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PubMed2000

Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer.

OBJECTIVES: Health-related quality of life (HRQOL) is an increasingly important endpoint in prostate cancer care. However, pivotal issues that are not fully assessed in existing HRQOL instruments include irritative urinary symptoms, hormonal symptoms, and multi-item scores quantifying bother between urinary, sexual, bowel, and hormonal domains. We sought to develop a novel instrument to facilitate more comprehensive assessment of prostate cancer-related HRQOL. METHODS: Instrument development was based on advice from an expert panel and prostate cancer patients, which led to expanding the 20-item University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) to the 50-item Expanded Prostate Index Composite (EPIC). Summary and subscale scores were derived by content and factor analyses. Reliability and validity were assessed by test-retest correlation, Cronbach's alpha coefficient, interscale correlation, and EPIC correlation with other validated instruments. RESULTS: Test-retest reliability and internal consistency were high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each r >/=0.80 and Cronbach's alpha >/=0.82) and for most domain-specific subscales. Correlations between function and bother subscales within domains were high (r >0.60). Correlations between different primary domains were consistently lower, indicating that these domains assess distinct HRQOL components. EPIC domains had weak to modest correlations with the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12), indicating rationale for their concurrent use. Moderate agreement was observed between EPIC domains relevant to the Functional Assessment of Cancer Therapy Prostate module (FACT-P) and the American Urological Association Symptom Index (AUA-SI), providing criterion validity without excessive overlap. CONCLUSIONS: EPIC is a robust prostate cancer HRQOL instrument that complements prior instruments by measuring a broad spectrum of urinary, bowel, sexual, and hormonal symptoms, thereby providing a unique tool for comprehensive assessment of HRQOL issues important in contemporary prostate cancer management.

Aged↗
PubMed1998

Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases.

OBJECTIVES: Prostate-specific membrane antigen (PSMA) is an integral membrane protein highly specific for the prostate. PSMA may be clinically useful for predicting outcome in patients with prostate cancer. We compared the expression of PSMA in prostate adenocarcinoma and lymph node metastases in a large series of patients with node-positive cancer. METHODS: We studied 232 patients with node-positive adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy at the Mayo Clinic between 1987 and 1992. Immunohistochemistry was performed using monoclonal antibody 7E11-5.3 directed against PSMA. For each case, the percentage of immunoreactive cells in benign prostate tissue, adenocarcinoma, and lymph node metastases was estimated in 10% increments. Intensity was recorded using a scale of 0 to 3 (0 = no staining, 3 = highest). RESULTS: Cytoplasmic immunoreactivity for PSMA was observed in all cases in benign epithelium and cancer, and most lymph node metastases. The number of cells stained was lowest in benign epithelium; cancer and lymph node metastases were similar (46.2% +/- 27.5% versus 79.3% +/- 18.5% versus 76.4% +/- 26.1%, respectively; all pairs P < 0.05). Intensity of staining was greatest in primary cancer and lowest in lymph node metastases. CONCLUSIONS: PSMA is expressed in benign prostatic epithelium and primary cancer in all cases and in 98% of cases with lymph node metastases. Expression of PSMA was greatest in primary cancer for both percentage and intensity of immunoreactive cells. PSMA expression allows the identification of benign and malignant prostatic epithelium and may be a potentially valuable marker in the treatment of patients with prostate cancer.

Adenocarcinoma↗
PubMed2003

A comparison of CT scan to transrectal ultrasound-measured prostate volume in untreated prostate cancer.

PURPOSE: To compare CT and transrectal ultrasound (TRUS)-measured prostate volumes in patients with untreated prostate cancer. METHODS AND MATERIALS: Between 1995 and 1999, 48 consecutive patients at the Portland Veterans Affairs Medical Center were treated with external beam radiotherapy. In 36 of these patients, TRUS and CT measurements of the prostate volume were obtained before treatment and <6 months apart. The TRUS volume was calculated using the prolate ellipsoid formula. The CT volume was calculated from the contours of the prostate drawn by one physician, who was unaware of the TRUS volume calculation, on axial CT images. RESULTS: The TRUS and CT prostate volume measurements correlated strongly (Pearson's correlation coefficient = 0.925, 95% confidence interval 0.856-0.961, p < 0.0001). The CT volume was consistently larger than the TRUS volume by a factor of approximately 1.5. In men with a TRUS prostate volume less than the median (<28 cm(3)), the CT/TRUS volume ratio was 1.7, and it was 1.4 for men whose volume was greater than the median. The CT volumes were correlated similarly with the TRUS volumes regardless of the CT slice interval. CONCLUSION: A strong correlation was found between CT scan and TRUS measurement of the prostate volume; however, CT consistently overestimated the prostate volume by approximately 50% compared with TRUS.

