleotide polymorphism had impaired ability to cross-present tumor antigen. However, pretreatment of tumor cells with Hsp70 inhibitors resulted in a highly statistically significant and robust prevention of antigen cross-presentation and CD86 upregulation on DCs cocultured with irradiated tumor cells. Blocking the Hsp70 receptor CD91 also abolished cross-presentation. Together, the results from our study demonstrate that irradiation induces immunologically relevant changes in tumor cells, which can trigger CD8(+) T-cell responses via a predominantly Hsp70-dependent antigen cross-presentation process.

  19. Cell Cycle Dependence of TRAIL Sensitivity in Prostate Cancer Cells

    DTIC Science & Technology

    2006-11-01

    or presence of proteasome inhibitors and measured HIF-1α levels by immunoblotting. We also incubated cells in cobalt chloride (to mimic hypoxia) in...Indistinguishable results were obtained in cells exposed to cobalt chloride . Figure 5: Effects of proteasome inhibitors on HIF- 1α promoter activity (LNCaP...havegenerated luciferase-transduced variants of our human prostate cancer cell lines in order touse them to generate orthotopic tumors in nude mice that can

  20. Identification and Reconstruction of Prostate Tumor-Suppressing Exosomes for Therapeutic Applications

    DTIC Science & Technology

    2015-01-01

    released by many cell types, exosomes serve as vehicles for long range intercellular communications, with the bioactive contents of exosomes as the...vehicles for long range intercellular communications, with the bioactive contents of exosomes as the messengers. It is hypothesized that normal prostate...alternative approach is to extract exosomes from normal prostate tissues and then evaluate their potential tumor suppressive activities as proposed. The use of

  1. Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis.

    PubMed

    Cai, Yuqi; Balli, David; Ustiyan, Vladimir; Fulford, Logan; Hiller, Andrea; Misetic, Vinko; Zhang, Yufang; Paluch, Andrew M; Waltz, Susan E; Kasper, Susan; Kalin, Tanya V

    2013-08-02

    The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11β-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for

  2. Regulation of protein translation and c-Jun expression by prostate tumor overexpressed 1.

    PubMed

    Marqués, N; Sesé, M; Cánovas, V; Valente, F; Bermudo, R; de Torres, I; Fernández, Y; Abasolo, I; Fernández, P L; Contreras, H; Castellón, E; Celià-Terrassa, T; Méndez, R; Ramón Y Cajal, S; Thomson, T M; Paciucci, R

    2014-02-27

    Prostate tumor overexpressed-1 (PTOV1), a modulator of the Mediator transcriptional regulatory complex, is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease. Here we show that PTOV1 interacts directly with receptor of activated protein C kinase 1 (RACK1), a regulator of protein kinase C and Jun signaling and also a component of the 40S ribosome. Consistent with this interaction, PTOV1 was associated with ribosomes and its overexpression promoted global protein synthesis in prostate cancer cells and COS-7 fibroblasts in a mTORC1-dependent manner. Transfection of ectopic PTOV1 enhanced the expression of c-Jun protein without affecting the levels of c-Jun or RACK1 mRNA. Conversely, knockdown of PTOV1 caused significant declines in global protein synthesis and c-Jun protein levels. High levels of PTOV1 stimulated the motility and invasiveness of prostate cancer cells, which required c-Jun, whereas knockdown of PTOV1 strongly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. In human prostate cancer samples, the expression of high levels of PTOV1 in primary and metastatic tumors was significantly associated with increased nuclear localization of active c-Jun. These results unveil new functions of PTOV1 in the regulation of protein translation and in the progression of prostate cancer to an invasive and metastatic disease.

  3. Molecular Mechanism for Prostate Cancer Resistance to the Anti-Tumor Activity

    DTIC Science & Technology

    2005-11-01

    Interleukin - 6 production in normal prostate cells via MAP Kinase Phosphatase 5: Implications for prostate cancer prevention by... Interleukin - 6 production in normal prostate cells via MAP Kinase Phosphatase 5: Implications for prostate cancer prevention by Vitamin D” (Appendix A...Vitamin D reduces Interleukin - 6 production in normal prostate cells via MAP Kinase Phosphatase 5: Implications for prostate cancer prevention by

  4. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer.

    PubMed

    Pollard, Harvey B; Levine, Mark A; Eidelman, Ofer; Pollard, Morris

    2010-01-01

    The aim of this study was to test for the influence of ascorbic acid on tumorigenicity and metastases of implanted PAIII prostate cancer adenocarcinoma cells in syngeneic LW rats. Hormone-refractory prostate cancer PAIII cells were implanted subcutaneously into immunologically intact, Lobund-Wistar (LW) rats. Intraperitoneal pharmacological doses of ascorbic acid were administered each day for the ensuing 30 days. On the 40th day, animals were sacrificed. Local tumor weights were measured, and metastases were counted. At the end of the 40 day experimental period, the primary tumors were found to be significantly reduced in weight (p=0.026). In addition, sub-pleural lung metastases were even more profoundly reduced in number and size (p=0.009). Grossly enlarged ipsilateral lymph node metastases declined from 7 of 15 rats to 1 of 15 rats. Pharmacological doses of ascorbic acid suppress tumor growth and metastases in hormone-refractory prostate cancer.

  5. Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.

    PubMed

    Riabov, Vladimir; Kim, David; Chhina, Surmeet; Alexander, Richard B; Klyushnenkova, Elena N

    2015-07-01

    Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects.

  6. Parthenolide Selectively Sensitizes Prostate Tumor Tissue to Radiotherapy while Protecting Healthy Tissues In Vivo.

    PubMed

    Morel, Katherine L; Ormsby, Rebecca J; Bezak, Eva; Sweeney, Christopher J; Sykes, Pamela J

    2017-05-01

    Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties and selectively induces radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Low doses of radiation have also been shown to protect from subsequent high-dose-radiation-induced apoptosis as well as DNA damage. These properties of PTL and low-dose radiation could be used to improve radiotherapy by killing more tumor cells and less normal cells. Sixteen-week-old male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) and C57BL/6J mice were treated with PTL (40 mg/kg), dimethylaminoparthenolide (DMAPT, a PTL analogue with increased bioavailability) (100 mg/kg), or vehicle control three times over one week prior to combinations of low (10 mGy) and high (6 Gy) doses of whole-body X-irradiation. Tissues were analyzed for apoptosis at a range of time points up to 72 h postirradiation. Both PTL and DMAPT protected normal tissues, but not prostate tumor tissues, from a significant proportion of high-dose-radiation-induced apoptosis. DMAPT provided superior protection compared to PTL in normal dorsolateral prostate (71.7% reduction, P = 0.026), spleen (48.2% reduction, P = 0.0001) and colorectal tissue (38.0% reduction, P = 0.0002), and doubled radiation-induced apoptosis in TRAMP prostate tumor tissue (101.3% increase, P = 0.039). Both drugs induced the greatest radiosensitivity in TRAMP prostate tissue in areas with higher grade prostatic intraepithelial neoplasia (PIN) lesions. A 10 mGy dose delivered 3 h prior to a 6 Gy dose induced a radioadaptive apoptosis response in normal C57Bl/6J prostate (28.4% reduction, P = 0.045) and normal TRAMP spleen (13.6% reduction, P = 0.047), however the low-dose-adaptive radioprotection did not significantly add to the PTL

  7. Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

    PubMed

    Onstenk, Wendy; Sieuwerts, Anieta M; Kraan, Jaco; Van, Mai; Nieuweboer, Annemieke J M; Mathijssen, Ron H J; Hamberg, Paul; Meulenbeld, Hielke J; De Laere, Bram; Dirix, Luc Y; van Soest, Robert J; Lolkema, Martijn P; Martens, John W M; van Weerden, Wytske M; Jenster, Guido W; Foekens, John A; de Wit, Ronald; Sleijfer, Stefan

    2015-12-01

    Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients. To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel. We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction. The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests. AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 [100%] treated vs 7 of 20 [35%] untreated; p=0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio [HR]: 0.8; 95% confidence interval [CI], 0.4-1.8) or overall survival (HR 1.6; 95% CI, 0.6-4.4). The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs. Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti

  8. SPOCK1 promotes tumor growth and metastasis in human prostate cancer

    PubMed Central

    Chen, Qi; Yao, Yuan-ting; Xu, Huan; Chen, Yan-bo; Gu, Meng; Cai, Zhi-kang; Wang, Zhong

    2016-01-01

    Prostate cancer is the most diagnosed noncutaneous cancer and ranks as the second leading cause of cancer-related deaths in American males. Metastasis is the primary cause of prostate cancer mortality. Survival rate is only 28% for metastatic patients, but is nearly 100% for patients with localized prostate cancers. Molecular mechanisms that underlie this malignancy remain obscure, and this study investigated the role of SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) in prostate cancer progression. Initially, we found that SPOCK1 expression was significantly higher in prostate cancer tissues relative to noncancerous tissues. In particular, SPOCK1 expression was also markedly high in metastatic tissues compared with nonmetastatic cancerous tissues. SPOCK1 expression knockdown by specific short hairpin RNA in PC3 cells was significantly inhibited, whereas SPOCK1 overexpression in RWPE-1 cells promoted cell viability, colony formation in vitro, and tumor growth in vivo. Moreover, the SPOCK1 knockdown in PC3 cells was associated with cell cycle arrest in G0/G1 phase, while the SPOCK1 overexpression in RWPE-1 cells induced cell cycle arrest in S phase. The SPOCK1 knockdown in PC3 cells even increased cell apoptosis. SPOCK1 modulation was also observed to affect cancerous cell proliferation and apoptotic processes in the mouse model of prostate cancer. Additionally, the SPOCK1 knockdown decreased, whereas the SPOCK1 overexpression increased cell migration and invasion abilities in vitro. Injection of SPOCK1-depleted PC3 cells significantly decreased metastatic nodules in mouse lungs. These findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer. PMID:27486308

  9. SPOCK1 promotes tumor growth and metastasis in human prostate cancer.

    PubMed

    Chen, Qi; Yao, Yuan-Ting; Xu, Huan; Chen, Yan-Bo; Gu, Meng; Cai, Zhi-Kang; Wang, Zhong

    2016-01-01

    Prostate cancer is the most diagnosed noncutaneous cancer and ranks as the second leading cause of cancer-related deaths in American males. Metastasis is the primary cause of prostate cancer mortality. Survival rate is only 28% for metastatic patients, but is nearly 100% for patients with localized prostate cancers. Molecular mechanisms that underlie this malignancy remain obscure, and this study investigated the role of SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) in prostate cancer progression. Initially, we found that SPOCK1 expression was significantly higher in prostate cancer tissues relative to noncancerous tissues. In particular, SPOCK1 expression was also markedly high in metastatic tissues compared with nonmetastatic cancerous tissues. SPOCK1 expression knockdown by specific short hairpin RNA in PC3 cells was significantly inhibited, whereas SPOCK1 overexpression in RWPE-1 cells promoted cell viability, colony formation in vitro, and tumor growth in vivo. Moreover, the SPOCK1 knockdown in PC3 cells was associated with cell cycle arrest in G0/G1 phase, while the SPOCK1 overexpression in RWPE-1 cells induced cell cycle arrest in S phase. The SPOCK1 knockdown in PC3 cells even increased cell apoptosis. SPOCK1 modulation was also observed to affect cancerous cell proliferation and apoptotic processes in the mouse model of prostate cancer. Additionally, the SPOCK1 knockdown decreased, whereas the SPOCK1 overexpression increased cell migration and invasion abilities in vitro. Injection of SPOCK1-depleted PC3 cells significantly decreased metastatic nodules in mouse lungs. These findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer.

  10. Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis.

    PubMed

    Li, Xin; Koh, Amy J; Wang, Zhengyan; Soki, Fabiana N; Park, Serk In; Pienta, Kenneth J; McCauley, Laurie K

    2011-01-01

    Prostate cancer cells commonly spread through the circulation, but few successfully generate metastatic foci in bone. Osteoclastic cellular activity has been proposed as an initiating event for skeletal metastasis. Megakaryocytes (MKs) inhibit osteoclastogenesis, which could have an impact on tumor establishment in bone. Given the location of mature MKs at vascular sinusoids, they may be the first cells to physically encounter cancer cells as they enter the bone marrow. Identification of the interaction between MKs and prostate cancer cells was the focus of this study. K562 (human MK precursors) and primary MKs derived from mouse bone marrow hematopoietic precursor cells potently suppressed prostate carcinoma PC-3 cells in coculture. The inhibitory effects were specific to prostate carcinoma cells and were enhanced by direct cell-cell contact. Flow cytometry for propidium iodide (PI) and annexin V supported a proapoptotic role for K562 cells in limiting PC-3 cells. Gene expression analysis revealed reduced mRNA levels for cyclin D1, whereas mRNA levels of apoptosis-associated specklike protein containing a CARD (ASC) and death-associated protein kinase 1 (DAPK1) were increased in PC-3 cells after coculture with K562 cells. Recombinant thrombopoietin (TPO) was used to expand MKs in the marrow and resulted in decreased skeletal lesion development after intracardiac tumor inoculation. These novel findings suggest a potent inhibitory role of MKs in prostate carcinoma cell growth in vitro and in vivo. This new finding, of an interaction of metastatic tumors and hematopoietic cells during tumor colonization in bone, ultimately will lead to improved therapeutic interventions for prostate cancer patients.

  11. Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial-Stromal Tumors by Targeting PDGFR-β.

    PubMed

    Jachetti, Elena; Rigoni, Alice; Bongiovanni, Lucia; Arioli, Ivano; Botti, Laura; Parenza, Mariella; Cancila, Valeria; Chiodoni, Claudia; Festinese, Fabrizio; Bellone, Matteo; Tardanico, Regina; Tripodo, Claudio; Colombo, Mario P

    2017-02-01

    Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-β, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Prostate stem cell antigen: Identification of immunogenic peptides and assessment of reactive CD8+ T cells in prostate cancer patients.

    PubMed

    Kiessling, Andrea; Schmitz, Marc; Stevanovic, Stefan; Weigle, Bernd; Hölig, Kristina; Füssel, Monika; Füssel, Susanne; Meye, Axel; Wirth, Manfred P; Rieber, Ernst Peter

    2002-12-01

    Identification of TAAs recognized by CD8(+) CTLs paved the way for new concepts in cancer therapy. In view of the heterogeneity of tumors and their diverse escape mechanisms, CTL-based cancer therapy largely depends on an appropriate number of TAAs. In prostate cancer, the number of antigens defined as suitable targets of CTLs remains rather limited. PSCA is widely distributed in prostate cancer. In this report, we define immunogenic peptides of PSCA which are recognized by circulating CD8(+) T cells from prostate cancer patients and able to activate CTLs in vitro. Screening the amino acid sequence of PSCA for peptides containing a binding motif for HLA-A*0201 resulted in 8 candidate peptides. Specificity and affinity of peptide binding were verified in a competition assay. Frequencies of CD8(+) T lymphocytes reactive against selected epitopes were determined in the blood of prostate cancer patients using the ELISPOT assay. Increased frequencies were revealed for CD8(+) T cells recognizing the peptides ALQPGTALL and AILALLPAL. CTLs from prostate cancer patients were raised against these 2 peptides in vitro when presented by autologous DCs. They specifically recognized peptide-pulsed T2 target cells and prostate cancer cells that were HLA-A*0201- and PSCA-positive, indicating that these peptides were naturally generated by tumor cells. These data suggest that PSCA is a promising target for the immunotherapy of prostate cancer.

  13. Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy.

    PubMed

    Tumati, Vasu; Mathur, Sanjeev; Song, Kwang; Hsieh, Jer-Tsong; Zhao, Dawen; Takahashi, Masaya; Dobin, Timothy; Gandee, Leah; Solberg, Timothy D; Habib, Amyn A; Saha, Debabrata

    2013-05-01

    The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3‑KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments.

  14. Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy

    PubMed Central

    TUMATI, VASU; MATHUR, SANJEEV; SONG, KWANG; HSIEH, JER-TSONG; ZHAO, DAWEN; TAKAHASHI, MASAYA; DOBIN, TIMOTHY; GANDEE, LEAH; SOLBERG, TIMOTHY D.; HABIB, AMYN A.; SAHA, DEBABRATA

    2013-01-01

    The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3-KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments. PMID:23525451

  15. Anti-tumor immunological response induced by cryoablation and anti-CTLA-4 antibody in an in vivo RM-1 cell prostate cancer murine model.

