INTERNATIONAL JOURNAL OF CANCER, Issue 10 2008
Jinhui Liao
Abstract Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression. © 2008 Wiley-Liss, Inc. [source]

Uncertainty in Breast, Prostate, and Colorectal Cancer: Implications for Supportive Care

JOURNAL OF NURSING SCHOLARSHIP, Issue 1 2008
Maya Shaha
Purpose:The aim of this paper was to identify and explore the literature for key aspects of uncertainty experienced by patients who have been diagnosed with breast, prostate, or colorectal cancer. Organizing Construct: Throughout the cancer journey important decisions are made about treatments, symptom control, and supportive care and many approaches have been adopted to examine coping and uncertainty associated with a cancer diagnosis. Uncertainty and its associated attributes, such as stress or anxiety, fluctuate across the disease trajectory. To appreciate the changing nature of uncertainty one should consider its effect on specific patient groups by considering the available evidence. Methods: A comprehensive literature search that was focused on reviews and studies about uncertainty in cancer patients was conducted in PubMed and CINAHL. In total, 40 articles were identified that indicated uncertainty in patients with breast, prostate, or colorectal cancer, although the emphasis in each differed according to the nature and treatment of the disease. Findings: Uncertainty was found to comprise three main themes: uncertainty because of limited or lack of information, uncertainty concerning the course and treatment choices related to the disease, and uncertainty related to everyday life and coping with the disease. Conclusions: Uncertainty influences patients' experiences of their cancer and their coping. Whilst it might be impossible to avoid uncertainty entirely, its negative effects might be ameliorated by understanding patients' specific needs along the disease trajectory of breast, prostate, and colorectal cancer. [source]

Early Results of Photoselective Vaporization of the Prostate in Medical Control-failed Patients

LUTS, Issue 2 2009
Shen Kuang CHANG
Objectives: We present here our early results and learning curve for photoselective vaporization of the prostate (PVP) performed by an experienced urologist and we provide an analysis of the morbidity and early functional outcomes. Methods: Forty-four patients were selected, from May 2006 to January 2009, who had benign prostate hyperplasia (BPH) accompanied by lower urinary tract symptoms (LUTS). After undergoing PVP for BPH at our hospital, the patients were followed up for approximately 2 years. PVP was performed by the same experienced urologist using potassium-titanyl-phosphate (KTP) laser. Baseline characteristics, preoperative and perioperative data, and postoperative complications were evaluated. Regular outpatient department follow-up was conducted after patients were discharged from the hospital at 1, 4 and 12 weeks. Results: The mean age of the 44 patients was 71.6 years. The mean prostate volume was 47.52 mL. The mean PVP surgery time was 79.11 min. The mean urinary catheterization time was 23.41 h. Few complications arose after PVP, except that 47.7% of the patients developed pyuria after being discharged from hospital. The average hospital stay was 2.45 days. There were no significant differences in the efficiency of tissue vaporization among the patients. Conclusion: PVP for BPH has various advantages, including reducing postoperative complications. An experienced urologist can easily perform PVP. However, early results show no significant differences in the efficiency for the PVP technique. [source]

Comparison of the Effect of the Aromatase Inhibitor, Anastrazole, to the Antioestrogen, Tamoxifen Citrate, on Canine Prostate and Semen

REPRODUCTION IN DOMESTIC ANIMALS, Issue 2009
G Gonzalez
Contents This study compared the efficiency of the aromatase inhibitor, anastrazole, with the antioestrogenic receptor blocker, tamoxifen, on normal (NRL) and hyperplastic prostate glands. Forty healthy dogs were classified as NRL (n = 18) or abnormal (ABN) with benign prostate hyperplasia (n = 22). The dogs were randomly assigned to one of the following six groups, treated for 60 days; oral placebo for normal (NRL-PLC; n = 6) and abnormal (ABN-PLC; n = 6), oral anastrazole 0.25,1 mg/day, for normal (NRL-ANZ, n = 6) and abnormal (ABN-ANZ, n = 8) and oral tamoxifen citrate 2.5,10 mg/day for normal (NRL-TMX; n = 6) and abnormal (ABN-TMX; n = 8) dogs. The dogs were evaluated before treatment and then monthly for 4 months. At the end of the treatment, the prostatic volume decreased by 28.5 ± 4.3%, 21.6 ± 6.3% and 0.7 ± 1.0% in the ABN-TMX, ABN-ANZ and ABN-PLC (p < 0.01), respectively. From then on, prostatic volume began to increase without reaching pre-treatment values at the end of the study. In the ABN animals, there were no differences for this parameter between ANZ and TMX treatment (p > 0.1), whereas in the NRL animals ANZ produced a less pronounced decrease (p < 0.05), libido, testicular consistency and scrotal diameter decreased during treatment in the TMX group (p > 0.05). These parameters and sperm volume, count, motility and morphological abnormalities remained unaltered throughout the study in the ANZ and PLC groups (p > 0.05). There were no haematological nor biochemical side effects. Anastrazole might offer a safe and effective alternative for the medical management of dogs with benign prostatic hyperplasia. [source]

Clinical and Pathological Findings in Testis, Epididymis, Deferens Duct and Prostate following Vasectomy in a Dog