Adenocarcinoma↗
PubMed2003

Permanent prostate brachytherapy in men with clinically localised prostate cancer.

Permanent prostate brachytherapy techniques are associated with excellent biochemical control for patients with localised prostate cancer. Ten-year data show that permanent prostate brachytherapy is compatible with external beam irradiation or radical prostatectomy. However, treatment protocols and techniques for prostate brachytherapy vary between centres and there is little conformity of treatment protocols. The selection of patients for monotherapy or combined external beam irradiation and brachytherapy is controversial. The role of neoadjuvant androgen deprivation also remains unanswered in patients with localised prostate cancer. In addition, post-implant dosimetry may in fact be more significant for predicting outcome than the addition of adjuvant therapies, and should be a requirement when performing prostate brachytherapy. Data now seem to support specific computed tomography (CT)-based criteria to evaluate implant quality and delivered dose to the prostate. Unfortunately, prostate oedema and poor imaging techniques are limiting factors for evaluating implant dosimetry. Treatment planning techniques that use new treatment planning computers may assist in improving the implant procedure and dosimetry and are now available.

Androgen Antagonists↗
PubMed2003

Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype.

Melatonin inhibited the proliferation of hormone-independent LNCaP prostate cancer cells partly via MT1 receptor activation both in vitro and in nude mice xenograft model. In this study, the melatonin receptor expression in the prostate cancer tissue of a patient with bone metastases and the effect of melatonin on the biochemical progression of hormone-refractory prostate tumor which later developed in the same patient were reported. Saturation and competition 2-[125I]iodomelatonin binding assays were conducted on prostate tumor tissue obtained by transurethral resection of the prostate from the index patient. The receptor subtype identity of melatonin receptor expressed in the cancer tissue was determined by comparison of the rank order of inhibition constants (Ki) of various melatonergic ligands and the affinity of 4-phenyl-2-propionamidotetraline relative to melatonin in inhibiting 2-[125I]iodomelatonin binding to the tumor sample and to human cell lines stably transfected with MT1 or MT2 melatonin receptor subtype. MT1 receptor expression in the cancer tissue was also examined by immunohistochemistry. The surgically castrated patient later developed biochemical relapse of his disease. His serum total prostate-specific antigen (PSA) level was monitored before and during treatment with 5 mg/day oral melatonin at 20:00 hr. High-affinity (Kd = 103.7 pm) MT1 melatonin receptor subtype was expressed by the patient's prostate cancer. As indicated by his PSA levels, melatonin induced stabilization of his hormone-refractory disease for 6 wk. This report validates melatonin's oncostatic action on prostate cancer and the potential involvement of MT1 receptor subtype in the attendant antiproliferative signal transduction as suggested by recent preclinical laboratory findings in a human.

Aged↗
PubMed1998

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

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

Aged↗
PubMed2005

An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line.

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.

Aged↗
PubMed2000

Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression.

Prostate cancer tends to become transformed to androgen-independent disease over time when treated by androgen-deprivation therapy. We used two variants of the human prostate cancer cell line LNCaP to study gene expression differences during prostate cancer progression to androgen-independent disease. Production of prostate-specific antigen was regarded as a marker of androgen-dependence and loss of prostate-specific antigen was regarded as a marker of androgen-independence. mRNA from both cell lines was used for cDNA microarray screening. Differential expression of several genes was confirmed by Northern blotting. Monoamine oxidase A, an Expressed Sequence Tag (EST) similar to rat P044, and EST AA412049 were highly overexpressed in androgen-dependent LNCaP cells. Tissue-type plasminogen activator, interferon-inducible protein p78 (MxB), an EST similar to galectin-1, follistatin, fatty acid-binding protein 5, EST AA609749, annexin I, the interferon-inducible gene 1-8U, and phospholipase D1 were highly overexpressed in androgen-independent LNCaP cells. All studied genes had low or no expression in PC-3 cells. The EST similar to rat P044, the EST similar to galectin-1, follistatin, annexin I, and the interferon-inducible gene 1-8U were also expressed in benign prostatic hyperplasia tissue. The Y-linked ribosomal protein S4, Mat-8, and EST AA307912 were highly expressed in benign prostatic hyperplasia tissue. Additionally, both confirmation of differential expression in Northern blots and in situ hybridization were carried out for monoamine oxidase A, the EST similar to rat P044, the EST similar to galectin-1, fatty acid-binding protein 5, and the interferon-inducible gene 1-8U. We identified several potential prostate cancer markers, indicating that the method used is a useful tool for the screening of cancer markers, but other methods, such as in situ hybridization, are needed to further investigate the observations.

