Showing papers on "Prostate published in 1997"

Prostate-specific membrane antigen expression in normal and malignant human tissues.

Abstract: Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.

Androgen Receptor Gene Amplification: A Possible Molecular Mechanism for Androgen Deprivation Therapy Failure in Prostate Cancer

Abstract: Progression of prostate cancer during endocrine therapy is a major clinical problem, the molecular mechanisms of which remain poorly understood. Amplification of the androgen receptor (AR) gene was recently described in recurrent prostate carcinomas from patients who had failed androgen deprivation therapy. To evaluate the hypothesis that amplification of the AR gene is a cause for the failure of androgen deprivation therapy in prostate cancer, we studied whether AR amplification leads to gene overexpression, whether the amplified AR gene is structurally intact, and whether tumors with AR amplification have distinct biological and clinical characteristics. Tumor specimens were collected from 54 prostate cancer patients at the time of a local recurrence following therapy failure. In 26 cases, paired primary tumor specimens from the same patients prior to therapy were also available. Fifteen (28%) of the recurrent therapy-resistant tumors, but none of the untreated primary tumors, contained AR gene amplification as determined by fluorescence in situ hybridization. According to single-stranded conformation polymorphism analysis, the AR gene was wild type in all but one of the 13 AR amplified cases studied. In one tumor, a presumed mutation in the hormone-binding domain at codon 674 leading to a Gly --> Ala substitution was found, but functional studies indicated that this mutation did not change the transactivational properties of the receptor. AR amplification was associated with a substantially increased level of mRNA expression of the gene by in situ hybridization. Clinicopathological correlations indicated that AR amplification was most likely to occur in tumors that had initially responded well to endocrine therapy and whose response duration was more than 12 months. Tumors that recurred earlier or those that showed no initial therapy response did not contain AR amplification. The median survival time after recurrence was two times longer for patients with AR amplification in comparison to those with no amplification (P = 0.03, Willcoxon-Breslow test). In conclusion, failure of conventional androgen deprivation therapy in prostate cancer may be caused by a clonal expansion of tumor cells that are able to continue androgen-dependent growth despite of the low concentrations of serum androgens. Amplification and the increased expression of a wild-type AR gene may play a key role in this process.

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

Abstract: On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.

Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements.

Abstract: Objective. —To determine the detection rate of prostate cancer in a screening population of men with prostate-specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies. Design. —A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations. Setting. —University medical center. Subjects. —A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate. Main Outcome Measures. —Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA. Results. —Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low-grade or moderately low-grade tumors (possibly harmless). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy. Conclusions. —There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.

Prostate Attenuated Replication Competent Adenovirus (ARCA) CN706: A Selective Cytotoxic for Prostate-specific Antigen-positive Prostate Cancer Cells

Abstract: Prostate-specific antigen (PSA) is a widely used marker for the diagnosis and management of prostate cancer Minimal enhancer/promoter constructs derived from the 5' flank of the human PSA gene (prostate-specific enhancer) were inserted into adenovirus type 5 DNA so as to drive the E1A gene, thereby creating a prostate-specific enhancer-containing virus, CN706 E1A was expressed at high levels in CN706-infected human PSA-producing LNCaP cells but not in CN706-infected DU145 cells, which are human prostate cells that do not express PSA The titer of CN706 was significantly higher in LNCaP cells compared to several human cell lines that do not produce PSA (HBL100, PANC-1, MCF-7, DU145, and OVCAR3) Furthermore, in LNCaP cells, the yield of CN706 was dependent on exogenous androgen (R1881) CN706 destroyed large LNCaP tumors (1 x 10(9) cells) and abolished PSA production in nu/nu mouse xenograft models with a single intratumoral injection

Association of Prostate Cancer Risk With Genetic Polymorphisms in Vitamin D Receptor and Androgen Receptor

Abstract: Background: Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility. Purpose: We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer. Methods: Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatel-lite (CAG repeats) in the AR gene and for a newly discovered poly-A micro-satellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests. Results: Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A 18 to A 22 ) VDR poly-A allele versus two short (A 14 to A 17 ) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. Conclusions : In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer. Implications: These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.