    PubMed

    Li, F; Guo, Z; Yu, H; Zhang, X; Si, T; Liu, C; Yang, X; Qi, L

    2014-01-01

    Cryoablation combination therapy with blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) may augment the anti-tumor immune response (ATIR). It is crucial to determine the duration of ATIR after cryoablation and anti-CTLA-4 antibody therapy to determine the most appropriate treatment interval of therapy. To investigate the characteristics of ATIR induced by cryoablation and anti-CTLA-4 antibody therapy, we developed a prostate cancer model system to test the capacity of cryoablation and anti -CTLA-4 antibody to generate ATIR. Mice were randomly assigned to receive no treatment (group A), cryoablation only (group B), cryoablation plus anti-CTLA-4 antibody (group C), or anti-CTLA-4 antibody only (group D). We collected specimens on days 0, 7, 14 and 21 to study the ATIR through different techniques. Our results indicated that cryoablation induced ATIR and further enhanced this effect and reduced the number of distant metastases through combination with anti-CTLA-4 antibody. ATIR induced by cryoablation was achieved through decreasing regulatory T cell (Treg) number. The number of Tregs induced by cryoablation was lowest on day 14 but then returned to preoperative levels on day 21, indicating that ATIR induced by cryoablation was time-dependent. However, ATIR induced by anti-CTLA-4 antibody might be mainly achieved through influencing Treg function, which was exactly not by decreasing Treg number and still maintain its ATIR effect on day 21 after therapy. In conclusion, ATIR induced by cryoablation was achieved through decreasing Treg number and is time-dependent, whereas ATIR caused by anti-CTLA-4 antibody was achieved exactly not by decreasing Treg number and not time-dependent in the first 21 days after therapy.

  16. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer.

    PubMed

    Scher, Howard I; Lu, David; Schreiber, Nicole A; Louw, Jessica; Graf, Ryon P; Vargas, Hebert A; Johnson, Ann; Jendrisak, Adam; Bambury, Richard; Danila, Daniel; McLaughlin, Brigit; Wahl, Justin; Greene, Stephanie B; Heller, Glenn; Marrinucci, Dena; Fleisher, Martin; Dittamore, Ryan

    2016-11-01

    A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane. To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes. For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7-positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7-positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7-positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7-positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7-positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative

  17. Novel series of (177)Lu-labeled bombesin derivatives with amino acidic spacers for selective targeting of human PC-3 prostate tumor cells.

    PubMed

    Pujatti, P B; Santos, J S; Couto, R M; Melero, L T U H; Suzuki, M F; Soares, C R J; Grallert, S R M; Mengatti, J; De Araújo, E B

    2011-06-01

    Bombesin (BBN) has demonstrated the ability to bind with high affinity and specificity to GRP receptor, overexpressed on human prostate cancer. A large number of BBN derivatives have been synthesized for this purpose but most of them exhibit high abdominal accumulation, which may represent a problem in their clinical use due to serious side effects to patients. In this study we describe the results of radiolabeling with lutetium-177, stability and in vivo studies of novel phenyl-glycine-extended bombesin derivatives. The spacers were inserted to improve bombesin in vivo properties and to reduce its target to non-tumor sites. Preliminary studies were done to establish the ideal conditions for labeling bombesin derivatives. Chromatography systems were applied to determine free lutetium and the stability of the preparations was evaluated either after storing at 2-8 ºC or incubation in human serum at 37 ºC. In vivo experiments included biodistribution, pharmacokinetics and SPECT images and were performed in Balb-c and Nude mice bearing PC-3 xenografts. The derivatives were labeled with high yield and kept stable at 2-8 ºC and are metabolized by human serum enzymes. In vivo studies showed fast blood clearance of labeled peptides and rapid excretion, performed mainly by renal pathway. In addition, biodistribution and imaging studies showed low abdominal accumulation and significant and specific tumor uptake of (177)Lu-labeled derivatives. The derivative with longer spacer holds a higher potential as radiopharmaceutical for prostate tumor diagnosis and the derivatives with shorter spacers are potential radiopharmaceuticals for prostate tumor treatment.

  18. Improved delivery of polymer therapeutics to prostate tumors using plasmonic photothermal therapy

    NASA Astrophysics Data System (ADS)

    Gormley, Adam Joseph

    When a patient is presented with locally advanced prostate cancer, it is possible to provide treatment with curative intent. However, once the disease has formed distant metastases, the chances of survival drops precipitously. For this reason, proper management of the disease while it remains localized is of critical importance. Treating these malignant cells with cytotoxic agents is effective at cell killing; however, the nonspecific toxicity profiles of these drugs often limit their use until the disease has progressed and symptom palliation is required. Incorporation of these drugs in nanocarriers such as polymers help target them to tumors with a degree of specificity, though major vascular barriers limit their effective delivery. In this dissertation, it is shown that plasmonic photothermal therapy (PPTT) can be used to help overcome some of these barriers and improve delivery to prostate tumors. First, the concept of using PPTT to improve the delivery of macromolecules to solid tumors was validated. This was done by measuring the tumor uptake of albumin. Next, the concept of targeting gold nanorods (GNRs) directly to the tumor's vasculature to better modulate vascular response to heating was tested. Surface conjugation of cyclic RGD (Arg-Gly-Asp) to GNRs improved their binding and uptake to endothelial cells in vitro, but not in vivo. Nontargeted GNRs and PPTT were then utilized to guide the location of polymer therapeutic delivery to prostate tumors. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, which were designed to be targeted to cells previously exposed to heat shock, were used in this study. Treatment of tumors with PPTT facilitated a burst accumulation of the copolymers over 4 hours, and heat shock targeting to cells allowed them to be retained for an extended period of time. Finally, the tumor localization of the HPMA copolymers following PPTT was evaluated by magnetic resonance imaging (MRI). These results show that PPTT may be a useful tool

  19. Prostate-targeted biodegradable nanoparticles loaded with androgen receptor silencing constructs eradicate xenograft tumors in mice

    PubMed Central

    Yang, Jun; Xie, Sheng-Xue; Huang, Yiling; Ling, Min; Liu, Jihong; Ran, Yali; Wang, Yanlin; Thrasher, J Brantley; Berkland, Cory; Li, Benyi

    2012-01-01

    Background Prostate cancer is the major cause of cancer death in men and the androgen receptor (AR) has been shown to play a critical role in the progression of the disease. Our previous reports showed that knocking down the expression of the AR gene using a siRNA-based approach in prostate cancer cells led to apoptotic cell death and xenograft tumor eradication. In this study, we utilized a biodegradable nanoparticle to deliver the therapeutic AR shRNA construct specifically to prostate cancer cells. Materials & methods The biodegradable nanoparticles were fabricated using a poly(dl-lactic-co-glycolic acid) polymer and the AR shRNA constructs were loaded inside the particles. The surface of the nanoparticles were then conjugated with prostate-specific membrane antigen aptamer A10 for prostate cancer cell-specific targeting. Results A10-conjugation largely enhanced cellular uptake of nanoparticles in both cell culture- and xenograft-based models. The efficacy of AR shRNA encapsulated in nanoparticles on AR gene silencing was confirmed in PC-3/AR-derived xenografts in nude mice. The therapeutic property of A10-conjugated AR shRNA-loaded nanoparticles was evaluated in xenograft models with different prostate cancer cell lines: 22RV1, LAPC-4 and LNCaP. Upon two injections of the AR shRNA-loaded nanoparticles, rapid tumor regression was observed over 2 weeks. Consistent with previous reports, A10 aptamer conjugation significantly enhanced xenograft tumor regression compared with nonconjugated nanoparticles. Discussion These data demonstrated that tissue-specific delivery of AR shRNA using a biodegradable nanoparticle approach represents a novel therapy for life-threatening prostate cancers. PMID:22583574

  20. Chemopreventive efficacy of inositol hexaphosphate against prostate tumor growth and progression in TRAMP mice.

    PubMed

    Raina, Komal; Rajamanickam, Subapriya; Singh, Rana P; Agarwal, Rajesh

    2008-05-15

    Herein, for the first time, we evaluated the in vivo chemopreventive efficacy of inositol hexaphosphate (IP6), a major constituent of high-fiber diets, against prostate tumor growth and progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Beginning at 4 weeks of age, male TRAMP mice were fed 2% (w/v) IP6 in drinking water or only drinking water till 24 weeks of age, and then sacrificed. Prostate tissue was subjected to histopathologic analysis and to immunohistochemical analyses for proliferation and apoptosis. IP6 feeding did not show any adverse effect on fluid and diet consumption and body weight. There was a significant reduction (40%; P < 0.01) in lower urogenital tract weight in IP6-fed mice. IP6 inhibited prostate cancer progression at prostatic intraepithelial neoplasia stage and strongly reduced the incidence of adenocarcinoma (prostatic intraepithelial neoplasia/adenocarcinoma, 75:25% in the IP6 group versus 39:61% in the control group; P < 0.05). The incidences of well-differentiated and poorly differentiated adenocarcinomas in the IP6-fed group were reduced by 44% and 62%, respectively. Immunohistochemical analysis of prostate tissue showed a 26% decrease (P < 0.05) in proliferation cell nuclear antigen-positive cells and a 3.5-fold increase in apoptotic cells with no effect on Tag expression by IP6. These findings are both novel and highly significant in establishing for the first time that oral IP6, without any toxicity, suppresses prostate tumor growth and progression at the neoplastic stage, thereby reducing the incidence of adenocarcinoma through its antiproliferative and proapoptotic effects, and thus indicating that IP6 could have potential chemopreventive effects against human prostate cancer.

  1. Role of the ARF Tumor Suppressor in Prostate Cancer

    DTIC Science & Technology

    2005-10-01

    as it is nearly identical from zebra fish to humans (Fig. 2D). Heterogeneous complexes containing NPM NES mutants and wild-type NPM fail to shuttle...independent mechanisms to regulate prostate cell proliferation. Table 1. Protein Expression in Prostate Adenocarcinomas Human prostate tissue samples...into why Arf-/- PEpC are not transformed. In addition, I have finally received a few samples from the Tissue Procurement Core at Washington

  2. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Prostate Cancer Cells after Treatment with Xanthohumol—A Natural Compound Present in Humulus lupulus L.

    PubMed Central

    Kłósek, Małgorzata; Mertas, Anna; Król, Wojciech; Jaworska, Dagmara; Szymszal, Jan; Szliszka, Ewelina

    2016-01-01

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. It has ability to selectively kill tumor cells showing no toxicity to normal cells. We tested the apoptotic and cytotoxic activities of xanthohumol, a prenylated chalcone found in Humulus lupulus on androgen-sensitive human prostate adenocarcinoma cells (LNCaP) in combination with TRAIL. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay (MTT) and lactate dehydrogenase assay (LDH). The expression of death receptors (DR4/TRAIL-R1 and DR5/TRAIL-R2) and apoptosis were detected using flow cytometry. We examined mitochondrial membrane potential (ΔΨm) by DePsipher reagent using fluorescence microscopy. The intracellular expression of proteins was evaluated by Western blotting. Our study showed that xanthohumol enhanced cytotoxic and apoptotic effects of TRAIL. The tested compounds activated caspases-3, -8, -9, Bid, and increased the expression of Bax. They also decreased expression of Bcl-xL and decreased mitochondrial membrane potential, while the expression of death receptors was not changed. The findings suggest that xanthohumol is a compound of potential use in chemoprevention of prostate cancer due to its sensitization of cancer cells to TRAIL-mediated apoptosis. PMID:27338375

  3. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Prostate Cancer Cells after Treatment with Xanthohumol-A Natural Compound Present in Humulus lupulus L.

    PubMed

    Kłósek, Małgorzata; Mertas, Anna; Król, Wojciech; Jaworska, Dagmara; Szymszal, Jan; Szliszka, Ewelina

    2016-06-22

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. It has ability to selectively kill tumor cells showing no toxicity to normal cells. We tested the apoptotic and cytotoxic activities of xanthohumol, a prenylated chalcone found in Humulus lupulus on androgen-sensitive human prostate adenocarcinoma cells (LNCaP) in combination with TRAIL. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay (MTT) and lactate dehydrogenase assay (LDH). The expression of death receptors (DR4/TRAIL-R1 and DR5/TRAIL-R2) and apoptosis were detected using flow cytometry. We examined mitochondrial membrane potential (ΔΨm) by DePsipher reagent using fluorescence microscopy. The intracellular expression of proteins was evaluated by Western blotting. Our study showed that xanthohumol enhanced cytotoxic and apoptotic effects of TRAIL. The tested compounds activated caspases-3, -8, -9, Bid, and increased the expression of Bax. They also decreased expression of Bcl-xL and decreased mitochondrial membrane potential, while the expression of death receptors was not changed. The findings suggest that xanthohumol is a compound of potential use in chemoprevention of prostate cancer due to its sensitization of cancer cells to TRAIL-mediated apoptosis.

  4. High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity.

    PubMed

    Haffner, Michael C; Laimer, Johannes; Chaux, Alcides; Schäfer, Georg; Obrist, Peter; Brunner, Andrea; Kronberger, Irmgard E; Laimer, Klaus; Gurel, Bora; Koller, Johann-Benedikt; Seifarth, Christof; Zelger, Bettina; Klocker, Helmut; Rasse, Michael; Doppler, Wolfgang; Bander, Neil H

    2012-08-01

    Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in prostate cancer as well as in the neo-vasculature of nonprostatic solid tumors. Here, we determined the expression pattern of PSMA in the vasculature of oral squamous cell carcinoma. Using a previously validated antibody, PSMA staining distribution and cyclooxygenase 2 (COX2) expression status was evaluated in a cohort of patients with squamous cell carcinoma of the oral cavity (n=96) using immunohistochemistry and was correlated with clinicopathological features as well as outcome. Twenty-four (25%) cases showed no detectable PSMA staining, 48 (50%) demonstrated positive immunoreactivity for PSMA in less than 50% of microvessels and 24 (25%) cases showed strong endothelial PSMA expression in more than 50% of tumor-associated microvessels. High endothelial PSMA expression was associated with greatly reduced survival (18.2 vs 77.3 months; P=0.0001) and maintained prognostic significance after adjusting for grade and stage in multivariate analysis (hazard ratio=2.19, P=0.007). Furthermore, we observed a strong association between endothelial PSMA and cancer cell-specific COX2 expression. In conclusion, we provide the first evidence for the prognostic significance of endothelial PSMA expression in oral squamous cell carcinoma and, suggest a potential interaction between arachidonic acid metabolites and endothelial PSMA expression in the tumor neo-vasculature.

  5. Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment.

    PubMed

    Lubik, Amy A; Nouri, Mannan; Truong, Sarah; Ghaffari, Mazyar; Adomat, Hans H; Corey, Eva; Cox, Michael E; Li, Na; Guns, Emma S; Yenki, Parvin; Pham, Steven; Buttyan, Ralph

    2017-01-15

    Despite the substantial benefit of androgen deprivation therapy (ADT) for metastatic prostate cancer, patients often progress to castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed androgen receptor activity in tumor cells and restoration of tumor androgen levels through acquired intratumoral steroidogenesis (AIS). Although prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize testosterone (T) from an adrenal precursor, DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG. Here, we show exposure of PrSCs to a different Smoothened (Smo) agonist, Ag1.5, or to conditioned medium from sonic hedgehog overexpressing LNCaP cells induces steroidogenic enzyme expression in PrSCs and significantly increases production of T and its precursor steroids in a Smo-dependent manner from 22-OH-cholesterol substrate. Hh agonist-/ligand-treated PrSCs produced androgens at a rate similar to or greater than that of PCa cell lines. Likewise, primary bone marrow stromal cells became more steroidogenic and produced T under the influence of Smo agonist. Treatment of mice bearing LNCaP xenografts with a Smo antagonist, TAK-441, delayed the onset of CRPC after castration and substantially reduced androgen levels in residual tumors. These outcomes support the idea that stromal cells in ADT-treated primary or metastatic prostate tumors can contribute to AIS as a consequence of a paracrine Hh signaling microenvironment. As such, Smo antagonists may be useful for targeting prostate tumor stromal cell-derived AIS and delaying the onset of CRPC after ADT.

