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PubMed2006

The prostate-specific G-protein coupled receptors PSGR and PSGR2 are prostate cancer biomarkers that are complementary to alpha-methylacyl-CoA racemase.

BACKGROUND: Immunohistochemistry (IHC) to detect alpha-methylacyl-CoA racemase (AMACR) expression can be useful in the diagnosis of small foci of prostate cancer on needle biopsy specimens, although it still has limitations in terms of both sensitivity and specificity. We have previously described the increased expression of two prostate-specific G-protein coupled receptors (PSGR and PSGR2) in human prostate cancer. To examine their potential usefulness as cancer biomarkers, we have evaluated their expression relative to AMACR in prostate cancer tissues. METHODS: Expression of PSGR, PSGR2, and AMACR were examined by quantitative reverse-transcriptase PCR in mRNAs from benign prostate and prostate cancer tissues. Expression of PSGR2 and AMACR was also examined by in situ hybridization using a prostate cancer tissue microarray. RESULTS: By in situ hybridization, 24 of 40 prostate cancer cases showed concordant expression of PSGR2 and AMACR. However, in 16 cases there was significant discordance between expression levels of these two markers. By quantitative RT-PCR all three markers were substantially increased in cancer, with AMACR the most overexpressed (30-fold), followed by PSGR2 (13-fold) and PSGR (10-fold). AMACR was the best single marker of prostate cancer but in 7 of the 59 total cases the expression of AMACR was not significantly elevated while PSGR and/or PSGR2 were substantially elevated. CONCLUSION: All three biomarkers are increased in prostate cancer but their expression is not completely concordant. There is a subset of cases in which analysis of expression of PSGR and/or PSGR2, in addition to AMACR, would be diagnostically useful.

Biomarkers, Tumor↗
PubMed1986

The induction of new ductal growth in adult prostatic epithelium in response to an embryonic prostatic inductor.

Tissue recombinants were prepared with a single epithelial ductal tip from adult prostate and mesenchyme from either the embryonic urogenital sinus or adult urinary bladder. Recombinants were grown in vivo beneath the renal capsule of male hosts. After 4 weeks of in vivo growth, extensive growth of arborizing ducts was apparent in recombinants composed of urogenital sinus mesenchyme and a single adult prostatic ductal tip. One-dimensional polyacrylamide gel electrophoresis indicated that these recombinants contained many of the proteins of the mature prostate. Heterospecific recombinants (rat urogenital sinus mesenchyme and mouse prostatic epithelium) showed the ductal tissue to be derived solely from the prostatic epithelium. In recombinants of a prostatic ductal tip with mesenchyme from the urinary bladder, ductal growth was absent, the ductal tip was maintained as a single, discrete, epithelial structure, and the protein composition of these recombinants more closely resembled that of the bladder. The results demonstrate that the epithelial cells of the adult prostate can participate in new ductal growth in response to an embryonic prostatic inductor. These data provide experimental evidence to support the hypothesis that human benign prostatic hyperplasia may result from the anomalous reactivation of embryonic growth potential in the adult prostate.

Adult↗
PubMed1998

Expression of gonadotropin-releasing hormone (GnRH) and GnRH receptor mRNA in prostate cancer cells and effect of GnRH on the proliferation of prostate cancer cells.

The purpose of this study was to determine the production of gonadotropin-releasing hormone (GnRH), the co-occurrence of GnRH receptors in prostate cancer cells, and the effect of GnRH on prostate cancer cell proliferation. Four human prostate cancer cell lines were studied. LNCaP is an androgen sensitive prostate cancer cell line, DU-145 and PC-3 are androgen resistant, and TSU-Pr1 is uncharacterized. The expression of GnRH and GnRH receptor mRNAs were assessed by in situ hybridization and the effect of exogenous GnRH on proliferation of prostate cancer cells was measured by thymidine incorporation assay. GnRH mRNA expression, determined by in situ hybridization, was found in 83.48% of the LNCaP, 89.7% of the TSU-Pr1, 86.2% of the PC-3 and 95.3% of the DU-145. Signals of GnRH receptor mRNA were detected in more than 95% of the cells of all four cell lines. The proliferation of the prostate cancer cells grown in media supplemented with peptide hormone lacking charcoal-stripped serum was significantly (P < 0.05) suppressed. No significant effect of GnRH on the proliferation of all four prostate cancer cells was observed. In summary, prostate cancer cells produced GnRH and its receptors, and exogenous GnRH treatment did not affect the prostate cancer cell proliferation. The existence of GnRH and GnRH receptor mRNA in the same cell suggests that the role of GnRH produced by prostate cancer cells would be autocrine.