Animals↗
PubMed2005

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer.

Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological actions not mediated by oestrogen receptors. We assessed the gene expression profiles of prostate cancer cells treated with DES, and investigated direct inhibitory effects of DES. DES inhibited the proliferation of LNCaP and PC-3 cells. cDNA microarray analysis showed that expression of many genes was downregulated by DES. However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells. IGFBP-6 gene expression and protein levels significantly increased after DES treatment. Recombinant IGFBP-6 inhibited cell proliferation, and the inhibitory effect of DES was neutralised by anti-IGFBP-6 antibody. From the immunohistochemical analysis of IGFBP-6 using biopsy samples from androgen-independent prostate cancer, we found IGFBP-6 expression in androgen independent prostate cancer, and that DES treatment increased the IGFBP-6 staining intensity of the cancer cells in one sample. These findings suggested that DES induces IGFBP-6, which inhibits cell proliferation in an androgen-independent prostate cancer cell line, PC-3. IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer.

Antineoplastic Agents, Hormonal↗
PubMed2003

Linkage of aggressive prostate cancer to chromosome 7q31-33 in German prostate cancer families.

It has been suggested that chromosome 7q32 contains genes that influence the progression of prostate cancer from latent to invasive disease. In an attempt to confirm this linkage to prostate cancer aggressiveness, 100 German prostate cancer families were genotyped using a panel of eight polymorphic markers on chromosome 7q. We used a multipoint allele sharing method based upon a likelihood ratio test implemented in GENEHUNTERPLUS v1.2 in order to calculate the nonparametric Z(lr) and the associated LOD scores. We applied the aggressiveness of prostate cancer given by the pathological tumour grade of each individual, and the mean age of onset of a family as covariates, and constructed two weighted models. The first (weight(0-1) model) puts weights on families with at least two cases of GIII prostate cancer. The second (weight(0-2) model) also adds weights to families with early and late onset cancer respectively. The unweighted analysis gave no evidence of linkage to chromosome 7q. The Z(lr) scores increased when including the covariates, to 2.60 (P=0.005) using the weight(0-1) and to 3.02 (P=0.001) using the weight(0-2) model for late onset prostate cancer. The associated LOD scores were respectively 1.47 (P=0.009) and 1.98 (P=0.002). The markers that gave most evidence for linkage were exactly in the range of the published prostate cancer aggressiveness region. Our results support a widespread relevance of this locus and suggest that aggressive and late onset prostate cancer is linked to chromosme 7q31-33 in the German population.

Age of Onset↗
PubMed1997

Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group.

OBJECTIVE: To compare the effect on the course of advanced prostate cancer of hormone treatment commenced on diagnosis with that deferred until clinically significant progression occurs. PATIENTS AND METHODS: Nine hundred and thirty-eight patients with locally advanced or asymptomatic metastatic prostate cancer were randomized either to immediate treatment (orchidectomy or luteinizing hormone-releasing hormone analogue) or to the same treatment deferred until an indication occurred. Follow-up and management were otherwise according to the participating clinician's normal practice. Information was collected annually on survival, local and distant progression, and major complications (pathological fracture, spinal cord compression, ureteric obstruction and extra-skeletal metastases). RESULTS: Follow-up data were returned on 934 patients; 51 deferred patients died from causes other than prostate cancer before treatment was started (but only five of these presented at age < 70 years) and 29 died from prostate cancer before treatment could be started. Treatment was commenced for local progression almost as frequently as for metastatic disease. Progression from M0 to M1 disease (P < 0.001, two-tailed) and development of metastatic pain occurred more rapidly in deferred patients; 141 deferred patients needed transurethral resection for local progression compared with 65 treated immediately (P < 0.001, two-tailed). Pathological fracture, spinal cord compression, ureteric obstruction and development of extra-skeletal metastases were twice as common in deferred patients. Of the patients who died, 67% did so from prostate cancer; 361 patients died in the deferred arm compared with 328 in the immediate arm (P = 0.02, two-tailed), where 257 and 203 were deaths from prostate cancer, respectively (P = 0.001 two-tailed). This difference was seen largely in MO patients, with 119 and 81 deaths from prostate cancer, respectively (P < 0.001 two-tailed). CONCLUSIONS: The results consistently favour immediate treatment, although some of the data, especially on MO patients, are immature. The implications for management of advanced prostate cancer are discussed.