Polymorphic Repeats in the Androgen Receptor Gene: Molecular Markers of Prostate Cancer Risk

Abstract: We analyzed the polymorphic (CAG)n and (GGN)n regions within the androgen receptor gene from participants in a population-based case-control study of prostate cancer in middle-aged (40-64 years) Caucasian men. The associations between repeat lengths and risk of prostate cancer and the effects of confounding and modifying factors, such as age, family history of prostate cancer, and body mass index, were evaluated. DNA was available for 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of (CAG) repeats as a continuous variable was 0.97 [95% confidence interval (CI), 0.92-1.03], suggesting a 3% decrease in risk of prostate cancer for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were men with less than the median number of CAG repeats ( 16 repeats. Overall, those men who had or = 22; GGN, > 16). These data suggest that determination of both androgen receptor repeats within germ-line DNA may be useful in assessing an individual's risk of developing prostate cancer.

Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18

Abstract: Prostate cancer and benign tumors of the prostate are the two most common neoplastic diseases in men in the United States, however, research on their causes and treatment has been slow because of the difficulty in obtaining fresh samples of human tissue and a lack of well characterized cell lines which exhibit growth and differentiation characteristics of normal prostatic epithelium. Non-neoplastic adult human prostatic epithelial cells from a white male donor were immortalized with human papillomavirus 18 which resulted in the establishment of the RWPE-1 cell line. Cells from the RWPE-1 cell line were further transformed by v-Ki-ras to establish the RWPE-2 cell line. The objectives of this study were to: (1) establish the prostatic epithelial origin and androgen responsiveness of RWPE-1 and RWPE-2 cell lines; (2) examine their response to growth factors; and (3) establish the malignant characteristics of the RWPE-2 cell line. Immunoperoxidase staining showed that both RWPE-1 and RWPE-2 cells express cytokeratins 8 and 18, which are characteristic of luminal prostatic epithelial cells, but they also coexpress basal cell cytokeratins. These cell lines show growth stimulation and prostate specific antigen (PSA) and androgen receptor (AR) expression in response to the synthetic androgen mibolerone, which establishes their prostatic epithelial origin. Both cell lines also show a dose-dependent growth stimulation by EGF and bFGF and growth inhibition when exposed to TGF-beta, however, the transformed RWPE-2 cells are less responsive. RWPE-1 cells neither grow in agar nor form tumors when injected into nude mice with or without Matrigel. However, RWPE-2 cells form colonies in agar and tumors in nude mice. In the in vitro invasion assay, RWPE-1 cells are not invasive whereas RWPE-2 cells are invasive. Nuclear expression of p53 and Rb proteins was heterogeneous but detectable by immunostaining in both cell lines. The RWPE-1 cells, which show many normal cell characteristics, and the malignant RWPE-2 cells, provide useful cell culture models for studies on prostate growth regulation and carcinogenesis.

Body Size and Prostate Cancer: A 20-Year Follow-up Study Among 135006 Swedish Construction Workers

Abstract: Background: Obesity is associated with endocrine changes (e.g., increased estrogen and decreased testosterone in the blood) that have been implicated in the cause of prostate cancer and, therefore, ...

The prostate: A target for carcinogenicity of 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods

Abstract: Prostate tissues obtained from rats given a food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), at a dose of 400 ppm in the diet for 52 weeks were histopathologically evaluated and found to contain prostate carcinomas limited to the ventral lobe in 18 of 27 cases. Atypical hyperplasias were also detected in the ventral and anterior prostate as well as the seminal vesicles. 32P-Postlabeling analysis of DNA demonstrated that PhIP-DNA adducts are produced in all lobes of the prostate of rats receiving PhIP. The findings indicate that PhIP is carcinogenic to rat prostate in addition to the previously demonstrated targeting of the colon and mammary glands, providing evidence of a possible role of PhIP in human prostate carcinogenesis and highlighting the potential importance of PhIP for man.

Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia

Abstract: Blood samples were collected from 52 incident cases of histologically confirmed prostate cancer, an equal number of cases of benign prostatic hyperplasia (BPH) and an equal number of apparently healthy control subjects. The three groups were matched for age and town of residence in the greater Athens area. Steroid hormones, sex hormone-binding globulin, and insulin-like growth factor 1 (IGF-1) were measured in duplicate by radioimmunoassay in a specialized US centre. Statistical analyses were performed using multiple logistical regression. The results for IGF-1 in relation to prostate cancer and BPH were adjusted for demographic and anthropometric factors, as well as for the other measured hormones. There was no relation between IGF-1 and BPH, but increased values of this hormone were associated with increased risk of prostate cancer; an increment of 60 ng ml(-1) corresponded to an odds ratio of 1.91 with a 95% confidence interval of 1.00-3.73. There was also some evidence for an interaction between high levels of testosterone and IGF-1 in relation to prostate cancer. This finding suggests that, in addition to testosterone, IGF-1 may increase the risk of prostate cancer in humans.

Androgen-independent prostate cancer progression in the TRAMP model

Abstract: We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecular mechanisms involved in the initiation and progression of prostate cancer. TRAMP mice display high grade prostatic intraepithelial neoplasia or well-differentiated prostate cancer by 10-12 weeks of age. To test the hypothesis that molecular events leading to androgen independence and metastasis can occur early in the natural history of prostate cancer yet remain silent until selective pressures such as androgen deprivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRAMP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 18 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T24) controls. Median T12/18 and T12/24 genitourinary (GU) weight was significantly less than T18 and T24, respectively. In addition, T12/24 GU weight was significantly greater than T12/18. Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice. All tumors that developed in castrated mice were poorly differentiated in contrast to 27% in noncastrated controls. Although castration significantly decreased GU tumor burden, overall progression to poorly differentiated and metastatic disease was not ultimately delayed. These results demonstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore, early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model to identify specific molecular mechanisms that determine androgen sensitivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.

Establishment of two human prostate cancer cell lines derived from a single bone metastasis.

Abstract: Human prostate cancer cell lines are particularly difficult to establish, and most existing cell lines do not exhibit features commonly seen in human prostate cancer. Most available models either grow only in vivo as xenografts or are androgen insensitive and fail to express prostate-specific antigen (PSA). The lack of functionally relevant model systems of advanced prostate cancer has limited prostate cancer research and therapy development. Of 30 processed samples derived from patients with prostate cancer, we established two cell lines (MDA PCa 2a and MDA PCa 2b) that express PSA and androgen receptor, grow in vitro, and are androgen sensitive. Cells from these lines produced tumors in nude mice when injected either s. c. or orthotopically (intraprostatic). Both cell lines were established from a bone metastasis of a patient whose cancer was exhibiting androgen-independent growth. Although both were derived from two samples of the same specimen, they have different genetic features (as assessed by karyotype analysis) and different phenotypes (e.g., morphology and growth rate). It is likely that they are distinct clones isolated by the use of different culture procedures and reflect the genetic heterogeneity of the tumor. These new cell lines are the first available derived from a bone metastasis of an androgen-independent prostatic adenocarcinoma that grow both in vivo and in vitro and have retained PSA expression and androgen sensitivity. They therefore constitute important model systems to address critical questions related to the androgen-independent growth of human prostate cancer and to the complex process of bone metastasis.

Zinc in the human prostate gland: normal, hyperplastic and cancerous

Abstract: Zinc concentration in a prostate gland is much higher than in other human tissues. Data for zinc changes in different prostate diseases are limited and greatly contradictory. To analyze transrectal puncture tissue biopsy and resected materials, zinc content was estimated in benign prostatic hyperplasia (BPH) and cancer. There were 109 patients studied (50 BPH and 59 cancer). The control group consisted of 37 intact glands of men who died an unexpected death (accident, murder, acute cardiac insufficiency, etc.). All materials studied were divided into two parts. One of them was morphologically examined, while the zinc content of another one was estimated. The radionuclide induced energy dispersive X-ray fluorescent analysis was used for zinc determination. Zinc content (M +/- SE) of normal prostate, BPH and cancer was 1018 +/- 124, 1142 +/- 77, and 146 +/- 10 micrograms/g dry tissue, respectively. It was shown that zinc assessment in the material of transrectal puncture biopsy of prostate indurated site can be used as an additional test for differential diagnosis of BPH and cancer. Accuracy, sensitivity and specificity of the test are 98 +/- 2%.