  6. Phyllodes tumor of the prostate: long-term followup study of 23 cases.

    PubMed

    Bostwick, David G; Hossain, Deloar; Qian, Junqi; Neumann, Roxann M; Yang, Ping; Young, Robert H; di Sant'agnese, P Anthony; Jones, Edward C

    2004-09-01

    Phyllodes tumor of the prostate is a rare neoplasm of uncertain malignant potential. We studied a large series of phyllodes tumors to define the combination of histological features that are most useful for predicting patient outcome. A total of 23 cases were obtained from our collective files from 1973 to 2002, and numerous clinical and pathological features were evaluated. A review of the reported cases of phyllodes tumor of the prostate was done. Patient age was 25 to 86 years (mean 55) and they usually presented with urinary obstructive symptoms and hematuria. The diagnosis was made in 18 tumors by transurethral resection, in 2 by enucleation, in 1 by tumor resection and in 2 by prostatectomy. We analyzed 5 histological features, including cellularity (scale of 1 to 3), cytologic atypia (scale of 1 to 3), the number of mitotic figures per 10 high power fields, the stroma-to-epithelium ratio (low or high) and necrosis (present or absent). This combination of features revealed that 14 cases were low grade phyllodes tumor, 7 were intermediate grade and 2 were high grade with the high grade cases characterized by increased cellularity, severe cytological atypia, more than 5 mitotic figures per 10 high power fields and a high stroma-to-epithelium ratio, indicating stromal overgrowth. Immunohistochemical studies of 8 tumors revealed consistent, intense cytoplasmic immunoreactivity in stromal cells for vimentin and actin, in luminal epithelial cells for prostate specific antigen, prostatic acid phosphatase and broad-spectrum keratin AE1/AE3, and in basal cells for high molecular weight keratin 34beta-E12. Recurrence was seen in 7 of 14 low grade tumors (50%) and in 1 patient low grade sarcoma emerged with subsequent distant metastases 14 years after initial diagnosis following 5 recurrences. Recurrence was seen in 6 of 7 intermediate grade tumors and low grade sarcoma emerged with subsequent abdominal wall metastases in 1 patient 11 years after initial diagnosis

  7. Detection of circulating prostatic cells during radical prostatectomy.

    PubMed

    Planz, B; Szyska, P; Valdor, M; Boeckmann, W; Füzesi, L; Jakse, G

    1997-01-01

    The detection of micrometastasis of prostate cancer could help to decide more appropriate therapeutic strategies in an individual patient. We have developed a flow cytometric method for detecting cytokeratin-positive cells in the peripheral blood before, during and after radical prostatectomy in patients with prostatic carcinoma. By means of this technique we were able to detect a higher number of cytokeratin-positive cells in the intraoperative blood sample than in the pre- and postoperative blood sample in 15 patients with prostate cancer (P < 0.05). Our results show an increase in the number of cytokeratin-positive cells with increasing tumor stage and grade, as well a good correlation of prostate-specific antigen (PSA) value with the number of cytokeratin-positive cells (r > 0.6). Our results underline the importance of no-touch techniques at prostatectomy to minimize release of tumor cells into the circulation during surgery. In the light of our results we consider that the indication for cell savers during radical prostatectomy should be reevaluated. The possibility of detecting single metastatic cells in peripheral blood will enable better individual patient management, and open up new modalities for diagnosing early prostate cancer and enhancing patient monitoring in relapse and tumor progression.

  8. Engineering chemically modified viruses for prostate cancer cell recognition.

    PubMed

    Mohan, K; Weiss, G A

    2015-12-01

    Specific detection of circulating tumor cells and characterization of their aggressiveness could improve cancer diagnostics and treatment. Metastasis results from such tumor cells, and causes the majority of cancer deaths. Chemically modified viruses could provide an inexpensive and efficient approach to detect tumor cells and quantitate their cell surface biomarkers. However, non-specific adhesion between the cell surface receptors and the virus surface presents a challenge. This report describes wrapping the virus surface with different PEG architectures, including as fusions to oligolysine, linkers, spacers and scaffolded ligands. The reported PEG wrappers can reduce by >75% the non-specific adhesion of phage to cell surfaces. Dynamic light scattering verified the non-covalent attachment by the reported wrappers as increased sizes of the virus particles. Further modifications resulted in specific detection of prostate cancer cells expressing PSMA, a key prostate cancer biomarker. The approach allowed quantification of PSMA levels on the cell surface, and could distinguish more aggressive forms of the disease.

  9. Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor.

    PubMed

    Vamadevan, Shankar; Shetty, Deepa; Le, Ken; Bui, Chuong; Mansberg, Robert; Loh, Han

    2016-10-01

    Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor.

  10. Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo.

    PubMed

    Abedinpour, Parisa; Baron, Véronique T; Welsh, John; Borgström, Per

    2011-06-01

    Hormonal ablation is the standard of treatment for advanced androgen-dependent prostate cancer. Although tumor regression is usually achieved at first, the cancer inevitably evolves toward androgen-independence, in part because of the development of mechanisms of resistance and in part because at the tissue level androgen withdrawal is not fully attained. Current research efforts are focused on new therapeutic strategies that will increase the effectiveness of androgen withdrawal and delay recurrence. We used a syngeneic pseudo-orthotropic mouse model of prostate cancer to test the efficacy of combining androgen withdrawal with FDA-approved COX-2 inhibitor celecoxib. GFP-tagged TRAMP-C2 cells were co-implanted with prostate tissue in the dorsal chamber model and tumors were allowed to establish and vascularize. Tumor growth and angiogenesis were monitored in real-time using fluorescent intravital microscopy (IVM). Androgen withdrawal in mice was achieved using surgical castration or chemical hormonal ablation, alone or in combination with celecoxib (15 mg/kg, twice daily). Celecoxib alone decreased the growth of prostate tumors mostly by inducing mitotic failure, which resulted in increased apoptosis. Surprisingly, celecoxib did not possess significant angiostatic activity. Surgical or chemical castration prevented the growth of prostate tumors and this, on the other hand, was associated with disruption of the tumor vasculature. Finally, androgen withdrawal combined with celecoxib caused tumor regression through decreased angiogenesis and increased mitosis arrest and apoptosis. Celecoxib, a relatively safe COX-2-selective anti-inflammatory drug, significantly increases the efficacy of androgen withdrawal in vivo and warrants further investigation as a complement therapy for advanced prostate cancer. Copyright © 2010 Wiley-Liss, Inc.

  11. Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

    PubMed Central

    Luo, Wei; Yu, Wei-Dong; Ma, Yingyu; Chernov, Mikhail; Trump, Donald L.; Johnson, Candace S.

    2013-01-01

    Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

  12. Bone Matrix Osteonectin Limits Prostate Cancer Cell Growth and Survival

    PubMed Central

    Kapinas, Kristina; Lowther, Katie M.; Kessler, Catherine B.; Tilbury, Karissa; Lieberman, Jay R.; Tirnauer, Jennifer S.; Campagnola, Paul; Delany, Anne M.

    2012-01-01

    There is considerable interest in understanding prostate cancer metastasis to bone and the interaction of these cells with the bone microenvironment. Osteonectin/SPARC/BM-40 is a collagen binding matricellular protein that is enriched in bone. Its expression is increased in prostate cancer metastases, and it stimulates the migration of prostate carcinoma cells. However, the presence of osteonectin in cancer cells and the stroma may limit prostate tumor development and progression. To determine how bone matrix osteonectin affects the behavior of prostate cancer cells, we modeled prostate cancer cell-bone interactions using the human prostate cancer cell line PC-3, and mineralized matrices synthesized by wild type and osteonectin-null osteoblasts in vitro. We developed this in vitro system because the structural complexity of collagen matrices in vivo is not mimicked by reconstituted collagen scaffolds or by more complex substrates, like basement membrane extracts. Second harmonic generation imaging demonstrated that the wild type matrices had thick collagen fibers organized into longitudinal bundles, whereas osteonectin-null matrices had thinner fibers in random networks. Importantly, a mouse model of prostate cancer metastases to bone showed a collagen fiber phenotype similar to the wild type matrix synthesized in vitro. When PC-3 cells were grown on the wild type matrices, they displayed decreased cell proliferation, increased cell spreading, and decreased resistance to radiation-induced cell death, compared to cells grown on osteonectin-null matrix. Our data support the idea that osteonectin can suppress prostate cancer pathogenesis, expanding this concept to the microenvironment of skeletal metastases. PMID:22525512

  13. 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.

  14. The Added Value of Circulating Tumor Cell Enumeration to Standard Markers in Assessing Prognosis in a Metastatic Castration-Resistant Prostate Cancer Population.

    PubMed

    Heller, Glenn; Fizazi, Karim; McCormack, Robert; Molina, Arturo; MacLean, David; Webb, Iain J; Saad, Fred; de Bono, Johann S; Scher, Howard I

    2016-09-27

    Purpose: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease for which better prognostic models for survival are needed. We examined the added value of circulating tumor cell (CTC) enumeration relative to common prognostic laboratory measures from patients with CRPC.Methods: Utility of CTC enumeration as a baseline and postbaseline prognostic biomarker was examined using data from two prospective randomized registration-directed trials (COU-AA-301 and ELM-PC4) within statistical models used to estimate risk for survival. Discrimination and calibration were used to measure model predictive accuracy and the added value for CTC enumeration in the context of a Cox model containing albumin, lactate dehydrogenase (LDH), PSA, hemoglobin, and alkaline phosphatase (ALK). Discrimination quantifies how accurately a risk model predicts short-term versus long-term survivors. Calibration measures the closeness of actual survival time to the predicted survival time.Results: Adding CTC enumeration to a model containing albumin, LDH, PSA, hemoglobin, and ALK ("ALPHA") improved its discriminatory power. The weighted c-index for ALPHA without CTCs was 0.72 (SE, 0.02) versus 0.75 (SE, 0.02) for ALPHA + CTCs. The increase in discrimination was restricted to the lower-risk cohort. In terms of calibration, adding CTCs produced a more accurate model-based prediction of patient survival. The absolute prediction error for ALPHA was 3.95 months (SE, 0.28) versus 3.75 months (SE, 0.22) for ALPHA + CTCs.Conclusion: Addition of CTC enumeration to standard measures provides more accurate assessment of patient risk in terms of baseline and postbaseline prognosis in the mCRPC population. Clin Cancer Res; 1-7. ©2016 AACR.

  15. SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer.

    PubMed

    Liu, Yifan; Zeng, Shan; Jiang, Xianhan; Lai, Dehui; Su, Zhengming

    2017-05-01

    SOX4 (sex-determining region Y-related high-mobility group box 4) is associated with tumor progression and poor clinical outcome in several cancers. This study aims to evaluate whether SOX4 affects the biological behaviors of prostate cancer and further elucidate whether this effect works through the epithelial-mesenchymal transition pathway. We investigated the expression of SOX4 in a series of prostate cancer tissues and adjacent noncancerous tissues, as well as in a panel of prostate cancer cell lines. Cell proliferation, migration, and invasion were evaluated in SOX4 knockdown prostate cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay. Our results showed that the expression of SOX4 was remarkably upregulated both in prostate cancer tissues and in cell lines. Knockdown of SOX4 repressed the ability of cell proliferation and migration of DU145 cells. Moreover, inhibition of SOX4 could reverse the epithelial-mesenchymal transition processes through upregulation of E-cadherin and downregulation of vimentin. This study provided evidence that SOX4 could serve as a potential therapeutic target in prostate cancer.

  16. 5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

    PubMed Central

    Masoodi, Khalid Z.; Ramos Garcia, Raquel; Pascal, Laura E.; Wang, Yujuan; Ma, Hei M.; O'Malley, Katherine; Eisermann, Kurtis; Shevrin, Daniel H.; Nguyen, Holly M.; Vessella, Robert L.; Nelson, Joel B.; Parikh, Rahul A.

    2013-01-01

    Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT. PMID:23671262

  17. [Clinical efficacy and relative factors of dendritic cell-based tumor vaccination for prostate cancer: a systematic review and meta-analysis].

    PubMed

    Wu, Kun; Meng, Jun-Song; Baihetiya, Azhati; Wang, Yu-Jie

    2013-06-01

    To evaluate the efficacy and safety of dendritic cell (DC)-based vaccines in the treatment of prostate cancer, and investigate the factors that influence the clinical benefit rate (CBR) of the vaccines. Based on pre-determined search criteria, we searched the Medline database for randomized controlled trials on DC-based vaccines immunotherapy of prostate cancer. We systematically analyzed the identified studies using RevMan 5.0 and SPSS 17.0 softwares. Ten randomized controlled trials involving 179 prostate cancer patients were identified and subjected to meta-analysis. The CBR of the DC vaccines for prostate cancer was 54.2% , and the objective response rate was 7.7%. Most adverse effects were local reactions at the injection site, fever and flu-like symptoms. The prostate cancer patients achieved cellular immune response (OR = 31.12, 95% CI = 5.52-175.6, P < 0.01) and reduction of log PSA slope (OR = 4.38, 95% CI = 1.17-16.35, P = 0.03) after administration of DC vaccines, which was positively correlated with CBR. The dose of DC vaccines had a significant correlation with CBR (OR = 5.98, 95% CI = 1.45-24.62, P = 0.01), but not the age of the patients (P = 0.53). Besides, density-enriched DCs achieved a higher CBR, while the route of administration had no effect on CBR. DC-based vaccines are effective, safe and well-tolerated in the treatment of prostate cancer. DC-mediated cellular immune response has a significant effect on CBR and can be used as an important index for the assessment of vaccines. More multi-centered randomized controlled trials of higher quality and larger sample size are needed to provide more valid evidence.

  18. Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models

    PubMed Central

    Kenmogne, Lucie Carolle; Roy, Jenny; Maltais, René; Rouleau, Mélanie; Neveu, Bertrand; Pouliot, Frédéric; Poirier, Donald

    2017-01-01

    In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17β-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17β-HSDs than 17β-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17β-HSD3 inhibitor RM-532-105 is concentrated inside tumors. PMID:28182747

  19. Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

    DTIC Science & Technology

    2015-12-01

    Hematologic cells depletion CTC-iChip Microfluidic Cell Concentrator (MCC) EPIC platform Multicellular rosettes 48,42,49,50 Combination of immunomagnetic...formation of large multicellular rosettes to help remove hematologic cells from the blood sample by Ficoll density centrifugation49. In the EPIC platform50,82...cross-section for ultra-fast, label-free enrichment of CTCs based on the larger CTC size compared with hematologic cells. In this device, the smaller

  20. In Vivo Hemin Conditioning Targets the Vascular and Immunologic Compartments and Restrains Prostate Tumor Development.

    PubMed

    Jaworski, Felipe M; Gentilini, Lucas D; Gueron, Geraldine; Meiss, Roberto P; Ortiz, Emiliano G; Berguer, Paula M; Ahmed, Asif; Navone, Nora; Rabinovich, Gabriel A; Compagno, Daniel; Laderach, Diego J; Vazquez, Elba S

    2017-09-01

    Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model.Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8(+) T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo A significant systemic increase in CD8(+) T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels.Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response. Clin Cancer Res; 23(17); 5135-48. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

    PubMed Central

    Osakabe, Asami; Waku, Tsuyoshi; Suzuki, Takashi; Akaogi, Kensuke; Fujimura, Tetsuya; Homma, Yukio; Inoue, Satoshi; Yanagisawa, Junn

    2015-01-01

    Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation. PMID:26483416

  2. Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway.

    PubMed

    Nakajima, Yuka; Osakabe, Asami; Waku, Tsuyoshi; Suzuki, Takashi; Akaogi, Kensuke; Fujimura, Tetsuya; Homma, Yukio; Inoue, Satoshi; Yanagisawa, Junn

    2016-01-01

    Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  3. Combination Therapy with Epigallocatechin-3-Gallate and Doxorubicin in Human Prostate Tumor Modeling Studies

    PubMed Central

    Stearns, Mark E.; Amatangelo, Michael D.; Varma, Devika; Sell, Chris; Goodyear, Shaun M.

    2010-01-01

    The polyphenol epigallocatechin-3-gallate (EGCG) in combination with doxorubicin (Dox) exhibits a synergistic activity in blocking the growth and colony-forming ability of human prostate cell lines in vitro. EGCG has been found to disrupt the mitochondrial membrane potential, induce vesiculation of mitochondria, and induce elevated poly (ADP-ribose) polymerase (PARP) cleavage and apoptosis. EGCG in combination with low levels of Dox had a synergistic effect in blocking tumor cell growth. In vivo tumor modeling studies with a highly metastatic tumor line, PC-3ML cells, revealed that EGCG (228 mg/kg or 200 μmol/L) appeared to sensitize tumors to Dox. EGCG combined with low levels of Dox (0.14 mg/kg or 2 μmol/L) blocked tumor growth by PC-3ML cells injected intraperitoneally (ie, in CB17 severe combined immunodeficiencies) and significantly increased mouse survival rates. Similarly, relatively low levels of EGCG (57 mg/kg or 50 μmol/L) plus Dox (0.07 mg/kg or 1 μmol/L) eradicated established tumors (ie, in nonobese diabetic–severe combined immunodeficiencies) that were derived from CD44hi tumor-initiating cells isolated from PCa-20a cells. Flow cytometry results showed that EGCG appeared to enhance retention of Dox by tumor cells to synergistically inhibit tumor growth and eradicate tumors. These data suggest that localized delivery of high dosages of EGCG combined with low levels of Dox may have significant clinical application in the treatment of metastatic prostate and/or eradication of primary tumors derived from tumor-initiating cells. PMID:20971741

  4. 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

  5. Superoxide Dismutase and Transcription Factor sox9 as Mediators of Tumor Suppression by mac25 (IGFBP-rp1) in Prostate Cancer Cells

    DTIC Science & Technology

    2006-10-01

    NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14 ...counted and measured weekly. * Significant difference from control (Po0.005) SOX9 in prostate cancer cells R Drivdahl et al 4589 Oncogene 14 (Vleminckx and...selective medium containing 400 mg/ml G418 and cultured for 10 days . Individual colonies were isolated from the plate by trypsinization in cloning rings

  6. Molecular Characterization of Prostate Cancer Cell Oncolysis by Herpes Simplex Virus ICP0 Mutants

    DTIC Science & Technology

    2006-04-01

    W81XWH-04-1-0859 TITLE: Molecular Characterization of Prostate Cancer Cell Oncolysis byHerpes Simplex Virus ICP0 Mutants PRINCIPAL...2. REPORT TYPE Final 3. DATES COVERED (From - To) 15 Sep 04 – 14 Mar 06 5a. CONTRACT NUMBER Molecular Characterization of Prostate Cancer Cell...Herpes simplex virus type 1 ICP0 mutants in prostate cancer cells given the relationship between ICP0 and two tumor suppressors, RNase L and PML

  7. Prostate stem cell antigen: a Jekyll and Hyde molecule?

    PubMed

    Saeki, Norihisa; Gu, Jian; Yoshida, Teruhiko; Wu, Xifeng

    2010-07-15

    Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. Although PSCA is thought to be involved in intracellular signaling, much remains unknown about its physiological function and regulatory mechanism in normal and cancer cells. It is up-regulated in several major cancers including prostate, bladder, and pancreatic cancers. The expression of PSCA is positively correlated with advanced clinical stage and metastasis in prostate cancers and is also associated with malignant progression of premalignant prostate lesions. Therefore, PSCA has been proposed as a biomarker of diagnosis and prognosis, as well as a target of therapy for these cancers. In addition, PSCA has also shown clinical potential in immunotherapy as a prostate-specific antigen, which, when presented by dendritic cells, may elicit strong tumor-specific immunity. In contrast, PSCA is down-regulated in esophageal and gastric cancer and may have a tumor-suppressing function in the gastric epithelium. Recent exciting findings that genetic variations of PSCA conferred increased risks of gastric cancer and bladder cancer have opened up a new avenue of research about the pathological function of PSCA. PSCA seems to be a Jekyll and Hyde molecule that plays differential roles, tumor promoting or suppressing, depending on the cellular context. Copyright 2010 AACR.