Adult↗
PubMed1999

Transurethral resection or incision of the prostate and other therapies: a survey of treatments for benign prostatic obstruction in the UK.

OBJECTIVE: To establish the current usage of transurethral incision of the prostate (TUIP) and other forms of treatment for benign prostatic obstruction (BPO). METHODS: The Prostate Trial Office (PROTO) sent a survey questionnaire to all 376 consultant urologists in the UK which asked for estimates of their clinical practice in treating BPO. The survey had three principle aims: to assess the role that the determination of prostate size has in clinical practice, to determine the nature and frequency of use of a range of therapies including TUIP, and to examine the feasibility of conducting a randomized controlled trial comparing transurethral resection of the prostate (TURP) and TUIP. RESULTS: Of the 376 urologists, 349 replied (response rate 93%); most respondents used prostate size as a determinant when deciding on therapy for BPO (60%). Of their patients with BPO who were treated, 38% received surgical treatment, 33% drug therapies and 29% conservative management. Of the types of surgical treatment, the most commonly used procedure was TURP, in 79% of patients, with only 15% undergoing TUIP. When compared with TURP, TUIP tended to be used for patients with a mean prostate volume of </=25 mL. Only 6% of surgical patients were treated using minimally invasive techniques. CONCLUSION: This survey provides some evidence that prostate size plays an important role in determining the treatment; TUIP appeared to be under-used and other minimally invasive techniques are rarely used in the UK.

Adult↗
PubMed2002

Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis.

Stem cells are believed to regulate normal prostatic homeostasis and to play a role in the etiology of prostate cancer and benign prostatic hyperplasia. We show here that the proximal region of mouse prostatic ducts is enriched in a subpopulation of epithelial cells that exhibit three important attributes of epithelial stem cells: they are slow cycling, possess a high in vitro proliferative potential, and can reconstitute highly branched glandular ductal structures in collagen gels. We propose a model of prostatic homeostasis in which mouse prostatic epithelial stem cells are concentrated in the proximal region of prostatic ducts while the transit-amplifying cells occupy the distal region of the ducts. This model can account for many biological differences between cells of the proximal and distal regions, and has implications for prostatic disease formation.

Animals↗
PubMed1988

In-vitro activity of fleroxacin against isolates causing complicated urinary tract infections and concentrations in seminal and prostatic fluid and in prostatic adenoma tissue.

Fleroxacin is a new fluoroquinolone with a broad antibacterial spectrum and a serum half-life of about 8-12 h. Eighty percent of 400 isolates from complicated or hospital-acquired urinary tract infections were inhibited by a concentration of 1 mg/l and 95% by 4 mg/l. As with other quinolones, fleroxacin is less active in acid urine (pH 5.4) than in Mueller-Hinton broth (pH 7.4). In 12 healthy volunteers the concentrations of fleroxacin were measured in plasma and seminal and prostatic fluid 2, 4 and 12 h after an oral dose of 400 mg. The mean plasma concentrations of three or four volunteers at each time were 4.2, 3.6 and 1.2 mg/l, respectively. The corresponding prostatic fluid/plasma ratios were 0.30, 0.27 and 1.96, respectively. By concomittant administration of ioxitalamic acid it could be demonstrated that in samples obtained 12 h after administration urinary contamination must be considered. Fleroxacin is concentrated in seminal fluid by a median ratio of 1.7. In 13 elderly patients the prostatic fluid and prostatic adenoma tissue concentrations were determined one to four hours following oral administration of 400 mg. The concentrations in prostatic fluid were similar to those of volunteers. The tissue concentrations exceeded plasma concentrations by only about 10% (median). Fleroxacin is very active against isolates causing complicated UTI. Concentrations in seminal and prostatic fluid and prostatic adenoma tissue are sufficiently high to treat bacterial prostatitis or vesiculitis caused by susceptible bacterial strains.

Adult↗
PubMed2005

Dietary genistein improves survival and reduces expression of osteopontin in the prostate of transgenic mice with prostatic adenocarcinoma (TRAMP).