Cell Division↗
PubMed2001

How to improve prostate biopsy detection of prostate cancer.

The combination of serum prostate-specific antigen (PSA) testing and transrectal ultrasonography is a highly effective strategy to diagnose prostate cancer at an early curable stage. Even though PSA is the most useful serum biomarker to aid in prostate cancer detection, it has limited specificity: as many as 75% of men who undergo prostate biopsy because of an elevated PSA do not have prostate cancer. Additionally, sextant prostate biopsies miss prostate cancer at least 20% of the time. To reduce the number of false-negative biopsies, many have advocated obtaining 12 or more cores in a single biopsy session. Studies have shown that this practice is safe and can enhance cancer detection modestly. Although it is unlikely that prostate cancer imaging will replace prostate biopsy in the near future, many exciting new imaging technologies should eventually improve targeting of prostate needle biopsy and reduce false-negative biopsies. Some of the most exciting areas include power Doppler sonography, microbubble intravenous ultrasound contrast agents, and magnetic resonance spectroscopy. These functional imaging modalities can assess tumor blood flow and metabolic activity at a cellular level and can detect malignant changes that may not be detected by standard anatomic imaging.

Biopsy, Needle↗
PubMed2006

Prostate saturation biopsy in the reevaluation of microfocal prostate cancer.

PURPOSE: We evaluated the ability of an extended, 32-core repeat transrectal ultrasound prostate biopsy protocol to improve the characterization of low volume, well differentiated disease in men with a diagnosis of potentially insignificant microfocal prostate cancer, as defined by 1 single focus positive core of 10 with less than 5 mm of Gleason score 6 or less tumor on primary biopsy. MATERIALS AND METHODS: A total of 35 consecutive patients, who were 62 to 75 years old, had a median serum prostate specific antigen of 8 ng/ml (range 0.5 to 14) and a diagnosis of minimal prostate cancer, and were willing to consider observation with delayed treatment at progression, were offered repeat saturation prostate biopsy with a median of 32 cores (range 18 to 36) under local anesthesia. This biopsy was to determine whether more extensive prostate sampling would confirm or disprove the initial diagnosis of microfocal, well differentiated prostate cancer. RESULTS: The procedure was aborted in 1 patient because of massive rectal hemorrhage. Another patient had acute prostatitis with gram-negative sepsis. Of 34 evaluable biopsy sets 11 (32%) were negative for cancer, suggesting that tumor detected at the primary biopsy was probably of low volume and amenable to observation with delayed treatment. Of the biopsies 23 (68%) were positive, 17 were at multiple sites and 7 were upgraded to Gleason score 7 or greater. These patients were then considered to have significant tumors and were offered active treatment. CONCLUSIONS: This study is to our knowledge the first to describe the clinical use of prostate saturation biopsies for re-evaluating potentially insignificant prostate cancer. Of patients with minimal disease on standard 10-core biopsy, results show that this technique may be helpful for distinguishing the 30% who probably have minimal disease based on negative repeat saturation biopsy from the 70% who almost certainly have a significant tumor, as characterized by multiple positive cores, with or without an increased Gleason score. The latter patients should be offered active therapy.

Adenocarcinoma↗
PubMed2005

Administration of extract of mushroom Phellinus linteus induces prostate enlargement with increase in stromal component in experimentally developed rat model of benign prostatic hyperplasia.