  8. Prostate stem cell antigen (PSCA): a Jekyll and Hyde molecule?

    PubMed Central

    Saeki, Norihisa; Gu, Jian; Yoshida, Teruhiko; Wu, Xifeng

    2010-01-01

    Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. Although PSCA is thought to be involved in intracellular signaling, much remain unknown regarding its physiological function and regulatory mechanism in normal and cancer cells. It is up-regulated in several major cancers including prostate, bladder and pancreatic cancers. The expression of PSCA is positively correlated with advanced clinical stage and metastasis in prostate cancers and is also associated with malignant progression of pre-malignant prostate lesions. Therefore, PSCA has been proposed as a biomarker of diagnosis and prognosis, as well as a target of therapy for these cancers. In addition, PSCA has also shown clinical potential in immunotherapy as a prostate specific antigen which, when presented by dendritic cells, may elicit strong tumor specific immunity. In contrast, PSCA is down-regulated in esophageal and gastric cancer and may have tumor-suppressing function in the gastric epithelium. Recent exciting findings that genetic variations of PSCA conferred increased risks of gastric cancer and bladder cancer have opened up a new avenue of research regarding the pathological function of PSCA. PSCA appears to be a Jekyll and Hyde molecule that plays differential roles, tumor promoting or suppressing, depending on the cellular context. PMID:20501618

  9. VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms.

    PubMed

    Latil, A; Bièche, I; Pesche, S; Valéri, A; Fournier, G; Cussenot, O; Lidereau, R

    2000-03-20

    Studies comparing tumor neovascularity with pathological findings suggest that angiogenesis contributes to the pathogenesis of prostate cancer. We have examined 42 primary sporadic prostate tumors at different clinical stages, together with 3 prostate cancer cell lines (DU145, PC3 and LNCaP), for expression of VEGF and the gene encoding the recently identified VEGF165 isoform-specific receptor neuropilin-1, by using a quantitative reverse transcription (RT)-PCR method. We also evaluated the VEGF transcription pattern. Upregulation of VEGF and neuropilin-1 was observed in 12 and 14 tumors, respectively. The VEGF165 isoform was slighly overrepresented in tumors that overexpressed VEGF. VEGF overexpression correlated with stage II disease (p < 0.05); neuropilin-1 overexpression correlated with advanced disease (p < 0. 01) and a high Gleason grade (p < 0.02). Our observations suggest that VEGF expression could be used as a prognostic marker in early-stage prostate tumors, whereas neuropilin-1 overexpression might be a marker of aggressiveness. Copyright 2000 Wiley-Liss, Inc.

  10. Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis

    PubMed Central

    Ray, Manisha; Hostetter, Daniel R.; Loeb, Carly RK; Simko, Jeffry; Craik, Charles S.

    2012-01-01

    Background In order for tumors to grow and proliferate, they must avoid recognition by immune cells and subsequent death by apoptosis. Granzyme B, a protease located in natural killer cells, initiates apoptosis in target cells. Inhibition of Granzyme B by PI-9, its natural inhibitor, can prevent apoptosis. Here we investigate whether PI-9 protects prostate cancer cells from apoptosis. Methods The expression of PI-9 was quantified by qPCR in several prostate cancer cell lines, and Granzyme B activity was tested in each cell line. PI-9 was overexpressed in LNCaP cells, which lack endogenous PI-9. Apoptosis was induced by natural killer cells in LNCaP cells that either contained or lacked PI-9, and the percent cell death in was quantified. Lastly, PI-9 levels were examined by qPCR and immunohistochemistry in prostate tumor tissue. Results Prostate cancer cell lines that expressed PI-9 could inhibit Granzyme B. Overexpression of PI-9 protected LNCaP cells from natural killer cell-mediated apoptosis. Examination of the levels of PI-9 in tissue from prostate tumors showed that PI-9 could be upregulated in low grade tumors and stochastically dysregulated in high grade tumors. Additionally, PI-9 is found consistently in high grade prostatic intraepithelial neoplasia and atrophic lesions. Conclusions These results indicate that overexpression of PI-9 can protect prostate cancer cells from apoptosis, and this effect may occur in human prostate tumors. These findings imply that early prostatic inflammation may trigger this increase in PI-9. This suggests that PI-9 upregulation is needed early in tumor progression, before additional protective mechanisms are in place. PMID:21919028

  11. Nonfunctioning Juxtaglomerular Cell Tumor

    PubMed Central

    Sakata, Ryoko; Shimoyamada, Hiroaki; Yanagisawa, Masahiro; Murakami, Takayuki; Makiyama, Kazuhide; Nakaigawa, Noboru; Inayama, Yoshiaki; Ohashi, Kenichi; Nagashima, Yoji; Yao, Masahiro; Kubota, Yoshinobu

    2013-01-01

    The juxtaglomerular cell tumor (JGCT) is a rare renal tumor characterized by excessive renin secretion causing intractable hypertension and hypokalemia. However, asymptomatic nonfunctioning JGCT is extremely rare. Here, we report a case of nonfunctioning JGCT in a 31-year-old woman. The patient presented with a left renal tumor without hypertension or hypokalemia. Under a clinical diagnosis of renal cell carcinoma, radical nephrectomy was performed. The tumor was located in the middle portion adjacent to the renal pelvis, measuring 2 cm in size. Pathologically, the tumor was composed of cuboidal cells forming a solid arrangement, immunohistochemically positive for renin. Based on these findings, the tumor was diagnosed as JGCT. In cases with hyperreninism, preoperative diagnosis of JGCT is straightforward but difficult in nonfunctioning case. Generally, JGCT presents a benign biological behavior. Therefore, we should take nonfunctioning JGCT into the differential diagnoses for renal tumors, especially in younger patients to avoid excessive surgery. PMID:23607027

  12. Tumor cell metabolism

    PubMed Central

    Romero-Garcia, Susana; Lopez-Gonzalez, Jose Sullivan; B´ez-Viveros, José Luis; Aguilar-Cazares, Dolores

    2011-01-01

    Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism. PMID:22057267

  13. The Inhibition of Stat5 by a Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target Gene Transactivation and the Growth of Breast and Prostate Tumor Cells

    PubMed Central

    Weber, Axel; Borghouts, Corina; Brendel, Christian; Moriggl, Richard; Delis, Natalia; Brill, Boris; Vafaizadeh, Vida; Groner, Bernd

    2013-01-01

    The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment. PMID:24276378

  14. Immunotherapy for Prostate Cancer: Lessons from Responses to Tumor-Associated Antigens

    PubMed Central

    Westdorp, Harm; Sköld, Annette E.; Snijer, Berit A.; Franik, Sebastian; Mulder, Sasja F.; Major, Pierre P.; Foley, Ronan; Gerritsen, Winald R.; de Vries, I. Jolanda M.

    2014-01-01

    Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy. PMID:24834066

  15. Analysis of fusion gene expression in prostate tumors by using single-end reads.

    PubMed

    Xie, D D; Li, J Y; Wang, Y; Chen, L; Yu, D X

    2013-08-12

    Fusion gene expression, a kind of chromosome rearrangement mode, has been strongly linked to prostate cancer diagnosis and prognosis as well as to the Gleason score and the American Joint Committee on Cancer stage assessment. In combination with traditional methods for locating fusion genes and scoring their association with cancer cell growth, proliferation, and invasion through the basement membrane, the emerging high-throughput sequencing technologies offer a panorama of fusion genes in a genome and facilitate the discovery of new fusion modes. We describe here a method for using single-end reads to analyze fusion gene expression in prostate tumors. We obtained the fusion gene expression profiling of prostate tumors, clustered them into several biological pathways, highlighted three "rediscovered" fusion genes (TMPRSS2-ERG, KLK2, and KLK3) and proved the reliability of our method.

  16. Extracellular vesicles such as prostate cancer cell fragments as a fluid biopsy for prostate cancer.

    PubMed

    Brett, S I; Kim, Y; Biggs, C N; Chin, J L; Leong, H S

    2015-09-01

    Extracellular vesicles (EVs) are cell-derived vesicles generated through a process of cell membrane shedding or storage vesicle release, as occurs during apoptosis, necrosis or exocytosis. Initially perceived as cellular by-products or 'dust' of insignificant biological importance, recent research has shed light on the role of EVs as mediators of intercellular communication, blood coagulation and disease progression. The prostate is a source of EVs and their abundance in complex biological fluids such as plasma, serum and urine make them compelling entities for a 'fluid biopsy'. As such, prostate cancer cell fragments (PCCF) are EVs generated by the tumor resident within the prostate and are also present in blood, expressing a portion of biomarkers representative of the primary tumor. High-throughput analytical techniques to determine biomarker expression on EVs is the last hurdle towards translating the full potential of prostate EVs for clinical use. We describe current state-of-the-art methods for the analysis of prostate-derived EVs in patient fluids such as plasma and the challenges that lie ahead in this emerging field of translational research.

  17. Gangliosides During Tumor Progression in Patients With Prostate Cancer

    DTIC Science & Technology

    2002-07-01

    Objectives of the project are: (1) to identify the gangliosides of Prostate cancer (CaP) cells that are immunogenic so that they can be used as...targets to develop immunotherapy for prostate cancer; (2) to determine the total and specific Cap- gangliosides released into the blood and (3) to assess...the nature of immunosuppression induced by CaP gangliosides . The major findings of the first year are as follows: Ganglioside GM1 is the major cell

  18. Role of the ARF Tumor Suppressor in Prostate Cancer

    DTIC Science & Technology

    2010-08-01

    literature. We asked Dr. Jeff Arbeit in the department of Surgery here at Washington University for his expertise in mouse prostate tumor development...18070929 6. Lu, Z.H., Wright, J.D., Belt, B., Cardiff, R.D. & Arbeit , J.M. Hypoxia-inducible factor-1 facilitates cervical cancer progression in human

  19. [Retroperitoneal germ cell tumor].

    PubMed

    Borrell Palanca, A; García Garzón, J; Villamón Fort, R; Domenech Pérez, C; Martínez Lorente, A; Gunthner, S; García Sisamón, F

    1999-03-01

    We report a case of retroperitoneal extragonadal germ-cell tumor in an 17 years old patient who presented with aedema and pain in left inferior extremity asociated with hemopthysis caused by pulmonar metastasis, who was treated with chemotherapy and resection of residual mass and pulmonary nodes. Dyagnosis was stableshed by fine neadle aspiration biopsy of the wass. We comment on the difficult of stableshing differential dyagnosis between retroperitoneal extragonadal germ-cell tumor and metastasis of a testicular tumor. Dyagnosis is stableshed by the finding of a histologically malignant germ-cell tumor with normal testis. We considered physical examination and ecographyc exploration enough for a correct dyagnosis.

  20. Milk stimulates growth of prostate cancer cells in culture.

    PubMed

    Tate, Patricia L; Bibb, Robert; Larcom, Lyndon L

    2011-11-01

    Concern has been expressed about the fact that cows' milk contains estrogens and could stimulate the growth of hormone-sensitive tumors. In this study, organic cows' milk and two commercial substitutes were digested in vitro and tested for their effects on the growth of cultures of prostate and breast cancer cells. Cows' milk stimulated the growth of LNCaP prostate cancer cells in each of 14 separate experiments, producing an average increase in growth rate of over 30%. In contrast, almond milk suppressed the growth of these cells by over 30%. Neither cows' milk nor almond milk affected the growth of MCF-7 breast cancer cells or AsPC-1 pancreatic cancer cells significantly. Soy milk increased the growth rate of the breast cancer cells. These data indicate that prostate and breast cancer patients should be cautioned about the possible promotional effects of commercial dairy products and their substitutes.

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2017-05-01

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

  3. Phenotypic characterization of the infiltrating immune cells in normal prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma.

    PubMed

    Hussein, Mahmoud-Rezk A; Al-Assiri, Mana; Musalam, Adel O

    2009-04-01

    Immune cell infiltrate is a constant feature in normal prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma. This study elaborates on the cells of the immune system present in normal prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma. Here, we hypothesized that "the development of benign nodular prostatic hyperplasia and prostatic adenocarcinoma is associated with numeric alterations of the immune cell infiltrate". A total of 50 transurethral prostatic resection specimens, each entailing normal prostate, benign nodular prostatic hyperplasia and high grade prostatic adenocarcinoma were evaluated for the density and phenotype of the immune cells using immunohistological methods and mouse monoclonal antibodies decorating T cells (CD3), histiocytes (CD68) and B lymphocytes (CD20). Immune cell infiltrate was composed of T cells, histiocytes and B-lymphocytes. CD(+)3 T lymphocytes and CD68(+) cells were the predominant cell populations. We observed variations in the density of the immune cells among the normal prostate, benign nodular prostatic hyperplasia and high grade prostatic adenocarcinoma. Compared with normal prostate, benign nodular prostatic hyperplasia had a statistically significant high density of immune cells (3.4+/-0.4versus 13.5+/-1.0, P<0.00). In contrast, a significant decrease in the counts of these cells was observed in high-grade prostatic adenocarcinoma compared to benign nodular prostatic hyperplasia (13.5+/-1.0 versus 5.2+/-0.3, P<0.01). The increased density of immune cells (predominantly CD(+)3 T cells) in benign nodular prostatic hyperplasia suggests that the initial response to cellular damage is mediated by cell-mediated immunity. The decreased density of immune cells in high-grade prostatic adenocarcinoma may reflect immunosuppression. The underlying mechanisms of these numeric variations are open for further investigations.

  4. Mifepristone inhibits GRβ-coupled prostate cancer cell proliferation

    PubMed Central

    Ligr, Martin; Li, Yirong; Logan, Susan K.; Taneja, Semir; Melamed, Jonathan; Lepor, Hebert; Garabedian, Michael J.; Lee, Peng

    2013-01-01

    Purpose The glucocorticoid receptor (GR) gene produces GRα and GRβ isoforms by alternative splicing of a C-terminal exon. GRα binds glucocorticoids, modulates transcription in a glucocorticoid-dependent manner, and plays a growth inhibitory role in prostate cells. Due to this role, glucocorticoids are often used to treat androgen-independent prostate cancer. By contrast, GRβ possesses intrinsic transcriptional activity and binds mifepristone (RU486), but not glucocorticoids, to control gene expression. The role of GRβ in prostate cell proliferation is unknown. Materials and Methods We determined the levels of GRβ in various prostate cancer cell lines by RT-PCR and western blotting. The effect of GRβ on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined following siRNA-mediated knock-down and overexpression of GRβ. Results GRβ mRNA and protein were upregulated in LNCaP cells overexpressing the androgen receptor co-factor ARA70β. Treatment of LNCaP-ARA70β with mifepristone or siRNA targeting GRβ inhibited proliferation, compared to parental LNCaP cells. An immortal but non-tumorigenic (RC165) prostate cell line, as well as a tumorigenic (DU145) prostate cell line with endogenous GRβ also showed partial growth reduction upon depletion of GRβ, albeit to a lesser extent than LNCaP-ARA70β cells. The growth-stimulatory effect of ARA70β on LNCaP cells is, in part, GRβ-dependent, as is the proliferation of RC165 and, to a lesser extent, DU145 cells. Conclusions These results suggest that patients whose primary tumors express GRβ and ARA70β may benefit from mifepristone treatment. PMID:22819113

  5. Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity.