Studies in vitro suggest that osteopontin (OPN), an extracellular matrix protein secreted by macrophages infiltrating prostate tumors, and by tumor cells, may have a role in the transition from clinically insignificant tumors to metastatic prostate cancer (PC). Latent PC occurs at equal rates in Western and Asian men, but the incidence of advanced PC is many-fold higher in Western men. Our earlier studies in TRAnsgenic Mouse Prostate adenocarcinoma (TRAMP) mice showed that genistein, an isoflavone found in soybeans, lowered the incidence of advanced PC. This suggested that lower intake of dietary soy may be one possible cause for higher incidence of advanced PC in Western men. The objective of the present study was to test the hypothesis that genistein may exert its preventive effect by inhibiting OPN expression. From 5 to 28 wk of age, 80, 68, and 30 TRAMP mice were fed AIN-76A diet containing 0, 250, or 500 mg genistein/kg body weight, respectively. Organ weights were measured. The steady-state level of OPN mRNA was evaluated by RT-PCR in a longitudinal study in 74 TRAMP and 32 nontransgenic litter mates (NTM). Administration of 250 and 500 mg genistein/kg AIN-76A improved survival (P = 0.008 and P = 0.005, respectively) and reduced mean weight of prostates with poorly differentiated cancer (PD) (P < 0.001), as well as the mean weight of periaortic lymph nodes (LN), although the latter was not significant. OPN was upregulated 10-fold in PD compared with prostates with a lower pathological score from TRAMP or NTM of any age (P = 0.003). OPN mRNA levels in the dorsolateral prostate and metastasis to LN were significantly correlated (r = 0.643; P = 0.00006). Genistein had a dose-dependent, significant inhibitory effect on OPN transcript levels in prostates displaying advanced prostate cancer (PD; score 6; P = 0.05). Studies are consistent with the possibility that dietary genistein may delay the progression from benign to malignant tumors by inhibiting OPN expression.

Adenocarcinoma↗
PubMed2000

2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring.

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

Tissue interactions and prostatic growth. I. Induction of adult mouse prostatic hyperplasia by fetal urogenital sinus implants.

A homologous chimeric prostate was produced by implantation of intact fetal urogenital sinus(es) (UGS) into the ventral prostate gland (VP) of an adult athymic mouse. A 10- to 20-fold overgrowth of the chimeric lobe of ventral prostate gland, as measured by glandular wet weight and by DNA content, was observed 4 to 9 wk following UGS implantation. The overgrowth was prostate-like as indicated by histologic composition and by responses to endogenous androgen, and was composed of both host and donor cells in about equal proportions as shown by glucose phosphate isomerase isozymic profiles. Unlike the canine model for prostatic hyperplasia, the mouse prostatic overgrowth occurred in the complete absence of exogenous sex steroids. The histoarchitecture of the chimeric VP and the isozymic detection of the contribution to the overgrowth by host cells have provided strong evidence that adult prostatic cells have been recruited to respond proliferatively by cellular interactions with fetal UGS. The demonstration of cellular interactions followed by reactivation of the fetal growth potential provides direct experimental evidence in support of McNeal's hypothesis that the reactivation of fetal growth potential may account for the development of human benign prostatic hyperplasia (BPH).

Androgens↗
PubMed2002

Role of prostate stem cell antigen in prostate cancer research.

PURPOSE OF REVIEW: The identification of cell surface antigens is critical to the development of future prognostic and therapeutic modalities for the treatment of prostate cancer. Several prostate-specific proteins have been identified and are under investigation. This review reports on prostate stem cell antigen (PSCA), a protein with restricted expression that may have prognostic and therapeutic utility. RECENT FINDINGS: PSCA is a glycosylphosphatidylinositol-anchored cell-surface protein belonging to the Ly-6/Thy-1 family of cell surface antigens, and a murine homologue has been described. It is expressed in the normal human prostate and overexpressed in human prostate cancers. Its overexpression has been correlated with increased Gleason score, advanced stage and bone metastasis. PSCA is co-amplified with MYC, an independent predictor of progression and death. PSCA may therefore be a useful predictor of tumor biology and a useful target of immunotherapy against prostate cancer. Evidence suggests a potential role in strategies employing cytotoxic T cell lymphocytes. Anti-tumor activity has been demonstrated with monoclonal antibodies in tumor take and established tumor xenograft models. Conjugated antibody has recently been reported to have anti-tumor activity in preclinical models. SUMMARY: PSCA may serve as a tool in refining the prognosis of an individual cancer and may be a useful therapeutic target for immunotherapy. Future studies will be required to confirm its clinical utility as a prognostic factor. Future animal and clinical studies will be required to test various immunotherapy strategies for safety and efficacy. The study of PSCA regulation and expression may provide information on normal prostate development and prostate carcinogenesis.

Antigens, Neoplasm↗