REPRODUCTION IN DOMESTIC ANIMALS, Issue 2 2006
CC Pérez-Marín
Contents We report the case of a bilateral and multilocular spermatocele and sperm granuloma in a dog that was vasectomized 5 years before. Clinical examination revealed scrotal dermatitis and benign prostatic hyperplasia. Orchiectomy was performed, and gross and histological examination showed testicular degeneration associated with epididymal sperm granuloma. In relation to this case, the literature about long-term effects of vasectomy in dogs has been reviewed. On the basis of these results, a preventive sonogram and physical assessment in prostate and other reproductive structures before vasectomy is recommended. [source]

Effect of Prostatein, the Major Protein Produced by the Rat Ventral Prostate, on Phagocytic Cell Functions

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2003
Mariana Maccioni
Problem:, To determine whether prostatein, the major protein produced and secreted into the seminal fluid by the rat ventral prostate has any effect on the phagocytic cell functions in vitro. Method of study:, Analysis was done by determining if purified prostatein added to cells obtained from the peritoneal cavity has any effect on their phagocytic and intracellular killing capacity. Also, we analyzed the effect of prostatein on the production of oxygen and nitrogen intermediates, measuring these metabolites by Nitroblue tetrazolium assay and by the Griess reaction respectively. Results:, Prostatein possess the ability to inhibit in vitro the phagocytic and killing properties of peritoneal rat leukocytes in a dose-dependent manner. The addition of a polyclonal antiserum against prostatein specifically blocks this inhibitory effect. Moreover, prostatein inhibits the production of oxygen and nitrogen intermediates by these cells. Conclusion:, Regulation of the production of reactive oxygen species in the reproductive tract is extremely necessary to avoid their deleterious effects on the sperm motility and the fertilization process. We propose that prostatein, a protein supplied by an accessory gland like prostate, can inhibit the macrophage function, showing an important antioxidant effect. [source]

Tissue expression of IL16 in prostate cancer and its association with recurrence after radical prostatectomy,

THE PROSTATE, Issue 15 2010
Eva Compérat
Abstract BACKGROUND Genetic polymorphism located within the IL16 gene has been reported to be associated with aggressive prostate cancer (PCa). Our aim was to establish whether the tissue expression of IL16 is a prognostic factor of survival in PCa. METHODS The files of patients who underwent radical prostatectomy (RP) between 1995 and 2001 were reviewed. The cases were selected and classified according to the D'Amico classification for risk of recurrence (intermediate or high). The value of IL16 and its receptor CCR5 (chemokine (C-C motif) receptor 5) expression levels were determined as witness of aggressiveness patterns and markers of biological relapse in patients with PCa treated by RP. A tissue microarray of 304 cases was constructed. IL16 and CCR5 expression levels were characterized by immunohistochemistry. RESULTS IL16 expression was correlated with high Gleason score (i.e., >7) (P,<,0.01). It was not significant for CCR5. IL16 and CCR5 were not associated with prostate-specific antigen (PSA) or capsular extension of the disease. The accurate prediction of disease outcome, using stratification of cases, according to negative margins and D'Amico classification was significantly enhanced by status of IL16 expression (P,,,0.01). In univariate analyses, Gleason score, PSA level, stage and loss of IL16 expression were related to better biological-free survival (P,<,0.05) but not CCR5. In a multivariate analysis, IL16 expression, Gleason score, and tumor stage were independent factors for biochemical-free survival (P,=,0.001). CONCLUSIONS IL16 appears to be a useful prognostic factor in PCa. Its expression in PCa tissue was correlated to tumor aggressiveness and biochemical relapse of the disease. Prostate 70: 1622,1627, 2010. © 2010 Wiley-Liss, Inc. [source]

Effects of castration on insulin levels and glucose tolerance in the mouse differ from those in man

THE PROSTATE, Issue 15 2010
Takamitsu Inoue
Abstract BACKGROUND Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior. To investigate the possible role of castration-induced hyperinsulinemia as a mechanism that may attenuate the beneficial effects of ADT in patients with prostate cancer, a murine model would be useful. We therefore investigated long-term metabolic effects of castration in several mouse models. METHODS We studied the long-term influence of castration on energy intake, body weight, glucose tolerance, plasma-insulin, plasma insulin-like growth factor-1 (IGF-1), plasma adiponectin, and plasma leptin in C57BL/6, Swiss nu/nu, and CB17 scid mice receiving various diets. In each case, mice were randomized to have either bilateral orchiectomy or a sham operation. RESULTS Energy intake, body weight, blood glucose levels in glucose tolerance test, plasma insulin, plasma IGF-1, and plasma leptin level in all had a trend to be decreased in castrated as compared to sham operated mice. Plasma adiponectin level was increased in the castrated mice. CONCLUSIONS The effects of castration on glucose, insulin, and related markers in several mouse models studied does not coincide with clinical observations; further studies in this area will require clinical research and/or the use of alternate models such as the dog. Prostate 70: 1628,1635, 2010. © 2010 Wiley-Liss, Inc. [source]

MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms

THE PROSTATE, Issue 14 2010
Keitaro Kojima
Abstract BACKGROUND Patients with hormone-refractory prostate cancer are treated with taxane drugs, but eventually become drug resistant. We aimed to elucidate the molecular mechanisms underlying paclitaxel resistance of hormone-refractory prostate cancer with a special focus on the roles of miR-34a and SIRT1. METHODS Paclitaxel-resistant cells (PC3PR) were generated from hormone-refractory PC3 cells. The expression levels of mRNA and miRNA were determined by reverse transcriptase PCR and those of protein were by Western blot analysis. Transfection of miRNA precursor or siRNA was performed using the liposome-mediated method. RESULTS MiR-34a over-expression and SIRT1 knockdown attenuated paclitaxel resistance of PC3PR cells. MiR-34a expression was reduced in PC3PR cells compared with PC3 cells, while the expression levels of HuR and Bcl2 as well as SIRT1 were elevated in PC3PR cells. Luciferase reporter assays revealed that both SIRT1 3,-UTR and promoter activities were higher in PC3PR cells than in PC3 cells. Introduction of miR-34a precursor into PC3PR cells resulted in decreases in HuR, Bcl2, and SIRT1 expression and inhibition of the SIRT1 3,-UTR activity. HuR knockdown reduced SIRT1 and Bcl2 expression. These results suggest that miR-34a not only directly but also indirectly via regulating HuR expression acts on the 3,-UTR of SIRT1 and Bcl2 mRNAs, thereby controlling their expression. Thus, in PC3PR cells, reduced expression of miR-34a confers paclitaxel resistance via up-regulating SIRT1 and Bcl2 expression. CONCLUSIONS MiR-34a and its downstream targets SIRT1 and Bcl2 play important roles in the development of paclitaxel resistance, all of which can be useful biomarkers and promising therapeutic targets for the drug resistance in hormone-refractory prostate cancer. Prostate 70: 1501,1512, 2010. © 2010 Wiley-Liss, Inc. [source]

Apoptosis regulators Fau and Bcl-G are down-regulated in prostate cancer

THE PROSTATE, Issue 14 2010
Mark R. Pickard
Abstract BACKGROUND The molecular control of cell death through apoptosis is compromised in prostate cancer cells, resulting in inappropriate cell survival and resistance to cytotoxic therapy. Reduced expression of the functionally connected apoptosis-regulators and candidate tumor suppressors Fau and Bcl-G has recently been implicated in oncogenesis in other tissues. The present study examines the hypothesis that reduced expression of these genes may be involved in prostate cancer. METHODS Fau and Bcl-G mRNA levels were determined by real time RT-PCR in two independent prostate tissue collections. In experiments in vitro, Fau and Bcl-G levels in prostate cancer cell lines were reduced using RNA interference and the effects on sensitivity to UVC irradiation were determined. RESULTS Fau and Bcl-G mRNA levels were both lower in prostate cancer tissue than in normal prostate and Benign Prostate Hyperplasia. Active down-regulation of Fau and Bcl-G expression in vitro resulted in decreased sensitivity to UVC-induced cytotoxicity. Simultaneous down-regulation of Fau and Bcl-G produced a decrease in sensitivity which was similar to either gene alone. CONCLUSIONS Fau and Bcl-G mRNA levels are both decreased in prostate cancer. In prostate cancer cell lines in vitro such down-regulation results in reduced sensitivity to UVC-induced cytotoxicity, consistent with the putative roles of these genes as candidate prostate tumor suppressors. The absence of an additive effect when Fau and Bcl-G were down-regulated simultaneously is consistent with the two genes acting in the same apoptosis pathway, for example, with the pro-apoptotic effects of Fau being mediated through modulation of Bcl-G. Prostate 70: 1513,1523, 2010. © 2010 Wiley-Liss, Inc. [source]

Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies

THE PROSTATE, Issue 13 2010
Mark Stein
Abstract BACKGROUND A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance. METHODS Patients received 2DG orally on days 1,14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance. RESULTS The dose of 45,mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60,mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45,µg/ml (277,µM), 73.7,µg/ml (449,µM), and 122,µg/ml (744,µM) in dose levels 30, 45, and 60,mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24,hr. CONCLUSIONS These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy. Prostate 70: 1388,1394, 2010. © 2010 Wiley-Liss, Inc. [source]

Serum prostate-specific antigen levels reflect the androgen milieu in patients with localized prostate cancer receiving androgen deprivation therapy: Tumor malignant potential and androgen milieu,,

THE PROSTATE, Issue 13 2010
Itsuhiro Takizawa
Abstract BACKGROUND Although androgen deprivation therapy (ADT) has a marked impact on the androgen milieu in vivo and outcomes of prostate cancer (PCa), it remains unclear which parameters reflect the androgen milieu during ADT or whether the milieu is associated with PCa aggressiveness. METHODS Seventy-two patients with localized PCa were prospectively studied based on their blood samples before and after ADT for 6 months. Serum androgens and related values were measured. RESULTS Before ADT, there was no correlation between the serum prostate-specific antigen (PSA) and androgen levels. After ADT, the serum PSA levels were correlated with each level of serum testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone-sulfate (DHEA-S), and 3alpha-diol G (P,<,0.010 in all). Before ADT, patients with Gleason score of ,8 were likely to have lower serum testosterone levels than those with Gleason score of ,6 (P,=,0.058). After ADT, conversely, the testosterone levels in patients with Gleason score of ,8 appeared to be higher than in those with Gleason score of ,6 (P,=,0.060). The serum DHEA-S level was correlated with Gleason score before and after ADT (P,=,0.050 and P,=,0.040, respectively). CONCLUSIONS The serum PSA levels well reflect the androgen milieu in localized PCa patients receiving ADT, which can be explained by the Saturation Model and disease control. The androgen milieu in men with high Gleason score PCa is probably less affected by conventional ADT than that in men with low score cancer, which was suggested to be associated with adrenal androgen levels. Prostate 70: 1395,1401, 2010. © 2010 Wiley-Liss, Inc. [source]

Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity

THE PROSTATE, Issue 12 2010
Kiran Mahajan
Abstract BACKGROUND Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known. METHODS We have generated two key resources, antibodies that specifically recognize pTyr267-AR and synthesized a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3-d]pyrimidine (named here as AIM-100) to test whether AIM-100 modulates ligand-independent AR activity and inhibits prostate cell growth. RESULTS Prostate tissue microarray analysis indicates that Ack1 Tyr284 phosphorylation correlates positively with disease progression and negatively with the survival of prostate cancer patients. Interestingly, neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens in activated Ack1 expressing or EGF stimulated prostate cells. However, the Ack1 inhibitor, AIM-100, not only inhibited Ack1 activation but also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity. CONCLUSION Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC. Prostate 70:1274,1285, 2010. © 2010 Wiley-Liss, Inc. [source]

Saporin toxin-conjugated monoclonal antibody targeting prostate-specific membrane antigen has potent anticancer activity

THE PROSTATE, Issue 12 2010
Kenji Kuroda
Abstract BACKGROUND Prostate-specific membrane antigen (PSMA) provides an attractive target for monoclonal antibody targeted therapies in the treatment of prostate cancer (PC). In this study, we generated an immunotoxin by linking a humanized anti-PSMA monoclonal antibody (hJ591) to the ribosome-inactivating protein toxin saporin. The hJ591,saporin immunoconjugate was evaluated for antitumor activity against PC cells. METHODS PSMA-positive cell lines, LNCaP and CWR22Rv1 and a PSMA-negative cell line, PC-3, were used in these experiments. The hJ591 was biotinylated and mixed with streptavidin,saporin (SAZAP). The binding ability of hJ591,SAZAP and the extent of internalization into the cells were tested. The viability of cells treated with hJ591,SAZAP was also examined and the apoptotic cells were measured. Lastly, the anticancer effect of hJ591,SAZAP was investigated in vivo. RESULTS The binding ability of hJ591,SAZAP to PSMA was equivalent to that of unconjugated J591. Internalization of hJ591,SAZAP was clearly detected in PSMA-positive, but not in PSMA-negative cell lines. IC50 of hJ591,SAZAP was 0.14,nM, 1.99,nM, and more than 100,nM in LNCaP, CWR22Rv1, and PC-3 cells, respectively. After 72,hr of hJ591,SAZAP treatment, the percentage of apoptotic cells was 60.29% and 40.73% in LNCaP and CWR22Rv1 cells, respectively, compared to 4.70% in PC-3 cells. The hJ591,SAZAP also had anticancer activity in a LNCaP xenograft model. CONCLUSIONS Our findings show that hJ591,SAZAP conjugate has potent and selective antitumor effects on PSMA-positive PC cells in vitro and in vivo. This study supports development of PSMA antibody,toxin conjugates for therapy of PC. Prostate 70:1286,1294, 2010. © 2010 Wiley-Liss, Inc. [source]

5-azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors

THE PROSTATE, Issue 11 2010
Giovanni Luca Gravina
Abstract BACKGROUND Epigenetic modifications play a key role in the in prostate cancer (Pca) progression to a hormone refractory state (HRPC) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. In this regard, 5-Azacitine (5-Aza) represents a promising epigenetic modulator. This study tested the hypothesis that 5-Aza may restore and enhance the responsiveness of HRPC cells to anti-hormonal therapy on Androgen receptor (AR) expressing (22rv1) and AR-deficient (PC3) cells. METHODS The effects were studied in vitro and in vivo models. This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines. RESULTS This combined treatment up-regulated the expression of FasL, phospho-FADD, p16INKA, Bax, Bak, and p21WAF1, and inhibited FLIP, Bcl-2, and Bcl-XL expression. The re-activation of hormonal response of AR-negative PC3 cell line was partially due to the AR re-expression mediated by 5-Aza treatment. In contrast, the increase in the response to anti-androgenic therapy in 22rv1 did not correlate with AR expression levels. Furthermore, xenograft studies revealed that the combined treatment of 5-Aza with AR-antagonist Bicalutamide had additive/synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis. CONCLUSIONS So, this study strongly suggests a therapeutic potential of 5-Aza in combination with anti-androgen therapy in patients with in AR expressing and AR-deficient HRPC. Prostate 70: 1166,1178, 2010. © 2010 Wiley-Liss, Inc. [source]