A Prevalent Missense Substitution That Modulates Activity of Prostatic Steroid 5α-Reductase

Abstract: Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, SRD5A2, encoding prostatic steroid 5alpha-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5alpha-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.

Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma

Abstract: BACKGROUND This study was designed to evaluate the efficacy of iodine-125 interstitial radiation in the treatment of prostate carcinoma classified as T1 or T2. METHODS One hundred twenty-six consecutive patients with adenocarcinoma of the prostate (T1, 23%; T2, 77%) were treated with iodine-125 radionuclides between January 1, 1988, and December 31, 1990. Four patients died of intercurrent illness within 1 year postimplant, leaving 122 men in the study. The prescribed minimum radiation dose was 160 gray. Median follow-up was 69.3 months. Prebiopsy prostate specific antigen (PSA) values (median, 5.0 ng/mL) were available for all patients. Posttherapy evaluation included clinical, biochemical (PSA), and pathologic (repeat needle biopsy) studies. No patient was surgically staged, and none received androgen deprivation therapy. Morbidity was graded according to the Radiation Therapy Oncology Group grading scale. Statistical appraisal was performed by the Kaplan-Meier method. PSA failure was defined in two ways: (1) PSA progression, i.e., 2 consecutive increases from a nadir value; and (2) failure to attain an arbitrary serum PSA value of 1.0 or 0.5 ng/mL at last follow-up. RESULTS The overall 7-year survival was 77%; there were no deaths from prostate carcinoma in this cohort. The 7-year actuarial PSA progression free outcome was 89%, and the PSA ≤1.0 ng/mL outcome was 87%. When PSA ≤0.5 ng/mL was selected as an outcome end point, and PSA values in this series of radiation-treated patients were compared with PSA values proposed to indicate disease free survival after radical prostatectomy (PSA ≤0.3-≤0.6 ng/mL), the 7-year actuarial disease free survival was 79%. Morbidity was minimal except in patients who had preimplant or postimplant transurethral prostate resection. CONCLUSIONS Outpatient-based iodine-125 prostate brachytherapy for prostate carcinoma classified as T1 or T2 resulted in biochemical outcomes comparable to end points resulting from radical prostatectomy and external beam radiation. Cancer 1997; 80:442-53. © 1997 American Cancer Society.

Diagnosis, management and screening of early localised prostate cancer

Abstract: The incidence of prostate cancer is rising worldwide, caused mainly by demographic factors, particularly the increasingly elderly population and, more importantly, the increasing number of cases identified following prostate specific antigen (PSA) testing. It is commonly quoted that many more men die with prostate cancer than of it. Autopsy/post-mortem studies show that while a very high proportion of elderly men have histological evidence of the disease, a much smaller proportion develop clinically apparent cancer. The natural history of prostate cancer is poorly understood, but progression appears to be related to stage and grade of tumour. Prostate cancer can be diagnosed by digital rectal examination (DRE), serum PSA test, and/or transrectal ultrasound (TRUS), with confirmation by biopsy. Each test identifies a proportion of cancers, with higher rates of detection when they are used in combination. The tests are also used to determine which tumours are localised within the prostate and are, thus, potentially treatable. Unfortunately, clinical staging is unreliable, with approximately one half of all tumours upstaged following surgery. Three major treatment options are available for localised prostate cancer: radical prostatectomy, radical radiotherapy and conservative management (involving monitoring and treatment of symptoms). Although radical treatment rates are rising, good quality evidence concerning their comparative effectiveness and cost-effectiveness is lacking. Observational studies of highly selected patient groups suggests that there may be a slightly lower mortality rate following radical treatments compared with conservative management, but there has been very little research into treatment complications and quality of life of men after any of the treatments. In the past, investigations of prostate cancer were reserved largely for patients exhibiting symptoms, but the introduction of the PSA test has opened up the possibility of screening healthy men for the disease. Observational studies suggest that DRE and PSA, combined with TRUS and biopsy, can identify localised prostate cancer in 3-5% of men, although the tests do result in a number of false positives and negatives. Major questions remain concerning the natural history of the disease, potential costs (financial, social and psychological) of a screening programme, and the effectiveness and cost-effectiveness of treatments for localised disease. The lack of good quality data and the strength of these concerns means that population screening for prostate cancer cannot be recommended.