OBJECTIVES: To clarify the effect of the mushroom extract Phellinus linteus on noncancerous prostate cells using an experimentally developed rat benign prostatic hyperplasia model. A growing number of people take some natural herbal extracts for maintenance of their health. Among them, the extracts of certain mushrooms are believed to have a marked tumoricidal effect but low toxicity for normal tissues, and they are being drunk widely in Japan and Korea. However, until now, their effect on noncancerous benign prostate growth has not been examined. METHODS: The mushroom extract was administered daily for 5 weeks to experimentally developed benign prostatic hyperplasia rats. Prostate organ weight, histologic composition, and gene expression levels of sex hormone receptors, transforming growth factor-beta, vascular endothelial growth factor, and endothelial nitric oxide synthase were examined. RESULTS: Prostate weight increased significantly by 37% owing to treatment with the mushroom extract (P < 0.05). In particular, the stromal component of the prostate increased significantly by 80% (P < 0.05). A suppression of transforming growth factor-beta1 expression by 56% was observed with the mushroom extract treatment (P < 0.05). CONCLUSIONS: We found that the mushroom extract enlarged the prostate. The effect was suggested to be on the prostate stroma, which may be involved in transforming growth factor-beta1 regulation. Administration of mushroom extract should be considered carefully by those with an enlarged prostate.

Agaricales↗
PubMed2005

Botulinum toxin type A improves benign prostatic hyperplasia symptoms in patients with small prostates.

OBJECTIVES: To expand the clinical use of botulinum toxin A (BTX-A) in treating patients with small prostates and symptomatic benign prostatic hyperplasia (BPH). BTX-A injection into the prostate in patients with voiding dysfunction and large prostates has been reported. METHODS: Sixteen men with symptomatic BPH, a prostate volume less than 30 cm3, peak flow rate less than 12 mL/s, and with refractory disease after at least 1 month of alpha-blocker treatment received BTX-A 100 U injection into the prostate transperineally under transrectal ultrasound guidance. The clinical effects were evaluated at baseline and after treatment. RESULTS: No significant local or systemic side effects were observed in any of the patients. All patients reported subjective improvement starting at approximately 1 week and achieved a maximal effect after 1 month that was maintained at 3 and 6 months. At 6 to 12 months (mean 10) of follow-up, no patient had symptom recurrence. The mean prostate volume, symptom score, and quality-of-life index were significantly reduced by 13.3% (from 19.6 +/- 1.2 to 17.0 +/- 1.1 cm3), 52.6% (from 18.8 +/- 1.6 to 8.9 +/- 1.9), and 44.7% (from 3.8 +/- 0.3 to 2.1 +/- 0.3), respectively. The maximal flow rate increased significantly by 39.8% (from 7.3 +/- 0.7 to 11.8 +/- 0.8 mL/s). In 2 patients who underwent biopsy 1 month after BTX-A injection, terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick end labeling staining demonstrated an increase in apoptotic activity, not only in the glandular component, but also in the stromal component of the prostatic tissue. CONCLUSIONS: BTX-A injected into the prostate is a promising treatment for patients with small prostates and symptomatic BPH.

Aged↗
PubMed1999

The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network.

PURPOSE: Chronic abacterial prostatitis is a syndrome characterized by pelvic pain and voiding symptoms, which is poorly defined, poorly understood, poorly treated and bothersome. Research and clinical efforts to help men with this syndrome have been hampered by the absence of a widely accepted, reliable and valid instrument to measure symptoms and quality of life impact. We developed a psychometrically valid index of symptoms and quality of life impact for men with chronic prostatitis. MATERIALS AND METHODS: We conducted a structured literature review of previous work to provide a foundation for the new instrument. We then conducted a series of focus groups comprising chronic prostatitis patients at 4 centers in North America, in which we identified the most important symptoms and effects of the condition. The results were used to create an initial draft of 55 questions that were used for formal cognitive testing on chronic prostatitis patients at the same centers. After expert panel review formal validation testing of a revised 21-item draft was performed in a diverse group of chronic prostatitis patients and 2 control groups of benign prostatic hyperplasia patients and healthy men. Based on this validation study, the index was finalized. RESULTS: Analysis yielded an index of 9 items that address 3 different aspects of the chronic prostatitis experience. The primary component was pain, which we captured in 4 items focused on location, severity and frequency. Urinary function, another important component of symptoms, was captured in 2 items (1 irritative and 1 obstructive). Quality of life impact was captured with 3 items about the effect of symptoms on daily activities. The 9 items had high test-retest reliability (r = 0.83 to 0.93) and internal consistency (alpha = 0.86 to 0.91). All but the urinary items discriminated well between men with and without chronic prostatitis. CONCLUSIONS: The National Institutes of Health chronic prostatitis symptom index provides a valid outcome measure for men with chronic prostatitis. The index is psychometrically robust, easily self-administered and highly discriminative. It was formally developed and psychometrically validated, and may be useful in clinical practice as well as research protocols.