Survivin mediates prostate cell protection by HIF-1, against zinc toxicity

THE PROSTATE, Issue 11 2010
Young-Joo Yun
Abstract BACKGROUND The prostate contains extremely high concentrations of zinc, but survives and grows without apparent injury. This begs the question as to how prostate cells avoid the toxic effects of zinc. In a previous study, the authors found that; HIF-1, is expressed concomitantly with the accumulation of zinc in the epithelial cells of normal rat prostates, the zinc ion stabilizes HIF-1, in prostate cells, and that HIF-1, protects prostate cells from zinc toxicity. In the present study, the authors addressed the mechanism responsible for the protective effect of HIF-1, in a high zinc environment. METHODS Immunofluorescent staining, immunoblotting, reverse transcription-polymerase chain reaction, reporter assay, and cell cycle analysis. RESULTS Survivin was induced by ZnCl2 in a HIF-1 dependent manner in both DU-145 and PNT2 prostate cells. Furthermore, HIF-1 induced survivin expression at the transcriptional level and the induction of survivin was abolished by HIF-1, knock-down. In addition, HIF-1-dependent survivin overexpression promoted prostrate cell survival and prevented cell arrest in the presence of high zinc concentrations, and si-survivin transfected cells under zinc rich conditions contained markedly higher levels of cleaved caspase-9 and PARP than si-con transfected cells. Finally, survivin expression patterns well matched rat prostate proliferation statuses. CONCLUSION Under zinc rich conditions, prostate epithelial cells HIF-1-dependently express survivin, which promotes prostate cell proliferation, and prevents apoptosis and cell cycle arrest. Accordingly, the HIF-1,-survivin pathway appears to facilitate prostate cell survival and growth in zinc rich environments, and this pathway could be a therapeutic target for the treatment of prostate hyperplasia. Prostate 70: 1179,1188, 2010. © 2010 Wiley-Liss, Inc. [source]

Antiproliferative and apoptotic effects of the herbal agent Pygeum africanum on cultured prostate stromal cells from patients with benign prostatic hyperplasia (BPH) ,,

THE PROSTATE, Issue 10 2010
Maria T. Quiles
Abstract BACKGROUND Previous reports show that the herbal agent Pygeum africanum (PA) used to treat benign prostatic hyperplasia (BPH) inhibits proliferation of prostate stromal cells from BPH tissues. To determine underlying mechanisms, we compared proliferative and apoptotic responses to PA between BPH and non-BPH prostate stromal cells with a focus on the specific reaction displayed by stromal cell subsets. An interaction of PA with growth factors and hormones was also investigated. METHODS Primary prostate stromal cells from BPH/LUTS patients undergoing open prostatectomy (n,=,3) and patients without benign prostatic hyperplasia (BPH) undergoing cystectomy (n,=,3) were treated with PA. Cells were characterized by immunofluorescence. Sensitivity to PA was determined using proliferation assays. Apoptosis, transforming growth factor B1 (TGFB1), fibroblast growth factor 2 (FGF2), vimentin, , smooth muscle actin (,SMA), and smoothelin expression were examined after PA treatment. Cell immunophenotype and proliferation were tested after incubating cells with PA plus either FGF2, TGFB1, vascular endothelial growth factor (VEGF), dihydrotestosterone (DHT) or 17,-estradiol (E2). RESULTS Antiproliferative potency and apoptosis induced by PA on stromal cells were increased in BPH versus non-BPH cells. Apoptosis targeted ,SMA+ cells, more abundant in BPH cells. Downregulation of TGFB1 expression was induced by PA. FGF2 increased cells sensitivity to PA. Incubation with other mitogenic factors like VEGF, DHT, and E2 decreased sensitivity to PA. Both TGFB1 and E2 blocked the antiproliferative activity of PA. CONCLUSIONS Results suggest that PA is antiproliferative and apoptotic on proliferative prostate fibroblasts and myofibroblasts but not on smooth muscle cells. Mechanisms of action include TGFB1 downregulation and inhibition of FGF2 specific signaling. Prostate 70: 1044,1053, 2010. © 2010 Wiley-Liss, Inc. [source]

Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: A case,control study

THE PROSTATE, Issue 10 2010
Sara Raimondi
Abstract BACKGROUND Despite the prevalence of prostate cancer worldwide, only a few risk factors have been well-established. The role of diet, especially of dairy products, in the etiology of prostate cancer is still controversial. METHODS This study assessed the association of dietary components, particularly dairy products and dietary calcium, on prostate cancer risk in a case,control study of 197 cases and an equal number of individually matched controls recruited in Montreal, Canada. A semi-quantitative food frequency questionnaire was administered in which the usual consumption frequency and amounts consumed of more than 200 food items were recorded. RESULTS We found a twofold increased risk of prostate cancer associated with an increased intake of dairy products {Odds Ratio (OR),=,2.19; 95% Confidence Intervals (CI) 1.22,3.94}. A significant trend of decreasing prostate cancer risk with higher intake was found for legumes, nuts, finfish/shellfish and for ,-tocopherol after adjustment for calcium intake. Milk was the only dairy product significantly associated with prostate cancer risk, with OR,=,2.27; 95% CI (1.25,4.09) for the highest versus lowest quartiles of consumption. Calcium, the main micronutrient contained in dairy products, showed only a borderline association with prostate cancer risk (P,=,0.09), with slightly higher risk for higher calcium intake. In conclusion, this study supports the hypothesis that dairy products, especially milk, are involved in the etiology of prostate cancer. However, the mechanisms by which the various nutrients in dairy products and total diet may interact to influence this risk remain unknown. Prostate 70: 1054,1065, 2010. © 2010 Wiley-Liss, Inc. [source]

Characterization of cis elements of the probasin promoter necessary for prostate-specific gene expression,