    PubMed

    Patnaik, Akash; Swanson, Kenneth D; Csizmadia, Eva; Solanki, Aniruddh; Landon-Brace, Natalie; Gehring, Marina P; Helenius, Katja; Olson, Brian M; Pyzer, Athalia R; Wang, Lily C; Elemento, Olivier; Novak, Jesse; Thornley, Thomas B; Asara, John M; Montaser, Laleh; Timmons, Joshua J; Morgan, Todd M; Wang, Yugang; Levantini, Elena; Clohessy, John G; Kelly, Kathleen; Pandolfi, Pier Paolo; Rosenblatt, Jacalyn M; Avigan, David E; Ye, Huihui; Karp, Jeffrey M; Signoretti, Sabina; Balk, Steven P; Cantley, Lewis C

    2017-03-08

    Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-cancer innate immune response, resulting in tumor clearance.

  6. Vitamin D, intermediary metabolism and prostate cancer tumor progression

    PubMed Central

    Wang, Wei-Lin W.; Tenniswood, Martin

    2014-01-01

    Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways. PMID:24860512

  7. [Markers of prostate cancer stem cells: research advances].

    PubMed

    Wang, Shun-Qi; Huang, Sheng-Song

    2013-12-01

    Prostate cancer is one of the most seriously malignant diseases threatening men's health, and the mechanisms of its initiation and progression are not yet completely understood. Recent years have witnessed distinct advances in researches on prostate cancer stem cells in many aspects using different sources of materials, such as human prostate cancer tissues, human prostate cancer cell lines, and mouse models of prostate cancer. Prostate cancer stem cell study offers a new insight into the mechanisms of the initiation and progression of prostate cancer and contributes positively to its treatment. This article presents an overview on the prostate cancer stem cell markers utilized in the isolation and identification of prostate cancer stem cells.

  8. The Relationship between Obesity, Prostate Tumor Infiltrating Lymphocytes and Macrophages, and Biochemical Failure.

    PubMed

    Zeigler-Johnson, Charnita; Morales, Knashawn H; Lal, Priti; Feldman, Michael

    2016-01-01

    Obesity reflects a chronic inflammatory environment that may contribute to prostate cancer progression and poor treatment outcomes. However, it is not clear which mechanisms drive this association within the tumor microenvironment. The aim of this pilot study was to examine prostatic inflammation via tumor infiltrating lymphocytes and macrophages characterized by obesity and cancer severity. We studied paraffin-embedded prostatectomy tissue from 99 participants (63 non-obese and 36 obese) from the Study of Clinical Outcomes, Risk and Ethnicity (University of Pennsylvania). Pathologists analyzed the tissue for type and count of lymphocytes and macrophages, including CD3, CD8, FOXP3, and CD68. Pathology data were linked to clinical and demographic variables. Statistical analyses included frequency tables, Kruskal-Wallis tests, Spearman correlations, and multivariable models. We observed positive univariate associations between the number of CD68 cells and tumor grade (p = 0.019). In multivariable analysis, CD8 counts were associated with time to biochemical failure (HR = 1.09, 95% CI = 1.004-1.192, p-value = 0.041.) There were no differences in lymphocytes or macrophages by obesity status or BMI. The number of lymphocytes and macrophages in the tumor microenvironment did not differ by obesity status. However, these inflammation markers were associated with poor prostate cancer outcomes. Further examination of underlying mechanisms that influence obesity-related effects on prostate cancer outcomes is warranted. Such research will guide immunotherapy protocols and weight management as they apply to diverse patient populations and phenotypes.

  9. Tumor expression of adiponectin receptor 2 and lethal prostate cancer

    PubMed Central

    Fiorentino, Michelangelo; Kelly, Rachel; Gerke, Travis; Jordahl, Kristina; Sinnott, Jennifer A.; Giovannucci, Edward L.; Loda, Massimo; Mucci, Lorelei A.; Finn, Stephen

    2015-01-01

    To investigate the role of adiponectin receptor 2 (AdipoR2) in aggressive prostate cancer we used immunohistochemistry to characterize AdipoR2 protein expression in tumor tissue for 866 men with prostate cancer from the Physicians’ Health Study and the Health Professionals Follow-up Study. AdipoR2 tumor expression was not associated with measures of obesity, pathological tumor stage or prostate-specific antigen (PSA) at diagnosis. However, AdipoR2 expression was positively associated with proliferation as measured by Ki-67 expression quartiles (P-trend < 0.0001), with expression of fatty acid synthase (P-trend = 0.001), and with two measures of angiogenesis (P-trend < 0.1). An inverse association was observed with apoptosis as assessed by the TUNEL assay (P-trend = 0.006). Using Cox proportional hazards regression and controlling for age at diagnosis, Gleason score, year of diagnosis category, cohort and baseline BMI, we identified a statistically significant trend for the association between quartile of AdipoR2 expression and lethal prostate cancer (P-trend = 0.02). The hazard ratio for lethal prostate cancer for the two highest quartiles, as compared to the two lowest quartiles, of AdipoR2 expression was 1.9 (95% confidence interval [CI]: 1.2–3.0). Results were similar when additionally controlling for categories of PSA at diagnosis and Ki-67 expression quartiles. These results strengthen the evidence for the role of AdipoR2 in prostate cancer progression. PMID:25863129

  10. Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population.

    PubMed

    Luk, Sze-Ue; Lee, Terence Kin-Wah; Liu, Ji; Lee, Davy Tak-Wing; Chiu, Yung-Tuen; Ma, Stephanie; Ng, Irene Oi-Lin; Wong, Yong-Chuan; Chan, Franky Leung; Ling, Ming-Tat

    2011-01-01

    Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer.

  11. Arum Palaestinum with isovanillin, linolenic acid and β-sitosterol inhibits prostate cancer spheroids and reduces the growth rate of prostate tumors in mice.

    PubMed

    Cole, Caitlin; Burgoyne, Thomas; Lee, Annie; Stehno-Bittel, Lisa; Zaid, Gene

    2015-08-05

    Arum palaestinum is a plant commonly found in the Middle East that is ingested as an herbal remedy to fight cancer. However, no studies have examined the direct effect of the plant/plant extract on tumor growth in an animal model. Verified prostate cancer cells were plated as 3D spheroids to determine the effect of extract from boiled Arum Palaestinum Boiss roots. In addition, male NU/NU mice (8 weeks old) with xenograft tumors derived from the prostate cancer cell line were treated daily with 1000 mg/kg body weight gavage of the suspension GZ17. The tumor growth was measured repeatedly with calipers and the excised tumors were weighed at the termination of the 3 week study. Control mice (10 mice in each group) received vehicle in the same manner and volume. The number of live prostate cancer cells declined in a dose/dependent manner with a 24 h exposure to the extract at doses of 0.015 to 6.25 mg/mL. A fortified version of the extract (referred to as GZ17) that contained higher levels of isovanillin, linolenic acid and β-sitosterol had a stronger effect on the cell death rate, shifting the percentage of dead cells from 30 % to 55 % at the highest dose while the vehicle control had no effect on cell numbers. When GZ17 was applied to non-cancer tissue, in this case, human islets, there was no cell death at doses that were toxic to treated cancer cells. Preliminary toxicity studies were conducted on rats using an up-down design, with no signs of toxic effect at the highest dose. NU/NU mice with xenograft prostate tumors treated with GZ17 had a dramatic inhibition of tumor progression, while tumors in the control group grew steadily through the 3 weeks. The rate of tumor volume increase was 73 mm(3)/day for the vehicle group and 24 mm(3)/day for the GZ17 treated mice. While there was a trend towards lower excised tumor weight at study termination in the GZ17 treatment group, there was no statistical difference. Fortified Arum palaestinum Boiss caused a reduction in

  12. Sodwanone and Yardenone Triterpenes from a South African Species of the Marine Sponge Axinella Inhibit Hypoxia-Inducible Factor-1 (HIF-1) Activation in both Breast and Prostate Tumor Cells

    PubMed Central

    Dai, Jingqiu; Fishback, James A.; Zhou, Yu-Dong; Nagle, Dale G.

    2010-01-01

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anti-cancer drug discovery. A T47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates and algae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract from Axinella sp. yielded seven new sodwanone triterpenoids [3-epi-sodwanone K (1), 3-epi-sodwanone K 3-acetate (2), 10,11-dihydrosodwanone B (4), sodwanones T–W (3, 7, 8, 9), the new yardenone triterpene 12R-hydroxyyardenone (10), and the previously reported compounds sodwanone A (5), sodwanone B (6), and yardenone (11). The structures and relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configuration of 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced and iron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC50 15 μM) and 8 was the only sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC50 15 μM). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells (IC50 values 20-25 μM). Compound 2 was cytotoxic to T47D cells (IC50 22 μM) and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC50 23 μM). PMID:17190448

  13. Clinical characteristics of bladder urothelial tumors in male patients--the influences of benign prostatic hyperplasia/benign prostatic enlargement.

    PubMed

    Zhang, Nian-Zhao; Chen, Jun; Ma, Lin; Xu, Zhi-Shun

    2012-09-01

    To investigate the clinical characteristics of bladder urothelial tumors in male patients. The clinical characteristics of 356 patients with newly diagnosed bladder urothelial tumors from July 2005 to January 2010 were analyzed. Characteristics of different age groups were compared. Furthermore, tumor characteristics were analyzed to define the relationship, if any, with benign prostatic hyperplasia/benign prostatic enlargement. For bladder urothelial tumors, the percentage of carcinoma increased significantly with increasing age (P < 0.001), and differences were found among 3 age groups in the distribution of high grade carcinoma (P = 0.012). Especially in non-muscle-invasive carcinoma, the percentage of high grade carcinoma increased significantly with increasing age (P = 0.006), with significant differences between the ≤50 years group and the 51-69 years group and ≥70 years group (P = 0.031, P = 0.002). Interestingly, compared with non-benign prostatic hyperplasia/benign prostatic enlargement patients, benign prostatic hyperplasia/benign prostatic enlargement patients were more frequently diagnosed with poorly differentiated tumors, and logistic regression confirmed associations between benign prostatic hyperplasia/benign prostatic enlargement and unfavorable carcinoma, controlling for age (P = 0.009). Age is an unfavorable influence on the clinical characteristics of bladder urothelial tumors in men, and it was observed that the percentage of unfavorable tumors increased with age. Interestingly, noticeable changes of tumor differentiation appeared at the age of 50 years, and it was indicated that the natural history of carcinoma appeared to differ according to benign prostatic hyperplasia/benign prostatic enlargement statuses. There was a tendency for the men, who were diagnosed with benign prostatic hyperplasia/benign prostatic enlargement, to present with unfavorable carcinoma. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Merkel cell tumor.

    PubMed

    Kitazawa, M; Watanabe, H; Kobayashi, H; Ohnishi, Y; Shitara, A; Nitto, H

    1987-06-01

    A Merkel cell tumor appeared on the left cheek of an 83-year-old female was reported. The tumor was located mainly in the dermis and infiltrated to the subcutaneous adipose tissue with an involvement of the blood vessels and lymphatics at the periphery. Electron-microscopically, few of the dense-cored granules and the single globular aggregates of intermediate filaments at the nuclear indentations were observed. Electron-microscopic uranaffin reaction proved positive reaction on the dense-cored granules. Half of the cytoplasmic border was smooth, while the rest had short projections. Desmosomes or junctional complexes were not detected among the tumor cells. Immunohistochemically, the cytoplasm of tumor cell showed positive reaction to both neuron-specific enolase (NSE) and keratin. The single globular positive spots of the latter were localized in accordance with the aggregates of intermediate filaments. These findings suggested a neurogenic origin with double differentiation, epithelial and neuroendocrine, of the Merkel cell tumor.

  15. Diagnosis and treatment of gastrointestinal stromal tumor extending to prostate

    PubMed Central

    Xu, Huan; Liu, Chong; Chen, Yanbo; Gu, Meng; Cai, Zhikang; Chen, Qi; Wang, Zhong

    2016-01-01

    Abstract Rationale: Gastrointestinal stromal tumor (GIST) is the neoplasm of gastrointestinal tract. Patient concerns: The patient complained about the retention of urinary. Diagnoses: GIST. Interventions: radical prostatectomy and the imatinib therapy. Outcomes: No recurrence and metastasis have been found during a 14-month follow-up. Lessons: comprehensive treatment is necessary for the GIST treatment. Furthermore, we summarize a review of the literature of GIST occurring in the prostate gland treated by different methods and 4 kinds of rare diseases in prostate. PMID:27861390

  16. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes.

    PubMed

    Shui, Irene M; Wong, Chao-Jen; Zhao, Shanshan; Kolb, Suzanne; Ebot, Ericka M; Geybels, Milan S; Rubicz, Rohina; Wright, Jonathan L; Lin, Daniel W; Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing; Ostrander, Elaine A; Feng, Ziding; Stanford, Janet L

    2016-07-15

    DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies

  17. Regulation of the Prostate Cancer Tumor Microenvironment

    DTIC Science & Technology

    2012-04-01

    infiltrating macrophage lineage in the absence of MyD88. We are in the process of understanding the activation of signaling pathways , local and...development, growth, and metastasis is unclear. We are interested in understanding the mechanisms for development of TILs and how they modulate prostate...chromatin component HMG-B1. Activation of these receptors leads to induction of multiple inflammatory pathways , including nuclear factor-kappa B (NF

  18. Bryostatin 1 Inhibits Phorbol Ester-Induced Apoptosis in Prostate Cancer Cells by Differentially Modulating Protein Kinase C (PKC) δ Translocation and Preventing PKCδ-Mediated Release of Tumor Necrosis Factor-α

    PubMed Central

    von Burstin, Vivian A.; Xiao, Liqing

    2010-01-01

    Bryostatin 1, a macrocyclic lactone that has been widely characterized as an ultrapotent protein kinase C (PKC) activator, displays marked pharmacological differences with the typical phorbol ester tumor promoters. Bryostatin 1 impairs phorbol 12-myristate 13-acetate (PMA)-induced tumor promotion in mice and is in clinical trials as an anticancer agent for a number of hematopoietic malignancies and solid tumors. In this study, we characterized the effect of bryostatin 1 on LNCaP prostate cancer cells, a cellular model in which PKC isozymes play important roles in the control of growth and survival. Although phorbol esters promote a strong apoptotic response in LNCaP cells via PKCδ-mediated release of TNFα, bryostatin 1 failed to trigger a death effect even at high concentrations, and it prevented PMA-induced apoptosis in these cells. Mechanistic analysis revealed that bryostatin 1 is unable to induce TNFα release, and it impairs the secretion of this cytokine from LNCaP cells in response to PMA. Unlike PMA, bryostatin 1 failed to promote the translocation of PKCδ to the plasma membrane. Moreover, bryostatin 1 prevented PMA-induced PKCδ peripheral translocation. Studies using a membrane-targeted PKCδ construct revealed that the peripheral localization of the kinase is a requisite for triggering apoptosis in LNCaP cells, arguing that mislocalization of PKCδ may explain the actions of bryostatin 1. The identification of an antiapoptotic effect of bryostatin 1 may have significant relevance in the context of its therapeutic efficacy. PMID:20516369

  19. Bryostatin 1 inhibits phorbol ester-induced apoptosis in prostate cancer cells by differentially modulating protein kinase C (PKC) delta translocation and preventing PKCdelta-mediated release of tumor necrosis factor-alpha.

    PubMed

    von Burstin, Vivian A; Xiao, Liqing; Kazanietz, Marcelo G

    2010-09-01

    Bryostatin 1, a macrocyclic lactone that has been widely characterized as an ultrapotent protein kinase C (PKC) activator, displays marked pharmacological differences with the typical phorbol ester tumor promoters. Bryostatin 1 impairs phorbol 12-myristate 13-acetate (PMA)-induced tumor promotion in mice and is in clinical trials as an anticancer agent for a number of hematopoietic malignancies and solid tumors. In this study, we characterized the effect of bryostatin 1 on LNCaP prostate cancer cells, a cellular model in which PKC isozymes play important roles in the control of growth and survival. Although phorbol esters promote a strong apoptotic response in LNCaP cells via PKCdelta-mediated release of TNFalpha, bryostatin 1 failed to trigger a death effect even at high concentrations, and it prevented PMA-induced apoptosis in these cells. Mechanistic analysis revealed that bryostatin 1 is unable to induce TNFalpha release, and it impairs the secretion of this cytokine from LNCaP cells in response to PMA. Unlike PMA, bryostatin 1 failed to promote the translocation of PKCdelta to the plasma membrane. Moreover, bryostatin 1 prevented PMA-induced PKCdelta peripheral translocation. Studies using a membrane-targeted PKCdelta construct revealed that the peripheral localization of the kinase is a requisite for triggering apoptosis in LNCaP cells, arguing that mislocalization of PKCdelta may explain the actions of bryostatin 1. The identification of an antiapoptotic effect of bryostatin 1 may have significant relevance in the context of its therapeutic efficacy.

  20. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors.

    PubMed

    Schlaberg, Robert; Choe, Daniel J; Brown, Kristy R; Thaker, Harshwardhan M; Singh, Ila R

    2009-09-22

    Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.

