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PubMed2004

Defective DNA strand break repair after DNA damage in prostate cancer cells: implications for genetic instability and prostate cancer progression.

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.

Animals↗
PubMed2006

Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D.

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor alpha-stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D.

Calcitriol↗
PubMed2005

Prostate stem cell antigen is overexpressed in prostate cancer metastases.

PURPOSE: Prostate stem cell antigen (PSCA) is expressed by a majority of prostate cancers and is a promising therapeutic target. PSCA protein and mRNA expression was examined in prostate cancer bone, lymph node, and visceral metastases to assess the potential of PSCA as an immunotherapeutic target in advanced prostate cancer. EXPERIMENTAL DESIGN: Immunohistochemical analysis of PSCA protein expression and quantitative mRNA expression analysis of PSCA was done on clinical specimens of prostate cancer bone, lymph node, and visceral metastases. PSCA protein and mRNA expression levels were quantified and compared between available matched pairs of bone and lymph node or visceral metastases. RESULTS: Bone metastases stained with higher intensity of PSCA compared with lymph node or liver metastases in seven of eight (87.5%) matched pairs (P = 0.035). PSCA mRNA expression was equal or greater than that of LAPC-9, a PSCA expressing xenograft, in 12 of 24 (50%) cases of prostate cancer metastases and was significantly correlated with PSCA protein expression (sigma = 0.84, P = 0.0019). Overall, PSCA protein expression was detected in 41 of 47 (87.2%), four of six (66.7%), and two of three (66.7%) cases of bone, lymph node, and liver metastases, respectively. Mean PSCA staining intensity was significantly higher in prostate cancer bone metastases compared with lymph node metastases (2.0 +/- 0.02 versus 0.83 +/- 0.31, P = 0.014). CONCLUSIONS: Prostate cancer metastases express PSCA. However, greater PSCA staining intensity and level of PSCA mRNA expression was associated with bone metastases compared with lymph node metastases. This study suggests that PSCA is a promising tumor marker and potential therapeutic target for patients with metastatic prostate cancer.

Antigens, Neoplasm↗
PubMed1997

Effects of steroid 5alpha-reductase inhibitor ONO-9302 and anti-androgen allylestrenol on the prostatic growth, and plasma and prostatic hormone levels in rats.

ONO-9302 [epristeride; (-)-17beta-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxy lic acid] is a novel inhibitor of steroid 5alpha-reductase. We studied in vitro and in vivo effects of ONO-9302 on the rat prostatic tissue in comparison with those of the anti-androgen allylestrenol. ONO-9302 inhibited the rat prostatic enzyme with an IC50 value of 11 nM, whereas allylestrenol was about 80,000-fold less potent. The growth of ventral prostate, which was induced by the subcutaneous injection of testosterone propionate in the castrated rats, was significantly reduced by ONO-9302 at oral doses of 1-100 mg/kg/day. Allylestrenol showed a significant effect only at a dose of 100 mg/kg/day. In mature male rats, ONO-9302 significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day and decreased prostatic 5alpha-dihydrotestosterone (DHT) content associated with a rise in testosterone (T) content at doses of 0.1-100 mg/kg/day. Plasma hormone levels (i.e., T, DHT, luteinizing hormone (LH) and follicle stimulating hormone (FSH)) were not altered significantly. Allylestrenol significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day. However, unlike ONO-9302, allylestrenol reduced both the prostatic DHT and T contents and also lowered plasma T, DHT, LH and FSH levels at a dose of 30 mg/kg/day. These results suggest that ONO-9302 reduces the prostatic growth by inhibiting the conversion of T to DHT in the prostate without lowering blood T level unlike anti-androgen drugs.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

[Prevalence of incidental prostatic adenocarcinoma after suprapubic adenomectomy with or without previous prostatic biopsy].