Chronic Disease↗
PubMed1999

Race is not independently associated with a positive prostate biopsy in men suspected of having prostate cancer.

OBJECTIVES: To examine whether race is associated with the prostate biopsy result after controlling for other clinical factors in men undergoing ultrasound-guided prostate biopsy to evaluate an elevated serum prostate-specific antigen (PSA) or an abnormal digital rectal examination (DRE), or both. METHODS: We reviewed the records of all men undergoing transrectal ultrasound-guided prostate biopsy at our facilities from January 1990 through March 1998. This included 1056 white men and 874 black men. Patient age, serum PSA, indication for prostate biopsy, and race were examined for association with the biopsy result. RESULTS: Of the 1 930 black and white men who underwent prostate biopsy, 639 (33%) had cancer, including 355 (41%) of 874 black men and 284 (27%) of 1056 white men. Serum PSA, abnormal DRE, and age were independent predictors of a prostate biopsy being positive for cancer. Race was not an independent predictor of cancer being identified in the prostate biopsy. CONCLUSIONS: After controlling for PSA, DRE, and age, black men were not at an increased risk of a positive prostate biopsy relative to white men. Our data do not support the need to consider race when estimating the probability that a man has prostate cancer.

Adult↗
PubMed2001

Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells.

In prostate carcinoma, overexpression of the anti-apoptotic gene Bcl-2 has been found to be associated with resistance to therapies including radiation and androgen ablation. Restoring the balance of Bcl-2 family members may result in the induction of apoptosis in prostate cancer cells previously resistant to treatment. To accomplish this, a strategy involving overexpression of the pro-apoptotic gene Bax was executed. The use of cytotoxic genes such as Bax require selective expression of the gene. In this study, we examined the ability of selective expression of Bax protein directed by a prostate-specific promoter to induce apoptosis in human prostate carcinoma. A second-generation adenoviral vector was constructed with the modified prostate-specific probasin promoter, ARR2PB, directing expression of an HA-tagged Bax gene and a green fluorescent protein reporter translated from an internal ribosome entry site (ARR2PB.Bax.GFP). ARR2PB promoter activity is tightly regulated and highly prostate specific and is responsive to androgens and glucocorticoids. The prostate-specific promoter-Bax-GFP transgene cassette was inserted into a cloning site near the right inverted terminal repeat of the adenoviral vector to retain specificity of the promoter. LNCaP cells infected with Ad/ARR(2)PB.Bax.GFP showed high levels of Bax expression 48 h after infection resulting in an 85% reduction in cell viability. Importantly, LNCaP cells stably transfected to overexpress Bcl-2 showed similar patterns of cell death when infected with Ad/ARR(2)PB.Bax.GFP, an 82% reduction in cell viability seen 48 h after infection. Apoptosis was confirmed by measuring caspase activation and using the TUNEL assay. Tissue specificity was evaluated using A549 cells (lung adenocarcinoma), SK-Hep-1 (liver cancer) cells, and Hela (cervical cancer) cells which did not show detectable expression of virally delivered Bax protein or any increase in cell death. Systemic administration of Ad/ARR2PB. Bax.GFP in nude mice revealed no toxicity in liver, lung, kidney, or spleen. This study shows that infection with the second-generation adenovirus, ARR2PB.Bax.GFP, results in highly specific cytotoxicity in LNCaP cells, and that consequent overexpression of Bax in prostate carcinoma, even in the context of high levels of Bcl-2 protein, resulted in apoptosis. These results suggest that a second-generation adenovirus-mediated, prostate-specific Bax gene therapy is a promising approach for the treatment of prostate cancer.

Adenoviridae↗
PubMed1998

Percutaneous transperineal radiofrequency ablation of prostate tumour: safety, feasibility and pathological effects on human prostate cancer.