THE PROSTATE, Issue 9 2010
JianFeng Zhang
Abstract BACKGROUND The androgen-regulated probasin (PB) promoter has been used extensively to target transgenes to the prostate in transgenic mice; however, limited data exist on the mechanism that dictates prostate-specific gene expression. Tissue-specific gene expression involves synergistic effects among transcription factors associated in a complex bound to cis -acting DNA elements. METHODS Using comprehensive linker scan mutagenesis, enzyme mobility shift and supershift assays, chromatin immunoprecipitation, and transgenic animal studies, we have extensively characterized the prostate-specific PB promoter. RESULTS We identified a series of nonreceptor transcription factors that are bound to the prostate-specific rat PB promoter. These factors include several ubiquitously distributed proteins known to participate in steroid receptor-mediated transcription. In addition, we identified two tissue-specific DNA elements that are crucial in directing prostate-specific PB expression, and confirmed the functional importance of both elements in transgenic animal studies. These two elements are functionally interchangeable and can be bound by multiple protein complexes, including the forkhead transcription factor FoxA1, a "pioneer factor" that has a restricted distribution to some cells type that are ectoderm and endoderm in origin. Using transgenic mice, we further demonstrate that the minimal PB promoter region (,244/,96,bp) that encompasses these tissue-specific elements results in prostate-specific gene expression in transgenic mice, contains androgen receptor and FoxA1-binding sites, as well as ubiquitous transcription factor binding sites. CONCLUSION We propose that these sequence-specific DNA-binding proteins, including tissue-restricted and ubiquitous factors, create the first level of transcriptional control, which responds to intracellular pathways that directs prostate-specific gene expression. Prostate 70: 934,951, 2010. © 2010 Wiley-Liss, Inc. [source]

Uro-words making history: Ureter and urethra

THE PROSTATE, Issue 9 2010
Franz Josef Marx
Abstract PURPOSE We comprehensively review the history of the terms "ureter" and "urethra" from 700 BC to the present. MATERIALS AND METHODS Using a case study approach, ancient medical texts were analyzed to clarify the etymology and use of both terms. In addition, selected anatomy textbooks from the 15th to 17th centuries were searched to identify and compare descriptions, illustrations, and various expressions used by contemporary authors to designate the upper and lower parts of the urinary tract. RESULTS The Ancient Greek words "ureter" and "urethra" appear early in Hippocratic and Aristotelian writings. However, both terms designated what we today call the urethra. It was only with increasing anatomical knowledge in Greek medical texts after the 1st century AD that definitions of these words evolved similar to those we employ today. Numerous synonyms were used which served as a basis for translation into Arabic and later Latin during the transfer of ancient knowledge to the cultures of the medieval period. When Greek original texts and their Arabic,Latin version were compared during the Renaissance, this led to terminological confusion which could only be gradually overcome. Around the year 1600, the use of the latinized terms "ureter" and "urethra" became generally accepted. The dissemination of these terms in modern national languages and the emergence of clinical derivatives complete this historical development. CONCLUSIONS The history of the terms "ureter" and "urethra" is exemplary of the difficulties with which the development of a precise urologic terminology had to struggle. The story behind the words also clarifies why even today we still have imprecise or misleading terms. Prostate 70: 952,958, 2010. © 2010 Wiley-Liss, Inc. [source]

Expression of toll-like receptor-9 is increased in poorly differentiated prostate tumors,

THE PROSTATE, Issue 8 2010
Marja-Riitta Väisänen
Abstract BACKGROUND Toll-like receptor-9 (TLR9) is a cellular receptor for bacterial and vertebrate DNA. In addition to cells of the immune system, it is also expressed in various human cancer cell lines, including prostate cancer. We demonstrated previously that synthetic TLR9 ligands induce matrix metalloproteinase-13-mediated invasion in TLR9-expressing prostate cancer cells in vitro. Other studies have suggested possible sex steroid regulation of the function of the various TLRs. The role of TLR9 in the pathophysiology of prostate or any cancer is, however, unknown. METHODS Expression of TLR9, androgen receptor (AR), or the estrogen receptors , (ER,) and , (ER,) were studied with immunohistochemistry in prostate cancer (n,=,62) and benign prostatic hyperplasia (n,=,45) specimens. TLR9 staining scores were compared with tumor stage, Gleason score, prostate-specific antigen (PSA) concentrations before tissue sampling and with the staining scores of AR, ER,, and ER,. RESULTS TLR9 expression was statistically significantly increased in prostate cancer epithelium and stroma, as compared with the same cellular compartments in benign hyperplasia. Significantly increased (P,=,0.04) TLR9 expression was detected in cancers with high Gleason score (>7, n,=,23), as compared with lower Gleason scores (,7, n,=,39). No statistically significant associations were detected between TLR9 expression scores and PSA concentrations or tumor staging. Prostate adenocarcinoma cells were all positive for TLR9, AR, and ER, but negative for ER, expression. In cancer stroma cells, increased TLR9 expression was associated with increased ER, expression. CONCLUSIONS Expression of TLR9 is increased in prostate cancer specimens, especially in the most poorly differentiated forms. Prostate 70: 817,824, 2010. © 2010 Wiley-Liss, Inc. [source]