OBJECTIVES: To establish the prevalence of incidental prostate cancer after transrectal ultrasound guided prostatic biopsy and subsequent suprapubic prostatic adenomectomy and to compare it with a similar group of patients who did not underwent biopsy before surgery. To evaluate treatment, outcomes, and disease progression in patients with incidental prostate cancer. METHODS: Retrospective study of 549 suprapubic adenomectomy performed between 1996-2001 (6 yr.), comparing the group of patients with biopsies before surgery vs. the group of patients without biopsies. RESULTS: 291 (53%) patients did not undergo biopsy before adenomectomy. 258 (47%) underwent biopsies. 25 incidental prostate cancers were detected, 19 (76%) in the group of no biopsy and 6 (24%) in the biopsy group. 88% pT1a and 12%pT1b. Mean Gleason score 4.5 (3-7). 84% of the patients did not receive treatment (21) ("wait and see"); 8% (2) androgen blockade; 8% (2) finasteride (2). Three patients (12%) in the group of no biopsy had disease progression. Mean follow-up was 48.1 months (22-96). No case of cancer-specific mortality was detected. CONCLUSIONS: Global prevalence of incidental prostate cancer in our series of patients undergoing suprapubic prostatic adenomectomy was 4.55%. Prevalence was higher in the group of patients without previous biopsy (3.46%) than in the biopsy group (1.09%). Tumor progression was 12% and cancer specific survival 100% after a mean follow-up of 48.1 months (22-92). Previous prostatic biopsy in patients with suspicions digital rectal examination or elevated PSA diminishes the prevalence of incidental prostate cancer. Watchful waiting may be a valid option in some cases.

Adenocarcinoma↗
PubMed2006

[Photoselective vaporization of the prostate (PVP) using 80 watt high power potassium-titanyl-phosphate (KTP) laser for benign prostatic hyperplasia: the first fifty-seven patients in Japan].

OBJECTIVE: To assess the safety and efficacy of photoselective vaporization of the prostate (PVP) using 80 watt high power potassium-titanyl-phosphate (KTP) laser for benign prostatic hyperplasia (BPH). METHODS: Fifty-seven patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia underwent 80 W KTP laser vaporization of the prostate. According to their International Prostate Symptom Score Index (IPSS) and Quality of life (QOL) score as well as measurements of their peak flow rate and postvoiding residual urine volume (RUV), they fulfilled the diagnostic criteria of BPH. Vaporization was performed with the GreenLight PV ADDStat fiber, which was inserted through a 22.5Fr. continuous flow laser cystoscope, and a saline solution was used for irrigation. KTP laser energy was generated by a GreenLight PV (Minnetonka, Minnesota) generator. The end point of the procedure was to create a cavity like in TURP. Once vaporization was completed, an18Fr Foley catheter was inserted and was removed the next morning, as a rule. Patients were evaluated preoperatively, and at 2 weeks and 1, 3 and 6 months postoperatively. RESULTS: The procedure could be performed without any intraoperative complication. None of the patients required continuous bladder irrigation or blood transfusion postoperatively. The mean age was 71.0 +/- 8.3 years (range 52 to 86). The preoperative prostate volume was 41.0 +/- 24.9 (mean +/- SD, range 6.7 to 107.2) and the preoperative serum PSA was 4.5 +/- 4.1 ng/ml. Preoperative and immediate postoperative serum sodium concentration was 141.9 +/- 1.8 mEq/L and 142.2 +/- 1.8 mEq/L, respectively (p = 0.23). The hemoglobin value changed from 14.0 +/- 1.4 mg/dl preoperatively to 13.4 +/- 1.4 mg/dl postoperatively. The operating time was 68.3 +/- 35.0 minutes (range 21 to 170) and total laser energy was 171.1 +/- 80.3 kJ (range 18.1 to 484.8). The catheter indwelling time was 18.6 +/- 3.3 hrs (range 15 to 48). At 2 weeks and 1, 3 and 6 months the International Prostate Symptom Score decreased from 20.2 +/- 8.9 to 11.4 +/- 7.8, 9.3 +/- 6.0, 6.6 +/- 5.0 and 6.1 +/- 5.0, respectively. The maximum urinary flow increased from 7.2 +/- 2.9 mL/s to 13.6 +/- 7.6, 12.2 +/- 6.1, 15.3 +/- 7.4, and 15.3 +/- 7.5 mL/s, respectively. CONCLUSIONS: Photoselective vaporization of the prostate (PVP) using the high power (80 W) potassium-titanyl-phosphate laser for benign prostatic hyperplasia (BPH) proved to be an effective and safe procedure for our patients.

Aged↗
PubMed1999

Human prostate-specific transglutaminase: a new prostatic marker with a unique distribution pattern.