OBJECTIVE: To evaluate the safety of radiofrequency (RF) energy delivered interstitially in patients with prostate cancer scheduled for radical prostatectomy and to correlate the proposed theoretical lesion size with the pathological findings. PATIENTS AND METHODS: Radiofrequency interstitial tumour ablation (RITA) was performed in 15 patients with localized prostate cancer before radical surgery. RF energy was delivered to the prostate by active needle electrodes (monopolar or bipolar) placed transperineally under transrectal ultrasonography guidance. Needle electrodes were used with different configurations and in some cases were covered by retractable shields to vary the length and circumference of the thermal lesions created. In eight patients, the procedure was performed immediately before radical prostatectomy, in six RITA was performed under spinal anaesthesia 1 week before surgery and in one patient, no surgery was performed but the patient was followed by serial determinations of prostate specific antigen (PSA). At least two lesions were created in each prostate, including both capsule and peripheral zones. NADPH and haematoxylin & eosin (H&E) staining were used to assess the extent of the necrotic lesion in the radical prostatectomy specimen. RESULTS: The mean energy delivered was 10.5 kJ, with central temperatures reaching up to 105 degrees C during 12 min of ablation; rectal temperature remained at < 38 degrees C. There were no complications. Macroscopic examination showed well-demarcated lesions including the prostatic capsule, up to 2.2 x 1.5 x 4.5 cm. With monopolar energy, the observed lesion size was comparable to the predicted 2 x 2 x 2 cm lesion, while with bipolar energy, lesion size was related to interneedle distance and uncovered needle length. Microscopic examination showed clearly delineated lesions both with NADPH (in prostates immediately removed after surgery) and H&E (at 1 week after RITA) staining. The lesion size observed on pathological analysis correlated with the predicted lesion size. In one patient, no residual cancer was found in the specimen. In the patient whose entire prostate was targeted and followed by serial PSA measurements, the latter were undetectable at 3 months of follow-up. CONCLUSION: Transperineally delivered RF energy is capable of safely creating extensive coagulative necrotic lesions in prostate cancer tissue, in a reproducible and controlled manner. The results presented here provide basic information for the potential future application of this form of energy for localized prostate cancer.

Catheter Ablation↗
PubMed2000

Combined sabal and urtica extract compared with finasteride in men with benign prostatic hyperplasia: analysis of prostate volume and therapeutic outcome.

OBJECTIVE: To test the hypothesis that in patients with benign prostatic hyperplasia (BPH), the outcome of drug therapy with finasteride may be predictable from the baseline prostate volume and that positive clinical effects might be expected only in patients with prostate volumes of > 40 mL, using a subgroup analysis of results from a previously reported clinical trial of finasteride and phytotherapy. PATIENTS AND METHODS: A subgroup of 431 patients was analysed from a randomized, multicentre, double-blind clinical trial involving 543 patients with the early stages of BPH. Patients received a fixed combination of extracts of saw palmetto fruit (Serenoa repens) and nettle root (Urtica dioica) (PRO 160/120) or the synthetic 5alpha-reductase inhibitor finasteride. The patients assessed had valid ultrasonographic measurements and baseline prostate volumes of either </= 40 mL or > 40 mL. All 516 patients were included in the safety analysis. The results of the original trial showed equivalent efficacy for both treatments. RESULTS: The mean (SD) maximum urinary flow (the main outcome variable) increased (from baseline values) after 24 weeks by 1.9 (5.6) mL/s with PRO 160/120 and by 2.4 (6.3) mL/s with finasteride. There were no statistically significant group differences (P = 0.52). The subgroups with small prostates (</= 40 mL) showed similar improvements, with mean values of 1.8 (5.2) mL/s with PRO 160/120 and 2.7 (7.4) mL/s with finasteride. The mean values for the subgroups with prostates of > 40 mL were similar, at 2.3 (6.1) and 2. 2 (5.3) mL/s, respectively. There were improvements in the International Prostate Symptom Score in both treatment groups, with no statistically significant differences. The subgroup analysis showed slightly better results for voiding symptoms in the patients with prostates of > 40 mL, but there were also improvements in the subgroup with smaller prostates. The safety analysis showed that more patients in the finasteride group reported adverse events and also there were more adverse events in this group than in patients treated with PRO 160/120. CONCLUSION: The present analysis showed that the efficacy of both PRO 160/120 and finasteride was equivalent and unrelated to prostate volume. However, PRO 160/120 had better tolerability than finasteride.

Aged↗
PubMed2005

Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice.

Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor.