  1. Laser immunotherapy in treatment of metastatic prostate tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Ritchey, Jerry W.; Bartles, Kenneth E.; Lucroy, Michael D.; Liu, Hong; Nordquist, Robert E.

    2002-07-01

    Laser immunotherapy is a special cancer treatment modality using an intratumor injection of a special formulation consisting of a novel immunoadjuvant and a laser-absorbing dye, followed by a non-invasive near-IR laser irradiation. Our early experiments using a metastatic mammary rat tumor model showed that laser immunotherapy could cause acute selective photothermal tumor destruction and induce a systemic, long-term specific anti-tumor immunity. In the current study, laser immunotherapy was used to treat metastatic prostate tumors in Copenhagen male rats. The transplantable tumors metastasize mainly to the lung and the lung cancer is usually the cause of death. Two experimental were performed in our study. The first was to study the effect of laser immunotherapy on the tumor burdens, both the primary and the metastasis in the lung. The second was to study the effect of laser immunotherapy on the long-term survival of the tumor-bearing rats. For comparison, some rat tumors were also treated by the laser-dye combination to study the photothermal effect. Tour results showed that both the photothermal effect and the laser immunotherapy could slow the growth of primary tumors and the metastatic tumors. The laser-dye-immunoadjuvant treatment resulted in more than 20 percent long-term survival rate in tumor-bearing rats. Our experimental results indicate that the laser immunotherapy has a great potential in treating metastatic tumors.

  2. Expression level and DNA methylation status of Glutathione-S-transferase genes in normal murine prostate and TRAMP tumors

    PubMed Central

    Mavis, Cory K.; Kinney, Shannon R. Morey; Foster, Barbara A.; Karpf, Adam R.

    2010-01-01

    BACKGROUND Glutathione-S-transferase (Gst) genes are down-regulated in human prostate cancer, and GSTP1 silencing is mediated by promoter DNA hypermethylation in this malignancy. We examined Gst gene expression and Gst promoter DNA methylation in normal murine prostates and Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors. METHODS Primary and metastatic tumors were obtained from TRAMP mice, and normal prostates were obtained from strain-matched WT mice (n=15/group). Quantitative real-time RT-PCR was used to measure GstA4, GstK1, GstM1, GstO1, and GstP1 mRNA expression, and Western blotting and immunohistochemical staining was used to measure GstM1 and GstP1 protein expression. MassARRAY Quantitative Methylation Analysis was used to measure DNA methylation of the 5’ CpG islands of GstA4, GstK1, GstM1, GstO1, and GstP1. TRAMP-C2 cells were treated with the epigenetic remodeling drugs decitabine and trichostatin A (TSA) alone and in combination, and Gst gene expression was measured. RESULTS Of the genes analyzed, GstM1 and GstP1 were expressed at highest levels in normal prostate. All five Gst genes showed greatly reduced expression in primary tumors compared to normal prostate, but not in tumor metastases. Gst promoter methylation was unchanged in TRAMP tumors compared to normal prostate. Combined decitabine + TSA treatment significantly enhanced the expression of 4/5 Gst genes in TRAMP-C2 cells. CONCLUSIONS Gst genes are extensively downregulated in primary but not metastatic TRAMP tumors. Promoter DNA hypermethylation does not appear to drive Gst gene repression in TRAMP primary tumors; however, pharmacological studies using TRAMP cells suggest the involvement of epigenetic mechanisms in Gst gene repression. PMID:19444856

  3. Evidence that selenium binding protein 1 is a tumor suppressor in prostate cancer.

    PubMed

    Ansong, Emmanuel; Ying, Qi; Ekoue, Dede N; Deaton, Ryan; Hall, Andrew R; Kajdacsy-Balla, Andre; Yang, Wancai; Gann, Peter H; Diamond, Alan M

    2015-01-01

    Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease.

  4. Evidence That Selenium Binding Protein 1 Is a Tumor Suppressor in Prostate Cancer

    PubMed Central

    Ansong, Emmanuel; Ying, Qi; Ekoue, Dede N.; Deaton, Ryan; Hall, Andrew R.; Kajdacsy-Balla, Andre; Yang, Wancai; Gann, Peter H.; Diamond, Alan M.

    2015-01-01

    Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease. PMID:25993660

  5. 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.

  6. Bioengineered viral vectors for targeting and killing prostate cancer cells.

    PubMed

    Zhang, Kai-xin; Jia, William; Rennie, Paul S

    2010-01-01

    Enabling the transduction of therapeutic gene expression exclusively in diseased sites is the key to developing more effective treatments for advanced prostate cancer using viral-based therapy. While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody. More importantly, after intravenous injection, this trastuzumab-bound lentivirus is able to target castration-resistant prostate tumor xenografts, albeit with low efficiency. This proof of principle opens up multiple possibilities for the prevention and treatment of prostate cancer using a viral-based therapy. However, to be safe and more effective, the viral vectors must target prostate cancer cells more selectively and efficiently. A higher degree of specificity and efficiency of cancer cell targeting can be achieved by engineering viral vectors to bind to a specific cell surface marker and by controlling the expression of the therapeutic payload at transcriptional level, with a tissue-specific promoter, and at the translational level, with a regulatory sequences inserted into either the 5'UTR or 3'UTR regions of the therapeutic gene(s). The latter would be designed to ensure that translation of this mRNA occurs exclusively in malignant cells. Furthermore, in order to obtain a potent anti-tumor effect, viral vectors would be engineered to express pro-apoptotic genes, intra-cellar antibodies/nucleotide aptamers to block critical proteins, or siRNAs to knockdown essential cellular mRNAs. Alternatively, controlled expression of an essential viral gene would restore replication competence to the virus and enable selective oncolysis of tumor cells. Successful delivery of such bioengineered viruses may provide a more effective way to treat advanced prostate cancer.

  7. TRPM8 Ion Channels Differentially Modulate Proliferation and Cell Cycle Distribution of Normal and Cancer Prostate Cells

    PubMed Central

    Valero, María Ll.; Mello de Queiroz, Fernanda; Stühmer, Walter; Viana, Félix; Pardo, Luis A.

    2012-01-01

    Overexpression of the cation-permeable channel TRPM8 in prostate cancers might represent a novel opportunity for their treatment. Inhibitors of TRPM8 reduce the growth of prostate cancer cells. We have used two recently described and highly specific blockers, AMTB and JNJ41876666, and RNAi to determine the relevance of TRPM8 expression in the proliferation of non-tumor and tumor cells. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in all tumor cells tested, but not of non-tumor prostate cells. We observed no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells. PMID:23251635

  8. Gross tumor volume and clinical target volume in prostate cancer: How do satellites relate to the index lesion.

    PubMed

    Hollmann, Birgit G; van Triest, Baukelien; Ghobadi, Ghazaleh; Groenendaal, Greetje; de Jong, Jeroen; van der Poel, Henk G; van der Heide, Uulke A

    2015-04-01

    There is an increasing interest for dose differentiation in prostate radiotherapy. The purpose of our study was to analyze the spatial distribution of tumor satellites inside the prostate. 61 prostatectomy specimens were stained with H&E. Tumor regions were delineated by the uro-pathologist. Volumes, distances and cell densities of all delineated tumor regions were measured and further analyzed. Multifocal disease was seen in 84% of the patients. The median number of tumor foci was 3. The median distance between the index lesion and the satellites was 1.0 cm, with a maximum of 4.4 cm. The index lesions accounted for 88% of the total tumor volume. The contribution of tumor foci<0.1 cm(3) to the total tumor volume was 2%. The median cell density of the index lesion and all satellites, regardless of size, were significantly higher than that of the prostate. Satellites do not appear in a limited margin around the index lesion (GTV). Consequently, a fixed CTV margin would not effectively cover all satellites. Thus if the aim is to treat all tumor foci, the entire prostate gland should be considered CTV. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Ad5/35E1aPSESE4: A novel approach to marking circulating prostate tumor cells with a replication competent adenovirus controlled by PSA/PSMA transcription regulatory elements.

    PubMed

    Hwang, Ji-Eun; Joung, Jae Young; Shin, Seung-Phil; Choi, Moon-Kyung; Kim, Jeong Eun; Kim, Yon Hui; Park, Weon Seo; Lee, Sang-Jin; Lee, Kang Hyun

    2016-03-01

    Circulating tumor cells serve as useful biomarkers with which to identify disease status associated with survival, metastasis and drug sensitivity. Here, we established a novel application for detecting PSA/PSMA-positive prostate cancer cells circulating in peripheral blood employing an adenovirus called Ad5/35E1aPSESE4. Ad5/35E1aPSESE4 utilized PSES, a chimeric enhancer derived from PSA/PSMA promoters that is highly active with and without androgen. A fluorescence signal mediated by GFP expression upon Ad5/35E1aPSESE4 infection was selectively amplified in PSA/PSMA-positive prostate cancer cells in vitro and ex vivo. Furthermore, for the in vivo model, blood drawn from TRAMP was tested for CTCs with Ad5/35E1aPSESE4 infection and was positive for CTCs at week 16. Validation was performed on patient blood at various clinical stages and found out 1-100 CTCs expressing GFP upon Ad5/35E1aPSESE4 infection. Interestingly, CTC from one patient was confirmed to be sensitive to docetaxel chemotherapeutic reagent and to abundantly express metastasis-related genes like MMP9, Cofilin1, and FCER1G through RNA-seq. Our study established that the usage of Ad5/35E1aPSESE4 is effective in marking PSA/PSMA-positive prostate cancer cells in patient blood to improve the efficacy of utilizing CTCs as a biomarker.

  10. Anterior tumors of the prostate: diagnosis and significance

    PubMed Central

    Werahera, Priya N.; Crawford, E. David; La Rosa, Francisco G.; Torkko, Kathleen C.; Schulte, Beth; Sullivan, Holly T.; van Bokhoven, Adrie; Lucia, M. Scott; Kim, Fernando J.

    2015-01-01

    Introduction Prostate biopsies are usually taken from the peripheral rather than anterior region of the prostate. Consequently, tumors originating from the anterior apical region and transition zones may be under-sampled. We examined whether addition of transrectal anterior biopsy (TAB) would improve efficacy of prostate biopsies. Materials and methods Simulations of TAB and sextant biopsy (SB) were performed using computer models of 86 autopsy prostates (AP) and 40 radical prostatectomy (RP) specimens. TAB was obtained bilaterally from apex, mid, and base regions by advancing the biopsy needle 5 mm–35 mm beyond the prostatic capsule. A phase I clinical trial with 114 patients was conducted to determine the performance of an extended biopsy protocol consisting of TAB, SB, and laterally-directed biopsy (LDB). Results The overall cancer detection rates of SB and TAB were 33% and 55% for AP series (p = 0.00003); 60% and 88% for RP series (p = 0.006). Alternatively, SB + bilateral apical TAB and SB + bilateral mid TAB had cancer detection rates of 45% and 42% for AP series; 80% and 78% for RP series. The extended biopsy protocol detected cancer in 33% (38/114) of patients with 29, 25, and 15 diagnosed by SB, LDB, and bilateral apical TAB, respectively. Patients diagnosed by bilateral apical TAB versus SB (p = 0.01) and LDB (p = 0.02) were statistically significant. Without bilateral apical TAB, the overall cancer detection rate decreased to 30% (34/114). Conclusions Inclusion of bilateral TAB from apical region for first time and repeat prostate biopsies may increase diagnosis of prostate cancer. The clinical significance of these findings needs further investigations and clinical follow up. PMID:24128826

  11. Progesterone receptor expression during prostate cancer progression suggests a role of this receptor in stromal cell differentiation.

    PubMed

    Yu, Yue; Yang, Ou; Fazli, Ladan; Rennie, Paul S; Gleave, Martin E; Dong, Xuesen

    2015-07-01

    The progesterone receptor, like the androgen receptor, belongs to the steroid receptor superfamily. Our previous studies have reported that the PR is expressed specifically in prostate stroma. PR inhibits proliferation of, and regulates cytokine secretion by stromal cells. However, PR protein expression in cancer-associated stroma during prostate cancer progression has not been profiled. Since the phenotypes of prostate stromal cells change dynamically as tumors progress, whether the PR plays a role in regulating stromal cell differentiation needs to be investigated. Immunohistochemistry assays measured PR protein levels on human prostate tissue microarrays containing 367 tissue cores from benign prostate, prostate tumors with different Gleason scores, tumors under various durations of castration therapy, and tumors at the castration-resistant stage. Immunoblotting assays determined whether PR regulated the expression of alpha smooth muscle actin (α-SMA), vimentin, and fibroblast specific protein (FSP) in human prostate stromal cells. PR protein levels decreased in cancer-associated stroma when compared with that in benign prostate stroma. This reduction in PR expression was not correlated with Gleason scores. PR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors progressed to the castration-resistant stage. Enhanced PR expression in human prostate stromal cells increased α-SMA, but decreased vimentin and FSP protein levels ligand-independently. These results suggest that PR plays an active role in regulating stromal cell phenotypes during prostate cancer progression. © 2015 Wiley Periodicals, Inc.

  12. Reconstitution of the ERG Gene Expression Network Reveals New Biomarkers and Therapeutic Targets in ERG Positive Prostate Tumors

    PubMed Central

    Dubovenko, Alexey; Serebryiskaya, Tatiana; Nikolsky, Yuri; Nikolskaya, Tatiana; Perlina, Ally; JeBailey, Lellean; Bureeva, Svetlana; Katta, Shilpa; Srivastava, Shiv; Dobi, Albert; Khasanova, Tatiana

    2015-01-01

    Background: Despite a growing number of studies evaluating cancer of prostate (CaP) specific gene alterations, oncogenic activation of the ETS Related Gene (ERG) by gene fusions remains the most validated cancer gene alteration in CaP. Prevalent gene fusions have been described between the ERG gene and promoter upstream sequences of androgen-inducible genes, predominantly TMPRSS2 (transmembrane protease serine 2). Despite the extensive evaluations of ERG genomic rearrangements, fusion transcripts and the ERG oncoprotein, the prognostic value of ERG remains to be better understood. Using gene expression dataset from matched prostate tumor and normal epithelial cells from an 80 GeneChip experiment examining 40 tumors and their matching normal pairs in 40 patients with known ERG status, we conducted a cancer signaling-focused functional analysis of prostatic carcinoma representing moderate and aggressive cancers stratified by ERG expression. Results: In the present study of matched pairs of laser capture microdissected normal epithelial cells and well-to-moderately differentiated tumor epithelial cells with known ERG gene expression status from 20 patients with localized prostate cancer, we have discovered novel ERG associated biochemical networks. Conclusions: Using causal network reconstruction methods, we have identified three major signaling pathways related to MAPK/PI3K cascade that may indeed contribute synergistically to the ERG dependent tumor development. Moreover, the key components of these pathways have potential as biomarkers and therapeutic target for ERG positive prostate tumors. PMID:26000039

  13. 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.

  14. 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

  15. [Testicular germ cell tumors].

    PubMed

    Dourthe, L M; Ouachet, M; Fizazi, K; Droz, J P

    1998-09-01

    Testicle germ cells tumors are the most common young men neoplasm. The incidence is maximal in Scandinavian countries. Cryptorchidism is a predisposing factor. Diagnosis is clinic, first treatment is radical orchidectomy by inguinal incision, after study of tumor markers. Histology shows seminoma or non seminomatous tumor. Carcinoma in situ is the precursor of invasive germ cell tumors. Germ cell tumors have no p53 mutation, and have isochrome of the short arm of chromosome 12 as a specific marker. With the results of histological, biochemical and radiographic evaluation, patient are classified as follows: good, intermediate and poor risk prognosis. Standard treatment of stage I seminoma is prophylactic irradiation. Stage II with less than 3 cm lymph node too. Other situations need a cisplatin based chemotherapy. In case of metastatic residuals masses more than 3 cm, surgery need to be discussed. Stage I non seminomatous germ cell tumors are treated by retroperitoneal lymphadenectomy, by surveillance or by two cycles of adjuvant chemotherapy with cisplatin, etoposide and bleomycin (BEP). Standard treatment of good prognosis stage II and III is three cycles of BEP, four for poor prognosis. Residual mass need surgery, adjuvant chemotherapy is necessary in presence of viable germ cell. Standard treatment for relapses is chemotherapy with cisplatin, ifosfamide and vinblastine with a 30% remission rate. The place of high dose chemotherapy with autologous stem cell transplantation is not yet standardised. New drugs, as paclitaxel, are under studies.