Human prostate-specific transglutaminase (hTGp) is a cross-linking enzyme, the physiologic function of which has not been established unequivocally yet. To gain insight into its distribution, we raised antisera against hTGp. By using Western blotting analysis, we found that these antisera specifically recognize a 77-kDa protein in prostatic fluids, seminal plasmas, and prostatic tissues. The concentrations of hTGp in these fluids and tissues were found to be highly variable among individuals. Immunohistochemical examination of several formalin-fixed paraffin-embedded human tissues revealed an exclusive expression in the prostate. The histologic localization and distribution of hTGp within the prostate was assessed by studying multiple sections from tumor-containing prostatectomy specimens and needle biopsies. hTGp expression was entirely restricted to luminal epithelial cells. No basal epithelial cells or stromal cells were stained. Within the prostate, large areas without any hTGp-positive cells were seen. Immunopositive cells were present either in a scattered pattern or concentrated in single or multiple glands in which all luminal epithelial cells expressed hTGp. The latter staining pattern occurred frequently, but not exclusively, in the peripheral zone, whereas scattered expression was most often observed in the transitional zone. Expression of the hTGp protein could occasionally be observed in high-grade prostatic intraepithelial neoplasia, but was not detected in prostate carcinoma cells. The expression pattern as observed for hTGp has not been found thus far for any other prostate-specific marker.

Androgen-Binding Protein↗
PubMed1999

Identification of an activin-follistatin growth modulatory system in the human prostate: secretion and biological activity in primary cultures of prostatic epithelial cells.

PURPOSE: To determine if the activin/follistatin system is present in human prostate tissue and primary cultures of prostatic epithelium and if these growth factors play a role in the control of epithelial cell growth. MATERIALS AND METHODS: Cells derived directly from human prostates were studied to determine: a) if they secrete activin and follistatin, and b) if they are growth inhibited by activin. Primary cell cultures were established from tissues removed from 13 unselected prostate carcinoma patients in order to examine the secretion of activin and follistatin and test the effects of these proteins on cell proliferation. RESULTS: Both primary explant cells and epithelial cells isolated and sub-cultured from explant cultures secreted activin A and follistatin. Treatment of cultured cells with recombinant human activin A resulted in a dose-dependent inhibition of thymidine incorporation, with an IC50 of 0.22 nM. Recombinant follistatin neutralized the inhibitory effects of activin A on cell proliferation whilst adding follistatin alone enhanced thymidine incorporation, suggesting a similar neutralizing effect on the endogenous activin produced by these cells. CONCLUSION: These results demonstrate that cells derived from human prostate tissue secrete activin and follistatin and, as observed in human prostate cancer cell lines, activin inhibited the growth of prostatic epithelial cells. Also consistent with our earlier studies of prostate cancer cell lines, the biological activity of activin was neutralized by follistatin. These observations support the hypothesis that the activin/follistatin system plays an important role in the local regulation of human prostate cell growth.

Activins↗
PubMed2000

The clinical burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model.

OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model's forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model's estimates of 96%, 92% and 84%. We also compared the model's forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model's estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.

Adult↗
PubMed2000

The economic burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model.

BACKGROUND: We developed an economic model of prostate cancer management from diagnosis until death. We have used the Montreal Prostate Cancer Model to estimate the total economic burden of the disease in a cohort of Canadian men. METHODS: Using this Markov state-transition simulation model, we estimated the probability of prostate cancer, annual prostate cancer progression rates and associated direct medical costs according to patient age, tumour stage and grade, and treatment modalities in a 1997 cohort of Canadian men. The estimated lifetime costs of prostate cancer included the costs of clinical staging, initial treatments and complications, follow-up cancer therapies, routine outpatient care, and palliative care following metastatic disease. RESULTS: The clinical burden of prostate cancer forecasted using the model was similar to the projections of the National Cancer Institute. In the 1997 cohort of 5.8 million Canadian men between 40 and 80 years old, prostate cancer would be diagnosed in an estimated 701,491 men (12.1%) over their lifetime. Direct medical costs would total $9.76 billion, or $3.89 billion when discounted 5% annually. INTERPRETATION: The Montreal Prostate Cancer Model indicates that the economic burden of prostate cancer to Canada's health care system will be substantial. Further analyses are needed to identify the most efficient means of treating this disease.