Animals↗
PubMed2005

Expandable and rigid endorectal coils for prostate MRI: impact on prostate distortion and rigid image registration.

Endorectal coils (ERCs) are used for acquiring high spatial resolution magnetic resonance (MR) images of the human prostate. The goal of this study is to determine the impact of an expandable versus a rigid ERC on changes in the location and deformation of the prostate gland and subsequently on registering prostate images acquired with and without an ERC. Sagittal and axial T2 weighted MR images were acquired from 25 patients receiving a combined MR imaging/MR spectroscopic imaging staging exam for prostate cancer. Within the same exam, images were acquired using an external pelvic phased array coil both alone and in combination with either an expandable ERC (MedRad, Pittsburgh, PA) or a rigid ERC (USA Instruments, Aurora, OH). Rotations, translations and deformations caused by the ERC were measured and compared. The ability to register images acquired with and without the ERC using a manual rigid-body registration was assessed using a similarity index (SI). Both ERCs caused the prostate to tilt anteriorly with an average tilt of 18.5 degrees (17.4 +/- 9.9 and 19.5 +/- 11.3 degrees, mean +/- standard deviation, for expandable and rigid ERC, respectively). However, the expandable coil caused a significantly larger distortion of the prostate as compared to the rigid coil; compressing the prostate in the anterior/posterior direction by 4.1 +/- 3.0 mm vs 1.2 +/- 2.2 mm (14.5% vs 4.8%) (p < 0.0001), and widening the prostate in the right/left direction by 3.8 +/- 3.7 mm vs 1.5 +/- 3.1 mm (8.3% vs 3.4%) (p = 0.004). Additionally, the ability to manually align prostate images acquired with and without ERC was significantly (p < 0.0001) better for the rigid coil (SI = 0.941 +/- 0.008 vs 0.899 +/- 0.033, for the rigid and expandable coils, respectively). In conclusion, the manual rigid-body alignment of prostate MR images acquired with and without the ERC can be improved through the use of a rigid ERC.

Biophysical Phenomena↗
PubMed2004

Short-term human prostate primary xenografts: an in vivo model of human prostate cancer vasculature and angiogenesis.

Transgenic spontaneously occurring and transplantable xenograft models of adenocarcinoma of the prostate (CaP) are established tools for the study of CaP progression and metastasis. However, no animal model of CaP has been characterized that recapitulates the response of the human prostate vascular compartment to the evolving tumor microenvironment during CaP progression. We report that primary xenografts of human CaP and of noninvolved areas of the human prostate peripheral zone transplanted to athymic nude mice provide a unique model of human angiogenesis occurring in an intact human prostate tissue microenvironment. Angiogenesis in human kidney primary xenografts established from human renal cell carcinoma and noninvolved kidney tissue, a highly vascular organ and cancer, was compared with angiogenesis in xenografts from the relatively less vascularized prostate. Immunohistochemical identification of the human versus mouse host origin of the endothelial cells and of human endothelial cell proliferation in the human prostate and human kidney xenografts demonstrated that: (a) the majority of the vessels in primary xenografts of benign and malignant tissue of both organs were lined with human endothelial cells through the 30-day study period; (b) the mean vessel density was increased in both the CaP and benign prostate xenografts relative to the initial tissue, whereas there was no significant difference in mean vessel density in the renal cell carcinoma and benign kidney xenografts compared with the initial tissue; and (c) the number of vessels with proliferating endothelial cells in primary xenografts of CaP and benign prostate increased compared with their respective initial tissue specimens, whereas the number of vessels with proliferating endothelial cells decreased in the benign kidney xenografts. Short-term primary human prostate xenografts, therefore, represent a valuable in vivo model for the study of human angiogenesis within a human tissue microenvironment and for comparison of angiogenesis in CaP versus benign prostate.

Animals↗
PubMed2005

PCOTH, a novel gene overexpressed in prostate cancers, promotes prostate cancer cell growth through phosphorylation of oncoprotein TAF-Ibeta/SET.