  16. Androgen deprivation and stem cell markers in prostate cancers

    PubMed Central

    Tang, Yao; Hamburger, Anne W; Wang, Linbo; Khan, Mohammad Afnan; Hussain, Arif

    2010-01-01

    In our previous studies using human LNCaP xenografts and TRAMP (transgenic adenocarcinoma of mouse prostate) mice, androgen deprivation therapy (ADT) resulted in a temporary cessation of prostate cancer (PCa) growth, but then tumors grew faster with more malignant behaviour. To understand whether cancer stem cells might play a role in PCa progression in these animal models, we investigated the expressions of stem cell-related markers in tumors at different time points after ADT. In both animal models, enhanced expressions of stem cell markers were observed in tumors of castrated mice, as compared to non-castrated controls. This increased cell population that expressed stem cell markers is designated as stem-like cells (SLC) in this article. We also observed that the SLC peaked at relatively early time points after ADT, before tumors resumed their growth. These results suggest that the SLC population may play a role in tumor re-growth and disease progression, and that targeting the SLC at their peak-expression time point may prevent tumor recurrence following ADT. PMID:20126580

  17. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.

    PubMed

    Schroeder, Anne; Herrmann, Andreas; Cherryholmes, Gregory; Kowolik, Claudia; Buettner, Ralf; Pal, Sumanta; Yu, Hua; Müller-Newen, Gerhard; Jove, Richard

    2014-02-15

    Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.

  18. TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway

    PubMed Central

    Qi, Li; Lu, Zhong; Sun, Yong-Hong; Song, Hai-Tao; Xu, Wei-Kang

    2016-01-01

    Prostate carcinoma is a devastating disease which is characterized by insidious early symptoms, rapid progression and a poor prognosis. Tripartite motif-containing protein 16 (TRIM16) was identified as an estrogen- and antiestrogen-regulated gene in epithelial cells stably expressing estrogen receptors. The protein encoded by this gene contains two B-box domains and a coiled-coiled region that are characteristic of the B-box zinc finger protein family. Proteins belonging to this family have been reported to be involved in a variety of biological processes including cell growth, differentiation and pathogenesis. TRIM16 expression has been detected in most tissues. However, the funtions of this gene remain to be elucidated. In the present study, immunohistochemical staining revealed that the expression of TRIM16 was decreased in prostate adenocarcinoma compared with that in normal prostate tissues. The patients with high TRIM16-expressing tumors had a significantly greater survival than those with low TRIM16-expressing tumors. Western blot analysis showed that TRIM16 was downregulated in distant metastatic cancer tissues compared with that in non-distant metastatic cancer tissues. The overexpression of TRIM16 inhibited the migration and invasion of prostate cancer cells as well as inhibiting the epithelial-to-mesenchymal transition process, whereas TRIM16 depletion enhanced these processes. Moreover, TRIM16 inhibited the Snail signaling pathway. The silencing of Snail by small interfering RNA was performed in order to determine the role of Snail in the TRIM16-mediated tumor phenotype. Taken together, these findings suggest that TRIM16 may be an important molecular target which may aid in the design of novel therapeutic agents for prostate cancer. PMID:27748839

  19. Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity.

    PubMed

    Oltean, Sebastian; Sorg, Brian S; Albrecht, Todd; Bonano, Vivian I; Brazas, Robert M; Dewhirst, Mark W; Garcia-Blanco, Mariano A

    2006-09-19

    In epithelial cells, alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts leads to the expression of the FGFR2(IIIb) isoform, whereas in mesenchymal cells, the same process results in the synthesis of FGFR2(IIIc). Expression of the FGFR2(IIIc) isoform during prostate tumor progression suggests a disruption of the epithelial character of these tumors. To visualize the use of FGFR2 exon IIIc in prostate AT3 tumors in syngeneic rats, we constructed minigene constructs that report on alternative splicing. Imaging these alternative splicing decisions revealed unexpected mesenchymal-epithelial transitions in these primary tumors. These transitions were observed more frequently where tumor cells were in contact with stroma. Indeed, these transitions were frequently observed among lung micrometastases in the organ parenchyma and immediately adjacent to blood vessels. Our data suggest an unforeseen relationship between epithelial mesenchymal plasticity and malignant fitness.

  20. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells

    PubMed Central

    Stoyanova, Tanya; Cooper, Aaron R.; Drake, Justin M.; Liu, Xian; Armstrong, Andrew J.; Pienta, Kenneth J.; Zhang, Hong; Kohn, Donald B.; Huang, Jiaoti; Witte, Owen N.; Goldstein, Andrew S.

    2013-01-01

    The relationship between the cells that initiate cancer and the cancer stem-like cells that propagate tumors has been poorly defined. In a human prostate tissue transformation model, basal cells expressing the oncogenes Myc and myristoylated AKT can initiate heterogeneous tumors. Tumors contain features of acinar-type adenocarcinoma with elevated eIF4E-driven protein translation and squamous cell carcinoma marked by activated beta-catenin. Lentiviral integration site analysis revealed that alternative histological phenotypes can be clonally derived from a common cell of origin. In advanced disease, adenocarcinoma can be propagated by self-renewing tumor cells with an androgen receptor-low immature luminal phenotype in the absence of basal-like cells. These data indicate that advanced prostate adenocarcinoma initiated in basal cells can be maintained by luminal-like tumor-propagating cells. Determining the cells that maintain human prostate adenocarcinoma and the signaling pathways characterizing these tumor-propagating cells is critical for developing effective therapeutic strategies against this population. PMID:24282295

  1. 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

  2. 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.

  3. Low production of reactive oxygen species and high DNA repair: mechanism of radioresistance of prostate cancer stem cells.

    PubMed

    Kim, Young Seok; Kang, Mun Jung; Cho, Yong Mee

    2013-10-01

    Cancer stem cells (CSCs) are resistant to radiotherapy and are responsible for tumor recurrence of various malignant tumors, including prostate cancer. In order to define the radioresistance mechanism of prostate CSCs, their proliferative activity, cell cycle distribution, expression of CD133 stem cell marker, reactive oxygen species (ROS) production, and DNA repair efficiency were examined using prostatospheres and adherent LNCaP cells as a model of prostate CSC and bulk model of differentiated cells, respectively. Compared to adherent cells, prostatospheres exhibited greater number of low-to-intermediate ROS-producing cells and CD133-positive cells. Prostatospheres showed higher expression of DNA repair proteins after ionizing radiation (IR). Low vulnerability to ROS-induced cellular damage and the efficient repair of IR-induced DNA injury may explain the radioresistance of prostate CSCs. Therefore, increasing ROS-induced cytotoxicity and inhibition of DNA repair in prostate CSCs may help achieve complete eradication of prostate CSCs by radiotherapy.

  4. Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

    PubMed

    Halin Bergström, Sofia; Nilsson, Maria; Adamo, Hanibal; Thysell, Elin; Jernberg, Emma; Stattin, Pär; Widmark, Anders; Wikström, Pernilla; Bergh, Anders

    2016-01-01

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

  5. The Prostate Tumor Microenvironment Exhibits differentially expressed Genes Useful for Diagnosis — EDRN Public Portal

    Cancer.gov

    To develop a multi-site prospective clinical validation trial of the multigene diagnostic signature for the diagnosis of prostate cancer from non tumor containing biopsy tissue. Prostate cancer now affects one in five men in the U.S. It is diagnosed by examination of a biopsy sample of the prostate gland by a pathologist and treatment decisions such as the choice of surgery are usually not made without direct visualization of the presence of cancer by a pathologist. There are about one million such biopsy procedures in the U.S. every year. However about 1-200,000 are ambiguous owing to the absence of tumor but the presence of small changes such as atypical small acinar proliferations (ASAP) or proliferations within otherwise normal glands (PIN, prostate intraepithelial neoplasia) that are highly suspicious for cancer. Studies by the UCI/NCI SPECS project on prostate cancer have led to a new way to diagnosis the presence of prostate cancer in these ambiguous changes. Researchers of the UCI/NCI SPECS project observed that the tissue around a tumor called stroma has many altered gene activities that are caused by molecules secreted by the tumor cells. Indeed these studies revealed that 114 genes exhibited altered activity in stroma near tumor compared to normal stroma. These changes can be used as a “signature” to examine new samples to determine the “presence of-tumor”. Such a test has many applications. Currently ambiguous cases are asked to return for a repeat biopsy in 3 to 12 months – an agonizing period for patients during which they receive no guidance and during which any tumor may continue to grow and spread. Thus, the new test would detect tumor 3 to 12 months prior to conventional practice. This will avoid repeated biopsy procedures. Patients who are positive by the new test may consider whether immediate medical treatment or neo adjuvant treatment is appropriate. In addition the ability to detect presence-of-tumor early will avoid the necessity

  6. Osteomimicry: how tumor cells try to deceive the bone.

    PubMed

    Rucci, Nadia; Teti, Anna

    2010-06-01

    Bone metastases are complications of multiple myeloma and solid tumors, including breast and prostate carcinomas. Several reports have demonstrated that the preference to metastasize to bone by tumor cells is not a casual but an addressed event, which relies on specific interactions among tumor cells, bone marrow microenvironment and bone cells. One of the features that gives tumor cells more chances to survive and proliferate into the bone tissue is osteomimicry, that is the ability to acquire a bone cell phenotype, especially osteoblast-like. As clearly demonstrated, prostate and breast cancer cells try to resemble osteoblasts by expressing bone matrix proteins, the specific marker alkaline phosphatase, and molecules regulating the osteoblast/osteoclast cross-talk. Based on this evidence it is crucial to dissect in more detail the molecular mechanisms underlying the osteomimetic properties of cancer cells and identify new therapeutic targets eventually leading to a better and prolonged life expectation for patients with bone.

  7. Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer.

    PubMed

    Mauri, Giorgio; Chiodoni, Claudia; Parenza, Mariella; Arioli, Ivano; Tripodo, Claudio; Colombo, Mario Paolo

    2013-12-01

    Intra-tumor injection of immunotherapeutic agents is often the most effective, likely because of concomitant modification of tumor microenvironment. We tested an immunotherapeutic regimen consisting of CpG oligonucleotides and of adenovirus-mediated gene delivery of CCL16 chemokine directly into orthotopically implanted prostate tumors by ultrasound-guided injection, followed by systemic administration of an anti-IL-10R antibody. This combination treatment induced rapid stromal rearrangement, characterized by massive leukocyte infiltration and large areas of necrosis, a scenario that eventually led to complete tumor rejection and systemic immunity in 75 % of the treated mice. In vivo T lymphocyte depletion experiments demonstrated that the efficacy of CCL16/CpG/anti-IL-10R combination treatment relies upon CD8 T lymphocytes whereas CD4 T cells are dispensable. The results underlie the feasibility of echo-guided local immunotherapy of tumors located in visceral organs that are not easily accessible.

  8. Proepithelin Regulates Prostate Cancer Cell Biology by Promoting Cell Growth, Migration, and Anchorage-Independent Growth

    PubMed Central

    Monami, Giada; Emiliozzi, Velia; Bitto, Alessandro; Lovat, Francesca; Xu, Shi-Qiong; Goldoni, Silvia; Fassan, Matteo; Serrero, Ginette; Gomella, Leonard G.; Baffa, Raffaele; Iozzo, Renato V.; Morrione, Andrea

    2009-01-01

    The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors. PMID:19179604

  9. SU-E-J-95: Predicting Treatment Outcomes for Prostate Cancer: Irradiation Responses of Prostate Cancer Stem Cells

    SciTech Connect

    Wang, K

    2014-06-01

    Purpose: Most prostate cancers are slow-growing diseases but normally require much higher doses (80Gy) with conventional fractionation radiotherapy, comparing to other more aggressive cancers. This study is to disclose the radiobiological basis of this discrepancy by proposing the concept of prostate cancer stem cells (CSCs) and examining their specific irradiation responses. Methods: There are overwhelming evidences that CSC may keep their stemness, e.g. the competency of cell differentiation, in hypoxic microenvironments and hence become radiation resistive, though the probability is tiny for aggressiveness cancers. Tumor hypoxia used to be considered as an independent reason for poor treatment outcomes, and recent evidences showed that even prostate cancers were also hypoxic though they are very slow-growing. In addition, to achieve comparable outcomes to other much more aggressive cancers, much higher doses (rather than lower doses) are always needed for prostate cancers, regardless of its non-aggressiveness. All these abnormal facts can only be possibly interpreted by the irradiation responses characteristics of prostate CSCs. Results: Both normal cancer cells (NCCs) and CSCs exiting in tumors, in which NCCs are mainly for symptoms whereas killing all CSCs achieves disease-free. Since prostate cancers are slow-growing, the hypoxia in prostate cancers cannot possibly from NCCs, thus it is caused by hypoxic CSCs. However, single hypoxic cell cannot be imaged due to limitation of imaging techniques, unless a large group of hypoxic cells exist together, thus most of CSCs in prostate cancers are virtually hypoxic, i.e. not in working mode because CSCs in proliferating mode have to be normoxic, and this explains why prostate cancers are unaggressive. Conclusion: The fractional dose in conventional radiotherapy (∼2Gy) could only kill NCCs and CSCs in proliferating modes, whereas most CSCs survived fractional treatments since they were hypoxic, thus to eliminate all

  10. Role of prostatic interstitial cells in prostate motility

    PubMed Central

    Lang, Richard J; Hashitani, Hikaru

    2017-01-01

    Abstract The prostate is a gland whose secretions contribute to the seminal fluids ejaculated upon activation of autonomic sympathetic nerves. In elder males, the prostate undergoes an increase in stroma mass and myogenic tone, leading to benign prostatic hyperplasia that occludes the proximal urethra and the presentation of various lower urinary tract symptoms that decrease their quality of life. This review summarises the role of prostatic interstitial cells (PICs) in the generation of the spontaneous tone in the prostate. It presents current knowledge of the role of Ca2+ plays in PIC pacemaking, as well as the mechanisms by which this spontaneous activity triggers slow wave generation and stromal contraction. PICs display a small T-type Ca2+ current (ICaT) and a large L-type Ca2+ current (ICaL). In contrast to other interstitial cells in the urinary and gastrointestinal tracts, spontaneous Ca2+ signalling in PICs is uniquely dependent on Ca2+ influx through ICaL channels. A model of prostatic pacemaking is presented describing how ICaL can be triggered by an initial membrane depolarization evoked upon the selective opening of Ca2+-activated Cl– channels by Ca2+ flowing only through ICaT channels. The resulting current flow through ICaL results in release of Ca2+ from internal stores and the summation of Cl–-selective spontaneous transient depolarizations (STDs) to form pacemaker potentials that propagate passively into the prostatic stroma to evoke regenerative action potentials and excitation-contraction coupling. PMID:28652517

  11. MicroRNAs 221/222 and Genistein mediated regulation of ARHI tumor suppressor gene in prostate cancer

    PubMed Central

    Chen, Yi; Zaman, Mohd Saif; Deng, Guoren; Majid, Shahana; Saini, Shranjot; Liu, Jan; Tanaka, Yuichiro; Dahiya, Rajvir

    2010-01-01

    INTRODUCTION ARHI, an imprinted tumor suppressor gene, is expressed in normal immortalized prostate epithelial cells, but is dramatically down-regulated in prostate cancer cell lines. Here we investigated the mechanisms of ARHI silencing in prostate cancer through miRNA and genistein mediated pathways. EXPERIMENTAL PROCEDURE We evaluated ARHI mRNA and protein levels by real time PCR and immunostaining of prostate tissue array. Then, ARHI was over-expressed in prostate cancer PC-3 cells followed by functional studies. Finally, miRNA inhibitor studies and dual luciferase pMIR-REPORT assay were performed to prove the direct target of miR-221&222 to ARHI. RESULTS Both ARHI mRNA and protein levels were down regulated in prostate cancer tissues compared to adjacent normal tissues. Over-expression of ARHI can inhibit cell proliferation, colony formation, invasion and induced apoptosis. Further studies on a new mechanism of ARHI down regulation showed a significant inverse relationship between ARHI and miR-221 & 222 which were up-regulated in cancer cell lines. Transfection of miR-221 & 222 inhibitors into PC-3 cells caused a significant induction of ARHI expression. A direct interaction of miR-221 or 222 with a target site on the 3’UTR of ARHI was confirmed by a dual luciferase pMIR-REPORT assay. CONCLUSIONS ARHI is a tumor suppressor gene down regulated in prostate cancer and over-expression of ARHI can inhibit cell proliferation, colony formation and invasion. This study demonstrates for the first time that prostate cancer cells have decreased level of ARHI which could be caused by direct targeting of 3’UTR of ARHI by miR221/222. PMID:21071579

  12. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    DTIC Science & Technology

    2015-10-01

    SUBJECT TERMS Prostate cancer, myeloid-derived suppressor cell (MDSC), Pten, Smad4, genetically engineered mouse model, Gr-1, peptide-Fc fusion protein...KEYWORDS Prostate cancer, myeloid-derived suppressor cell (MDSC), Pten, Smad4, genetically engineered mouse model, Gr-1, peptide-Fc fusion protein 3...which should provide a genetic method for MDSC functional evaluation. Currently, the compound mouse Ptenpc-/- Smad4pc-/- CD11b-DTR+ are still in

  13. Tumor-infiltrating immune cells: triggers for tumor capsule disruption and tumor progression?

    PubMed

    Jiang, Bin; Mason, Jeffrey; Jewett, Anahid; Liu, Min-ling; Chen, Wen; Qian, Jun; Ding, Yijiang; Ding, Shuqing; Ni, Min; Zhang, Xichen; Man, Yan-gao

    2013-01-01

    Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC). Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging. Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination. Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis.