Adult↗
PubMed2000

Determination of transition zone volume by transrectal ultrasound in patients with clinically benign prostatic hyperplasia: agreement with enucleated prostate adenoma weight.

PURPOSE: Accurately estimating transition zone volume is important for the medical or surgical management of symptomatic benign prostatic hyperplasia and determination of prostate specific antigen density of the transition zone. We evaluated whether preoperative transrectal ultrasound measurements of the transition zone predict enucleated adenoma weight. MATERIALS AND METHODS: We measured transition zone volume preoperatively using transrectal ultrasound and the prolate ellipsoid method in 50 patients with presumed benign prostatic hyperplasia who underwent suprapubic prostatectomy. Transition zone volume corresponds to the adenoma. Enucleated adenoma weight was then correlated with preoperatively determined transition zone volume. RESULTS: As measured by transrectal ultrasound, mean transition zone volume plus or minus standard deviation was 80.88 +/- 37.42 cc (range 31 to 200). Mean enucleated adenoma weight was 68.70 +/- 36.26 gm. (range 18 to 180). There was a statistically significant correlation of estimated transrectal ultrasound volume of the transition zone with enucleated prostate adenoma weight (r = 0.95, p <0.001). However, when prostate adenoma weight was determined using the formula, prostate adenoma weight = -6.00 + 0.92 x transition zone volume, we noted a significant difference in mean prostate adenoma weight and mean transition zone volume (p <0.001). Since the regression coefficient of transition zone volume was significantly different from 1, we identified no agreement of prostate adenoma weight with estimated transrectal ultrasound volume of the transition zone. CONCLUSIONS: These data reveal a significant difference in mean prostatic adenoma weight and mean transition zone volume. Although transition zone volume measurements are well described, clear agreements on such measurements should be obtained to determine transition zone volume more precisely.

Aged↗
PubMed2001

Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer.

Zinc alpha-2-glycoprotein (ZAG) is a M(r) 41,000 glycoprotein secreted by a variety of normal epithelia. ZAG was recently shown to stimulate lipolysis in adipocytes, leading to the development of cachexia in animals with ZAG-producing tumors. To understand the possible contribution of ZAG to the development of cachexia in men with prostate cancer, ZAG production by normal and malignant prostate tissue was investigated using immunohistochemical assays. Anti-ZAG monoclonal antibodies reacted strongly with normal prostate epithelium but not with other components of prostate or seminal vesicles. The majority of prostate cancers tested (35 of 48; 73%) also reacted with anti-ZAG antibodies. High-grade tumors expressed significantly less ZAG than moderate-grade tumors (mean ZAG score 1.1 versus 1.9; P < 0.01). Men with ZAG-producing prostate carcinomas had elevated levels of serum ZAG relative to their normal age- and race-matched controls (P < 0.02). Furthermore, s.c. growth of human ZAG-producing murine tumors in syngeneic mice and orthotopic growth of ZAG-producing human prostate carcinomas in nude rats resulted in readily detectable levels of human ZAG in the serum. Taken together, these studies show that ZAG production by prostate cancer can lead to systemically elevated serum ZAG levels that may be useful diagnostically. The effects of elevated systemic ZAG on cachexia-associated complications in patients with advanced prostate cancer deserves additional investigation.

Aged↗
PubMed1998

[Study on treatment of blood stasis syndrome of chronic prostatitis using prostatitis decoction and its extract capsule].

OBJECTIVE: To test and verify the effects of prostatitis decoction and its capsule on the treatment of chronic prostatitis with blood stasis Syndrome, and its therapeutic mechanism. METHODS: Five hundred and sixty-one Patients were treated for 2 months, decoction group 322 cases, and capsule group 239 cases. As control group, 95 cases were treated with Qianliekang tablets. Expressed prostatic secretion(EPS)-pH and Zn content were measured before and after treatment. Observation on hemorheology and microcirculation disturbance with animal experiments were conducted. RESULTS: The cure rate of Prostatitis decoction and capsule groups was 65.8%, and 54.4% respectively, that of control group was only 17.9%. EPS-pH and Zn were markedly improved after Prostatitis decoction treatment. Experimental work revealed that Prostatitis decoction and its capsule had lowered the whole blood viscosity, thrombocyte adhesiveness rate and dry weight of thrombus in blood stasis rabbit model; and on rats model of microcirculation disturbance caused by adrenalin, the Prostatitis decoction and its capsules had obviously delayed the occurrence of reduction and stopping of blood flow in arterioles. CONCLUSION: Prostatitis decoction (capsule) was effective in treating chronic prostatitis.