Through genome-wide cDNA microarray analysis coupled with microdissection of prostate cancer cells, we identified a novel gene, prostate collagen triple helix (PCOTH), showing overexpression in prostate cancer cells and its precursor cells, prostatic intraepithelial neoplasia (PIN). Immunohistochemical analysis using polyclonal anti-PCOTH antibody confirmed elevated expression of PCOTH, a 100-amino-acid protein containing collagen triple-helix repeats, in prostate cancer cells and PINs. Knocking down PCOTH expression by small interfering RNA (siRNA) resulted in drastic attenuation of prostate cancer cell growth, and concordantly, LNCaP derivative cells that were designed to constitutively express exogenous PCOTH showed higher growth rate than LNCaP cells transfected with mock vector, suggesting the growth-promoting effect of PCOTH on prostate cancer cell. To investigate the biological mechanisms of this growth-promoting effect, we applied two-dimensional differential gel electrophoresis (2D-DIGE) to analyze the phospho-protein fractions in LNCaP cells transfected with PCOTH. We found that the phosphorylation level of oncoprotein TAF-Ibeta/SET was significantly elevated in LNCaP cells transfected with PCOTH than control LNCaP cells, and these findings were confirmed by Western blotting and in-gel kinase assay. Furthermore, knockdown of endogenous TAF-Ibeta expression by siRNA also attenuated viability of prostate cancer cells as well. These findings suggest that PCOTH is involved in growth and survival of prostate cancer cells thorough, in parts, the TAF-Ibeta pathway, and that this molecule should be a promising target for development of new therapeutic strategies for prostate cancers.

Cell Growth Processes↗
PubMedDate not supplied

Secondary colonic adenocarcinoma of the prostate histologically mimicking prostatic ductal adenocarcinoma.

PURPOSE: To study the clinical presentation and pathological features of secondary colonic adenocarcinoma of the prostate. MATERIALS AND METHODS: Six cases of colonic adenocarcinoma extending into the prostate were retrieved from the surgical pathology and autopsy files of the period 1985-1999. Immunostaining for prostatic acid phosphatase (PAP), prostate specific antigen (PSA), cytokeratin 7 (CK7), cytokeratin 20 (CK20) and carcinoembryonic antigen (CEA) was carried out in all cases. Clinical charts were also reviewed. RESULTS: Secondary colonic carcinoma spread into the prostatic stroma and along the prostatic ducts. In all four surgical cases, patients with a known history of rectal carcinoma presented with symptoms of urinary obstruction after 12 to 36 months of being free of recurrent or metastatic disease. In three surgical cases the secondary carcinoma involved the prostatic urethra in a form mimicking endometrioid carcinoma, which led to an incorrect diagnosis of prostatic endometrioid carcinoma in one case. The tumor cells were immunoreactive to CK20 and CEA and not reactive to CK7, PAP and PSA. CONCLUSIONS: Colonic carcinoma involving the prostate may mimic prostatic duct carcinoma due to the ductal and urethral involvement. Using a panel of immunostaining and clinical history is helpful in the differential diagnosis.

Adenocarcinoma↗
PubMed1992

Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia.

The oral administration of finasteride, a 4-aza-steroid inhibitor of 5 alpha-reductase, decreases serum dihydrotestosterone levels, but has little effect on serum testosterone. The current study was designed to assess the effect of finasteride on dihydrotestosterone levels in the prostates of men with benign prostatic hyperplasia. In a double blind, placebo-controlled study, 69 men with symptomatic prostatic hyperplasia were treated with placebo or 1, 5, 10, 50, or 100 mg/day finasteride for 7 days before transurethral resection of the prostate. In the placebo group the mean concentration of prostatic dihydrotestosterone was 10.3 +/- 0.6 nmol/kg (+/- SE), and the mean concentration of testosterone was 0.7 +/- 0.1 nmol/kg. After 7 days of treatment with all doses of finasteride, prostatic dihydrotestosterone declined to 15% or less of control levels, and the testosterone concentration increased in a reciprocal fashion. Compared to the placebo group, there was no significant difference in the mean prostatic dihydrotestosterone level achieved in any of the finasteride-treated groups. However, prostatic dihydrotestosterone levels were lower in the groups receiving higher doses of the drug. In two additional patients, finasteride treatment for 2 days also caused a decrease in prostatic dihydrotestosterone levels. No significant adverse experiences occurred during the study. We conclude that finasteride causes profound decrease in prostatic dihydrotestosterone.

5-alpha Reductase Inhibitors↗