New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer

THE PROSTATE, Issue 8 2010
Bulbul Pandit
Abstract BACKGROUND We previously described the identification of a transcriptional inhibitor ARC and FoxM1 inhibitors, thiazole antibiotics, Siomycin A and thiostrepton that were able to induce potent p53-independent apoptosis in cancer cell lines of different origin. Here, we report the characterization of these drugs individually or in combination with ABT-737 and bortezomib on a panel of prostate cancer cell lines. METHODS DU 145, LNCaP and PC-3 prostate cancer cells were treated with ARC, Siomycin A and thiostrepton to evaluate their activity as single agents or in combination with ABT-737 and bortezomib to measure their synergistic potential in anti-proliferative and cell cycle assays. Chou-Talalay method was used to quantitate the synergistic interaction. Western blot method was used to determine Mcl-1 and FoxM1 expression and caspase-3 cleavage. RESULTS We show that ARC inhibited the viability of prostate cancer cells and induced apoptosis in low nanomolar concentration. It potently downregulated the expression of Mcl-1 and showed synergistic combination effect with Bcl-2 inhibitor ABT-737. Thiazole antibiotics, Siomycin A and thiostrepton inhibited growth, FoxM1 expression and induced cell death in prostate cancer cells in low micromolar concentrations. In addition, thiostrepton and ARC synergistically induced apoptosis in prostate cancer cells following combination treatment with proteasome inhibitor bortezomib. Furthermore, we found that all tested drug combinations were able to induce apoptosis selectively in transformed, but not normal cells of the same origin. CONCLUSIONS Based on their in vitro activity as single or combination agents, ARC, Siomycin A and thiostrepton represent potential candidates for drug development against prostate cancer. Prostate 70: 825,833, 2010. © 2010 Wiley-Liss, Inc. [source]

Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin

THE PROSTATE, Issue 8 2010
Adil A. Babiker
Abstract BACKGROUND Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium. Prostate 70: 834,847, 2010. © 2010 Wiley-Liss, Inc. [source]

Controversies in the treatment of high-risk prostate cancer,what is the optimal combination of hormonal therapy and radiotherapy: a review of literature,

THE PROSTATE, Issue 7 2010
Abrahim Al-Mamgani
Abstract BACKGROUND In high-risk prostate carcinoma, there is controversy whether these patients should be treated with escalated-dose (,74 Gy) or conventional-dose radiotherapy (<74 Gy) combined with hormonal therapy. Furthermore, the issue of the optimal duration and timing of hormonal therapy are not well crystallized. PATIENTS AND METHODS A search for evidence from randomized- and large non-randomized studies in order to address these issues, was therefore initiated. For this purpose, MedLine, EMbase, and PubMed and the data base of the Dutch randomized dose-escalation trial, were consulted. RESULTS AND CONCLUSIONS From this search it was concluded that the benefit of hormonal therapy in combination with conventional-dose radiotherapy (<74 Gy) in high-risk prostate cancer is evident (Level 2 evidence); Levels 2 and 3 evidence were provided by several studies supporting the use of escalated-dose radiotherapy in high-risk prostate cancer. For the combination of hormonal therapy with escalated-dose radiotherapy in these patients, there is Level 2 evidence for moderately escalated dose (74 Gy) and high escalated dose (,78 Gy). The optimal duration and timing of hormonal therapy are not well defined. More randomized-controlled trials and meta-analyses are therefore needed to clearly determine the independent role of dose-escalation in high-risk patients treated with hormonal therapy and the optimal duration and timing of hormonal therapy. Prostate 70: 701,709, 2010. © 2009 Wiley-Liss, Inc. [source]

ELL is an HIF-1, partner that regulates and responds to hypoxia response in PC3 cells

THE PROSTATE, Issue 7 2010
Lingqi Liu
Abstract BACKGROUND Eleven,nineteen lysine-rich leukemia (ELL) plays an important role in tumorigenesis and animal development. HIF-1 is a transcriptional factor that functions as a master regulator of O2 homeostasis. Our previous studies showed that a binding partner of ELL, U19/Eaf2, can modulate HIF-1, activity and hypoxia response, suggesting that ELL may also influence HIF-1, pathway and hypoxia response. METHODS Co-localization and co-immunoprecipitation were performed to test the interaction between ELL and HIF-1,. PC3 cells with stable ELL knockdown and PC3 cells with stable ELL overexpression, along with their controls, were established using lentiviral expression system. Western blot and real-time PCR were performed to test the effect of ELL on HIF-1, protein and its down-stream gene transcription. To elucidate potential effect of hypoxia on ELL, cell growth and colony formation assays were performed using PC3 subline with stable ELL overexpression. RESULTS ELL is associated with HIF-1, in transfected cells. In PC3 prostate cancer cells, ELL inhibited HIF-1, protein level and down-stream gene expression. As expected, ELL inhibited cell growth and colony formation under normoxia. Interestingly, the inhibition was alleviated under hypoxia. CONCLUSIONS Our findings suggest that ELL and HIF-1, are binding partners and can modulate the functions of each other in hypoxia. Prostate 70: 797,805, 2010. © 2010 Wiley-Liss, Inc. [source]

Downmodulation of Bcl-2 sensitizes metastatic LNCaP-LN3 cells to undergo apoptosis via the intrinsic pathway