Adult↗
PubMed2002

The chronic prostatitis-chronic pelvic pain syndrome can be characterized by prostatic tissue pressure measurements.

PURPOSE: We performed a prospective study to confirm early results implying that intraprostatic tissue pressure is elevated in men with the chronic prostatitis-chronic pelvic pain syndrome. We planned to determine further whether this technique would detect a significant difference in inflammatory and noninflammatory categories IIIA and IIIB. MATERIALS AND METHODS: A total of 48 patients with the chronic prostatitis-chronic pelvic pain syndrome, including 18 with inflammatory category IIIA and 30 with noninflammatory category IIIB disease, and 12 asymptomatic controls completed a Finnish version of the National Institutes of Health-Chronic Prostatitis Symptom Index. In addition, culture and microscopy of lower urinary tract segmented specimens, serum prostate specific antigen determination, transrectal ultrasound, uroflowmetry and ultrasound post-void residual urine measurement were done. All patients and controls also underwent independent intraprostatic right and left lobe tissue pressure measurement using a standard intracompartmental tissue pressure monitor system. Pressure was measured via an intraprostatic needle placed percutaneously in the perineum at baseline, and 10, 60 and 120 seconds after standard saline injection. RESULTS: All patients with the chronic prostatitis-chronic pelvic pain syndrome had significantly higher pressure at all measurement points compared with controls (p <0.001). Mean intraprostatic tissue pressure was significantly higher (p <0.01) in category IIIA with greater than 10 leukocytes per high power field in prostate specific specimens compared with category IIIB with less than 10. CONCLUSIONS: Our study supports the suggestion that patients with the chronic prostatitis-chronic pelvic pain syndrome have significantly higher prostate tissue pressure than controls. Findings also validated the previous clinical assumption that there is a rationale for differentiating chronic prostatitis-chronic pelvic pain syndrome cases into inflammatory and noninflammatory categories.

Adult↗
PubMed2002

Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells.

Prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface antigen expressed in normal prostate and associated with human and murine prostate cancer. To begin to investigate a possible link between PSCA expression in normal prostate and prostate carcinogenesis, we characterized the phenotype and proliferative behavior of normal PSCA-expressing prostate epithelial cells (PrEC) in tissue culture. PSCA was expressed in a subset of prostate epithelial cells that coexpress basal and secretory cytokeratins. PSCA-positive cells were the direct progeny of PSCA-negative cells and were characterized by a more differentiated morphology and a slower proliferative rate than PSCA-negative cells. Although PSCA-positive cells continued to express basal cell markers such as CD44, they lost expression of the basal cell marker p63. In contrast, expression of prostate specific antigen and androgen receptor transcripts was detectable in PSCA-positive PrEC. These findings suggest that PSCA is a unique marker of an intermediate subpopulation of PrEC in transition from a basal to a terminally differentiated secretory phenotype and may be a useful marker for the study of normal and malignant prostate development.

Antigens, Neoplasm↗
PubMed2003

Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.