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

    PubMed Central

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

    2013-01-01

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

  15. Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects.

    PubMed

    Sheikh, Nadeem; Cham, Jason; Zhang, Li; DeVries, Todd; Letarte, Simon; Pufnock, Jeff; Hamm, David; Trager, James; Fong, Lawrence

    2016-07-01

    Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T-cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T-cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T-treated subjects versus tissue of nonsipuleucel-T-treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T-cell response to immunotherapy both in the periphery and in tumor tissue. Cancer Res; 76(13); 3711-8. ©2016 AACR.

  16. Defective DNA strand break repair after DNA damage in prostate cancer cells: implications for genetic instability and prostate cancer progression.

    PubMed

    Fan, Rong; Kumaravel, Tirukalikundram S; Jalali, Farid; Marrano, Paula; Squire, Jeremy A; Bristow, Robert G

    2004-12-01

    Together with cell cycle checkpoint control, DNA repair plays a pivotal role in protecting the genome from endogenous and exogenous DNA damage. Although increased genetic instability has been associated with prostate cancer progression, the relative role of DNA double-strand break repair in malignant versus normal prostate epithelial cells is not known. In this study, we determined the RNA and protein expression of a series of DNA double-strand break repair genes in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145, and PC-3) prostate cultures. Expression of genes downstream of ATM after ionizing radiation-induced DNA damage reflected the p53 status of the cell lines. In the malignant prostate cell lines, mRNA and protein levels of the Rad51, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated approximately 2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-beta and -delta proteins were also elevated. There were no consistent differences in gene expression relating to the nonhomologous end-joining pathway. Despite increased expression of DNA repair genes, malignant prostate cancer cells had defective repair of DNA breaks, alkali-labile sites, and oxidative base damage. Furthermore, after ionizing radiation and mitomycin C treatment, chromosomal aberration assays confirmed that malignant prostate cells had defective DNA repair. This discordance between expression and function of DNA repair genes in malignant prostate cancer cells supports the hypothesis that prostate tumor progression may reflect aberrant DNA repair. Our findings support the development of novel treatment strategies designed to reinstate normal DNA repair in prostate cancer cells.

  17. 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

  18. Retraction: 'Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells' by Nobuyuki Kikuno, Hiroaki Shiina, Shinji Urakami, Ken Kawamoto, Hiroshi Hirata, Yuichiro Tanaka, Shahana Majid, Mikio Igawa and Rajvir Dahiya.

    PubMed

    2017-10-01

    The above article, published online on 22 April 2008 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, Prof. Peter Lichter, and John Wiley & Sons Ltd. The retraction has been agreed due to errors identified in Figs, 3, 4, and 5. The concerns about these figures cannot be resolved because the original data can no longer be retrieved. Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Majid S, Igawa M and Dahiya R. (2008), Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells. Int J Cancer, 123:552-560. DOI: 10.1002/ijc.23590. © 2017 UICC.

  19. Therapeutic Value of PLK1 Knockdown in Combination with Prostate Cancer Drugs in PIM-1 Overexpressing Prostate Cancer Cells

    DTIC Science & Technology

    2014-11-13

    of tumor cells on its activity in mitosis (Fink et al., 2007). Silencing of PLK1 has been shown to enhance drug sensitivity in some cancer cells...crucial role at various steps of mitosis and is overexpressed in many tumor types including prostate cancer, where PLK1 overexpression was found to...the co-localization of PIM1 and PLK1. PLK1 was detected in centrosome, kinetochore and midbody during mitosis (Fig. 2B), consistent with its multiple

  20. 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

  1. [Neuroendocrine features of prostatic tumors: state of the art].

    PubMed

    Turitto, Giacinto; Frattolillo, Adele; Iodice, Patrizia; Auriemma, Annunziata; Tortoriello, Annamaria; di Grazia, Maria; Iaffaioli, Rosario Vincenzo

    2003-12-01

    Neuroendocrine (NE) differentiation in prostate cancer has received much attention recently because it has been found to be associated with androgen independence and shortened patient survival in some studies. The present review focuses on morphogenics origins of NE cells, growth properties and the androgen receptor status and relationship between NE-secreted products and regulation of angiogenesis and apoptosis.

  2. Escape from Tumor Cell Dormancy

    DTIC Science & Technology

    2012-10-01

    prostate cancer cells increases chemoresistance. Clinical and Experimental Metastasis 29, 39-50. PMID: 21964676. YL Chao, Q Wu, M Acquafondata, R...Dhir, A Wells (2012). Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenvironment 5, 19- 28... cancer is its propensity to recur in metastatic sites even over a decade after all evidence of cancer has passed. It is obvious that these cells had

  3. Hypoxic Tumor Kinase Signaling Mediated by STAT5A in Development of Castration-Resistant Prostate Cancer

    PubMed Central

    Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen

    2013-01-01

    In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. PMID:23675504

  4. Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.

    PubMed

    Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen

    2013-01-01

    In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein.

  5. Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone.

    PubMed

    Jacob, K; Webber, M; Benayahu, D; Kleinman, H K

    1999-09-01

    The mechanism underlying the "organ-specific" metastasis of prostate cancer cells to the bone is still poorly understood. It is not clear whether the cells only invade the bone and proliferate there or whether they invade many tissues but survive mainly in the bone ("seed and soil"). Extracts from various organs were used as chemoattractants in the in vitro chemotaxis and invasion assays. Results show that, in comparison with extracts of other tissues, bone extracts promote a 2- to 4-fold increase in chemotaxis by human prostate epithelial cells and a 4-fold increase in the invasive ability of human prostate carcinoma cells. The purified active factor from bone and from marrow stromal-cell-conditioned medium is a low glycosylated osteonectin that specifically promotes the invasive ability of bone-metastasizing prostate (and breast) cancer cells but not that of non-bone-metastasizing tumor cells. It does not stimulate the growth of prostate cancer cells in vitro or in vivo. Because osteonectin specifically enhances matrix metalloprotease activity in prostate and breast cancer cells (and not in other tumor cell types), we conclude that prostate cancer cell metastasis to the bone is, in part, mediated by the ability of osteonectin to promote migration, protease activity, and invasion.

  6. Synchronous Malignant Peripheral Nerve Sheath Tumor and Adenocarcinoma of the Prostate: Case Report and Literature Review

    PubMed Central

    Bouropoulos, Konstantinos; Farmakis, Antonios

    2016-01-01

    Malignant Peripheral Nerve Sheath Tumors (MPNSTs) of the prostate are extremely rare. A very unusual case of simultaneous adenocarcinoma and MPNST of the prostate is reported. A 60-year-old Caucasian male presented for annual urologic examination. Digital rectal examination revealed a painless, toughish, and asymmetrically enlarged prostate. Serum prostate-specific antigen was 1 ng/mL. Radiologic examinations demonstrated a large mass, which was arising from the left peripheral lobe of the prostate. The patient underwent transrectal ultrasound-guided biopsy of the prostate which revealed a smooth muscle tumor of uncertain malignant potential. Radical retropubic prostatectomy with en bloc removal of the mass and the seminal vesicles was performed and histology demonstrated low-grade MPNST and adenocarcinoma of the prostate. To the best of our knowledge, this is the first report of simultaneous prostatic adenocarcinoma and MPNST in the English literature. PMID:27872787

  7. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  8. Multiplexed Analysis of Circulating Prostate Tumor and Host Response Markers

    DTIC Science & Technology

    2005-04-01

    patients with benign prostatic hyperplasia , organ-confined prostate cancer, "metastatic prostate cancer, and no disease. Further development of high...organ-confined prostate cancer, non-organ-confined prostate cancer, benign prostatic hyperplasia , and no disease. These experiments were performed on

  9. 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

  10. Altered glycosylation in tumor cells

    SciTech Connect

    Reading, C.L. ); Hakomori, S. ); Marcus, D.M. )

    1988-01-01

    This book contains the proceeding on the following: Glycoconjugates of normal and tumor cells; Glycosyltransferases in normal and neoplastic cells; Mammalian lectins of normal tissues and tumor cells; and Immune recognition of carbohydrates and clinical applications.

  11. Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents.

    PubMed

    Uzzo, Robert G; Leavis, Paul; Hatch, William; Gabai, Vladimir L; Dulin, Nickolai; Zvartau, Nadezhda; Kolenko, Vladimir M

    2002-11-01

    Prostate carcinogenesis involves transformation of zinc-accumulating normal epithelial cells to malignant cells, which do not accumulate zinc. In this study, we demonstrate by immunoblotting and immunohistochemistry that physiological levels of zinc inhibit activation of nuclear factor (NF)-kappa B transcription factor in PC-3 and DU-145 human prostate cancer cells, reduce expression of NF-kappa B-controlled antiapoptotic protein c-IAP2, and activate c-Jun NH(2)-terminal kinases. Preincubation of PC-3 cells with physiological concentrations of zinc sensitized tumor cells to tumor necrosis factor (TNF)-alpha, and paclitaxel mediated cell death as defined by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. These results suggest one possible mechanism for the inhibitory effect of zinc on the development and progression of prostate malignancy and might have important consequences for the prevention and treatment of prostate cancer.

  12. Frequently rearranged in advanced T-cell lymphomas-1 demonstrates oncogenic properties in prostate cancer

    PubMed Central

    Zhang, Wei; Xiong, Hua; Zou, Yanmei; Xu, Sanpeng; Quan, Lanping; Yuan, Xianglin; Xu, Ningzhi; Wang, Yihua

    2016-01-01

    Prostate cancer is the fifth most common cause of cancer-associated mortality for males worldwide. Although dysregulation of the β-catenin/T-cell factor (TCF) pathway has been previously reported in prostate cancer, the mechanisms underlying this process remain unknown. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) functions as a positive regulator of the β-catenin/TCF signaling pathway. However, to the best of our knowledge, the molecular association between FRAT1 and the β-catenin/TCF pathway in prostate cancer has not been investigated. In the present study, FRAT1 expression was analyzed in normal prostate tissues and prostate adenocarcinoma samples using publicly available databases, a commercial tissue microarray and immunohistochemistry techniques. In addition, FRAT1 expression levels were altered by overexpression or RNA interference-mediated depletion in prostate cancer cells. The effects of FRAT1 expression on tumor growth were determined using cell growth curves in vitro and xenografts in nude mice in vivo. The effects of FRAT1 on β-catenin/TCF activity were measured using the TOPFLASH reporter assay. FRAT1 was expressed exclusively in the nuclei of normal prostate basal cells, and nuclear FRAT1 was detected in 68% (40/59) of prostate adenocarcinoma samples. In addition, FRAT1 activated the TCF luciferase reporter gene promoter in prostate cancer cells, and was observed to promote the growth of prostate cancer cells in vitro. Furthermore, FRAT1 expression was sufficient to transform NIH3T3 mouse embryonic fibroblast cells and lead to tumor formation in vivo. These results suggest that FRAT1 demonstrates oncogenic properties in prostate cancer, potentially by suppressing the inhibitory effect of nuclear glycogen synthase 3β against β-catenin/TCF activity, thus activating the Wnt/β-catenin signaling pathway and promoting cell growth. PMID:27599661

  13. Prostate cancer marker panel with single cell sensitivity in urine.

    PubMed

    Nickens, Kristen P; Ali, Amina; Scoggin, Tatiana; Tan, Shyh-Han; Ravindranath, Lakshmi; McLeod, David G; Dobi, Albert; Tacha, David; Sesterhenn, Isabell A; Srivastava, Shiv; Petrovics, Gyorgy

    2015-06-15

    Over one million men undergo prostate biopsies annually in the United States, a majority of whom due to elevated serum PSA. More than half of the biopsies turn out to be negative for prostate cancer (CaP). The limitations of both the PSA test and the biopsy procedure have led to the development for more precise CaP detection assays in urine (e.g., PCA3, TMPRSS2-ERG) or blood (e.g., PHI, 4K). Here, we describe the development and evaluation of the Urine CaP Marker Panel (UCMP) assay for sensitive and reproducible detection of CaP cells in post-digital rectal examination (post-DRE) urine. The cellular content of the post-DRE urine was captured on a translucent filter membrane, which is placed on Cytoclear slides for direct evaluation by microscopy and immuno-cytochemistry (ICC). Cells captured on the membrane were assayed for PSA and Prostein expression to identify prostate epithelial cells, and for ERG and AMACR to identify prostate tumor cells. Immunostained cells were analyzed for quantitative and qualitative features and correlated with biopsy positive and negative status for malignancy. The assay was optimized for single cell capture sensitivity and downstream evaluations by spiking a known number of cells from established CaP cell lines, LNCaP and VCaP, into pre-cleared control urine. The cells captured from the post-DRE urine of subjects, obtained prior to biopsy procedure, were co-stained for ERG, AMACR (CaP specific), and Prostein or PSA (prostate epithelium specific) rendering a whole cell based analysis and characterization. A feasibility cohort of 63 post-DRE urine specimens was assessed. Comparison of the UCMP results with blinded biopsy results showed an assay sensitivity of 64% (16 of 25) and a specificity of 68.8% (22 of 32) for CaP detection by biopsy. This pilot study assessing a minimally invasive CaP detection assay with single cell sensitivity cell-capture and characterization from the post-DRE urine holds promise for further development of this

  14. Osteoclast derived matrix metalloproteinase-9 directly impacts angiogenesis in the prostate tumor-bone microenvironment

    PubMed Central

    Bruni-Cardoso, Alexandre; Johnson, Lindsay C.; Vessella, Robert L.; Peterson, Todd E.; Lynch, Conor C.

    2010-01-01

    In human prostate to bone metastases and in a novel rodent model that recapitulates prostate tumor induced-osteolytic and osteogenic responses, we found that osteoclasts are a major source of the proteinase, MMP-9. Since MMPs are important mediators of tumor-host communication, we tested the impact of host derived MMP-9 on prostate tumor progression in bone. To this end, immunocompromised mice that were wild type or null for MMP-9 received transplants of osteolytic/osteogenic inducing prostate adenocarcinoma tumor tissue to the calvaria. Surprisingly, we found that that host MMP-9 significantly contributed to prostate tumor growth without impacting prostate tumor induced osteolytic or osteogenic change as determined by μCT, μSPECT and histomorphometry. Subsequent studies aimed at delineating the mechanism of MMP-9 action on tumor growth focused on angiogenesis since MMP-9 and osteoclasts have been implicated in this process. We observed; 1) significantly fewer and smaller blood vessels in the MMP-9 null group by CD-31 immunohistochemistry; 2) MMP-9 null osteoclasts had significantly lower levels of bioavailable VEGF-A164 and; 3) using an aorta sprouting assay, conditioned media derived from wild type osteoclasts was significantly more angiogenic than conditioned media derived from MMP-9 null osteoclasts. In conclusion, these studies demonstrate that osteoclast derived MMP-9 impacts prostate tumor growth in the bone microenvironment by contributing to angiogenesis without altering prostate tumor induced osteolytic or osteogenic changes. PMID:20332212

  15. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

    PubMed Central

    2011-01-01

    Background Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. Methods The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors Results We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in

  16. Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels.

    PubMed

    Nimmanapalli, R; Perkins, C L; Orlando, M; O'Bryan, E; Nguyen, D; Bhalla, K N

    2001-01-15

    We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo-2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL-induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4:Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells.

  17. Expression and initial promoter characterization of PCAN1 in retinal tissue and prostate cell lines.

    PubMed

    Cross, D; Reding, D J; Salzman, S A; Zhang, K Q; Catalona, W J; Burke, J; Burmester, J K

    2004-01-01

    Prostate cancer is the most frequently diagnosed neoplasia in men and one of the leading causes of cancer-related deaths in men over 60. In an effort to understand the molecular events leading to prostate cancer, we have identified PCAN1 (prostate cancer gene 1) (also known as GDEP), a gene that is highly expressed in prostate epithelial tissue and frequently mutated in prostate tumors. Here we demonstrate its expression in neural retina, and retinoblastoma cell culture but not retinal pigment epithelial cell culture. We further characterize PCAN1 expression in the prostate cell lines RWPE1, RWPE2, and LnCAP FGC. We demonstrate an increase in expression when the cells are grown in the presence of Matrigel, an artificial extracellular basement membrane. Expression was time dependent, with expression observed on d 6 and little or no expression on d 12. Testosterone was not found to increase PCAN1 expression in this culture system. In addition, normal prostate epithelial cells co-cultured with normal prostate stromal cells did not exhibit PCAN1 expression at any time. To definitively locate the transcription initiation sites, we performed restriction-ligase-mediated 5' RACE, to selectively amplify only mRNA with a 5' cap. An initial characterization of the sequence upstream of the initiation sites determined six possible binding sites for the prostate specific regulatory protein NKX3.1 and four potential binding sites for the PPAR/RXR heterodimer that is involved in the control of cell differentiation and apoptosis.

  18. Astaxanthin Inhibits PC-3 X