THE PROSTATE, Issue 6 2010
Renduo Song
Abstract BACKGROUND We explored the mechanisms of apoptosis after Bcl-2 protein downmodulation in metastatic LNCaP-LN3 cells (LN3). METHODS LNCaP, LNCaP-Pro5 (Pro5) and LN3 cells were cultured in 5% charcoal-stripped serum (CSS) or in R1881 (synthetic androgen) and bicalutamide (synthetic anti-androgen) and growth inhibition was assessed. Expression levels of androgen receptor (AR) and Bcl-2 were determined. LN3 cells were transfected with small interfering RNA Bcl-2 (siRNA Bcl-2) or control siRNA oligonucleotides. Rates of apoptosis and proliferation were obtained. Cytochrome c localization in treated and control cells was assessed,±,cyclosporine A (CsA). Caspases 9, 3, and poly (ADP-ribose) polymerase cleavage (PARP) were measured upon downmodulation of Bcl-2; and cell growth inhibition in vitro after Bcl-2 modulation combined with docetaxel chemotherapy was determined. RESULTS LN3 cells maintained growth under castrate conditions in vitro. AR protein amplification did not explain castrate-resistant LN3 cell growth. Bcl-2 protein levels in LN3 cells were significantly higher than in Pro5 cells, and were effectively downmodulated by siRNA Bcl-2. Subsequently increased apoptosis and decreased proliferation mediated by cytochrome c was noted and this was reversed by CsA. siRNA Bcl-2-transfected LN3 cells exhibited elevated levels of caspases 9, 3, and PARP cleavage. Exposure of LN3 cells to docetaxel led to increased apoptosis, and simultaneous downmodulation of Bcl-2 substantially enhanced this effect. CONCLUSIONS Downmodulation of Bcl-2 in metastatic castrate-resistant LNCaP-LN3 cells led to apoptosis via a cytochrome c -dependent pathway that was enhanced with docetaxel treatment. Prostate 70: 571,583, 2010. © 2009 Wiley-Liss, Inc. [source]

Androgen receptor CAG repeat length is not associated with the risk of incident symptomatic benign prostatic hyperplasia: Results from the prostate cancer prevention trial

THE PROSTATE, Issue 6 2010
Alan R. Kristal
Abstract BACKGROUND To examine whether androgen receptor (AR) CAG repeat length was associated with the risk of incident benign prostatic hyperplasia (BPH). METHODS A nested case-control study of 416 BPH cases and 527 controls drawn from Prostate Cancer Prevention Trial placebo-arm participants who were free of BPH at baseline. BPH was assessed over 7 years and was defined as receipt of medical or surgical treatment, two scores > 14 on the International Prostate Symptom Score (IPSS), or two increases in IPSS , 5 with at least one score , 12. RESULTS Compared to men with AR repeat length , 19, the covariate-adjusted odds ratios [95% CI] were 1.07 [0.73, 1.57] and 0.90 [0.55, 1.45]) for repeat length 20,24 and ,25, respectively. There was a weak association of AR repeat length with baseline serum testosterone (T) (Spearman r = 0.09, p < 0.02); however, control for or stratification by T did not change study results. Further, results did not differ when stratified by body mass index or baseline concentration of 3,-diol glucoronide, and were similar for all BPH definitions. CONCLUSIONS There were no associations of AR CAG repeat length and BPH risk. Knowledge of AR CAG repeat length provides no clinical useful information for the prevention of symptomatic BPH. Prostate 70: 584,590, 2010. © 2009 Wiley-Liss, Inc. [source]

Hepsin cooperates with MYC in the progression of adenocarcinoma in a prostate cancer mouse model

THE PROSTATE, Issue 6 2010
Srinivas Nandana
Abstract BACKGROUND Hepsin is a cell surface protease that is over-expressed in more than 90% of human prostate cancer cases. The previously developed Probasin-hepsin/Large Probasin-T antigen (PB-hepsin/LPB-Tag) bigenic mouse model of prostate cancer demonstrates that hepsin promotes primary tumors that are a mixture of adenocarcinoma and neuroendocrine (NE) lesions, and metastases that are NE in nature. However, since the majority of human prostate tumors are adenocarcinomas, the contribution of hepsin in the progression of adenocarcinoma requires further investigation. METHODS We crossed the PB-hepsin mice with PB-Hi-myc transgenic mouse model of prostate adenocarcinoma and characterized the tumor progression in the resulting PB-hepsin/PB-Hi-myc bigenic mice. RESULTS We report that PB-hepsin/PB-Hi-myc bigenic mice develop invasive adenocarcinoma at 4.5 months. Further, histological analysis of the 12- to 17-month-old mice revealed that the PB-hepsin/PB-Hi-myc model develops a higher grade adenocarcinoma compared with age-matched tumors expressing only PB-Hi-myc. Consistent with targeting hepsin to the prostate, the PB-hepsin/PB-Hi-myc tumors showed higher hepsin expression as compared to the age-matched myc tumors. Furthermore, endogenous expression of hepsin increased in the PB-Hi-myc mice as the tumors progressed. CONCLUSIONS Although we did not detect any metastases from the prostates in either the PB-hepsin/PB-Hi-myc or the PB-Hi-myc mice, our data suggests that hepsin and myc cooperate during the progression to high-grade prostatic adenocarcinoma. Prostate 70: 591,600, 2010. © 2009 Wiley-Liss, Inc. [source]