PURPOSE: Prostate cancer specifically metastasizes to bone where it leads to bone formation. We previously reported that coculturing MDA PCa 2b prostate cancer cells with primary mouse osteoblasts (PMOs) induced PMO proliferation and differentiation. An osteoblastic reaction was also observed in vivo after injection of MDA PCa 2b cells into the bones of severe combined immunodeficient disease mice. The aim of this study was to identify the sequence of events that leads to these osteoblastic lesions in vivo and, using this in vitro model, to define the contributions of various genes and cellular pathways in the pathophysiology of osteoblastic bone metastases of prostate cancer. EXPERIMENTAL DESIGN AND RESULTS: We show histological evidence of de novo bone formation as early as 2 weeks after injection of MDA PCa 2b cells in the bone of severe combined immunodeficient disease mice. In vitro, we show that PMOs induce MDA PCa 2b proliferation, suggesting a synergistic paracrine loop between these cells and PMOs. Endothelin (ET)-1, which is a mitogen for several cell types, is produced by all prostate cancer cell lines tested, and Atrasentan, an antagonist of ET-1 receptor A, partially reversed PMO proliferation induced by MDA PCa 2b cells. ET-1 is known to be comitogenic with a number of growth factors, including insulin-like growth factor (IGF)-I. In this study, we report that IGF-binding protein (IGFBP)-3 transcripts (that regulate levels of free IGF) are down-regulated in prostate cancer cells cocultured with PMO, whereas prostate-specific antigen (a protease known to cleave IGFBP-3) is detected in the 150-400 ng/ml range. Accordingly, IGFBP-3 has antiproliferative effects in PMOs, which were attenuated in our in vitro system. Taken together, our studies also implicate the IGF axis to play a role in this model of bone metastases. Secondly, the transcript level of mouse double minute 2 (a protein that regulate p53) was increased in prostate cancer cells grown with PMOs. The p53-dependent and -independent oncogenic activities of mouse double minute 2 suggest that osteoblasts induce a survival advantage in prostate cancer cells. Lastly, we show that expression of osteoprotegerin is decreased and of receptor activator of nuclear factor-kappaB ligand is increased in PMOs cultured in the presence of MDA PCa 2b cells, two events associated with osteoclast activation and bone resorption. CONCLUSIONS: Our results provide evidence that multiple and distinct molecular events affecting both bone formation and bone resorption concur to the increase bone mass in prostate cancer bone metastases. These data also provide a rationale for developing therapeutic strategies designed to target these molecular changes.

Alkaline Phosphatase↗
PubMed2004

Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells.

In order to analyze differential gene expression of putative prostate tumor markers we compared the expression levels of >400 cancer-related genes using the cDNA array technique in a set of prostate tumors and matched normal prostate tissues. Up-regulated expression of mammary tumor 8 kDa protein (MAT-8), complement component C1S (C1S), ferritin heavy chain (FTH1), peptidyl-prolyl cis-trans isomerase A (PPIA), RNA-binding protein regulatory subunit DJ-1 protein (DJ-1) and vacuolar ATP synthase subunit F (ATP6V1F) was determined in prostate carcinoma and confirmed by using quantitative real-time RT-PCR analyses. Furthermore, quantitative real time RT-PCR on intact RNAs from 11 paired laser microdissected epithelial tissue samples confirmed up-regulated MAT-8 expression in 6 out of 11 prostate tumors. To determine the function of MAT-8 in vitro, human PC-3 and LNCaP prostate carcinoma cells were transfected with small interfering double-stranded RNA (siRNA) oligonucleotides against the MAT-8 gene leading to a specific down-regulation of MAT-8 expression. In addition, suppression of MAT-8 expression caused a significant decrease in cellular proliferation of both prostate cancer cell lines, whereas invasive capacity and cellular apoptosis remained unaffected. Taken together, our results indicate that the human MAT-8 gene contains the potential to serve as a prostate cancer expression marker and that MAT-8 plays an important role in cellular growth of prostate carcinomas.

Aged↗
PubMed1986

[Transference of antibiotics into prostatic tissues: sampling method by transurethral resection for the measurement of the concentration of antibiotics in prostatic tissue].

The transeference of two antibiotics, i.e. cefmetazole (CMZ) and fosfomycin (FOM), into prostatic tissues was examined. Prostatic tissue samples were obtained from patients with benign prostatic hyperplasia while undergoing open prostatectomy or transurethral resection of the prostate (TUR-P). 2 g of CMZ or 4 g of FOM was intravenously administered within about 10 minutes starting 1 hour before the removal or resection of the prostate, and blood samples were collected at the end of the administration and during surgery. In TUR-P, resected prostatic tissues were washed with the TUR perfusate and the antibiotic in the tissue was presumed to be released into the perfusate. The following preliminary experiments were, therefore, carried out. The removed prostate was divided into three segments, i.e. urethral region, central region and capsular region, and the CMZ or FOM level in each tissue was measured. The remaining tissues were cut into small pieces for immersion in the TUR perfusate for 10-90 minutes. The tissue fragments were removed every 10 minutes to measure the tissue concentration of CMZ or FOM. The concentration of CMZ or FOM in the prostatic tissues did not vary among the three regions, however it markedly decreased with increase in the period of immersion. This suggested that the concentration of these agents into the prostatic tissues was represented by the concentration in the tissues near the urethra obtained immediately after the start of TUR-P.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