Aberrant E-Cadherin and α-Catenin Expression in Prostate Cancer: Correlation with Patient Survival

Abstract: E-cadherin maintains the normal differentiated phenotype in epithelial cells; this function is partly mediated by alpha-catenin, which links E-cadherin to the cell cytoskeleton. Dysfunction of E-cadherin in vitro and in vivo is associated with an invasive phenotype. However, the role of alpha-catenin is largely undetermined. We analyzed the expression of E-cadherin and alpha-catenin in prostate cancer to assess the relationship of abnormal expression to stage, grade and survival. E-cadherin expression was evaluated in 99 prostate cancers. In 79 of those specimens, alpha-catenin was also assessed. In benign prostatic epithelium, both E-cadherin and alpha-catenin were expressed uniformly at the cell membrane. Abnormal E-cadherin expression was found in 56% of cancer specimens, whereas alpha-catenin expression was abnormal in 42%. Abnormal expression of each molecule was significantly correlated with Gleason score (P < 0.0001) and the ratio of resection chippings infiltrated by tumor (P < 0.0001). E-cadherin expression was also associated with the extent of disease on the initial bone scan (P = 0.017). Univariate analysis showed significantly lower survival rate for patients with abnormal E-cadherin (P = 0.0003) or alpha-catenin expression (P = 0.031). Multivariate regression analysis showed that the prognostic value of E-cadherin was independent of tumor grade but not of metastasis. These results suggest that perturbation of cell-cell adhesion is involved in the progression of prostate cancer and that analysis of E-cadherin expression may be clinically useful.

Bicalutamide for advanced prostate cancer: the natural versus treated history of disease

Abstract: PURPOSETo determine the therapeutic effects of bicalutamide 200 mg in patients with prostate cancers of different hormone sensitivities.METHODSPatients with progressive prostate cancer were treated with bicalutamide 200 mg daily. Before treatment, patients' tumors were classified on the basis of prior hormone exposure and by serum testosterone levels into androgen-dependent and androgen-independent groups. Prior exposure to flutamide and response to flutamide withdrawal was also considered. Outcomes were reported independently on the basis of posttherapy changes in prostate-specific antigen (PSA), measurable disease, and radionuclide bone scans.RESULTSOutcomes varied by prior hormone exposure as a higher proportion of patients with progression of androgen-dependent tumors showed posttherapy PSA decreases of more than 50% or more than 80%, measurable disease regression, and improvement on radionuclide bone scans than did patients with androgen-independent progression. Within the category of androgen-indepe...

Specific and Efficient Peptide Substrates for Assaying the Proteolytic Activity of Prostate-specific Antigen

Abstract: Prostate-specific antigen (PSA) is a serine protease secreted by both normal prostate glandular cells and prostate cancer cells. The major proteolytic substrates for PSA are the gel-forming proteins in semen, semenogelin (Sg) I and II. On the basis of the PSA cleavage map for Sg I and II, a series of small peptides (i.e., < or = 7 amino acids) was synthesized and coupled at the COOH terminus to 7-amino-4-methyl coumarin. Using these fluorescently tagged substrates, K(m)s and k(cat)s were determined for PSA hydrolysis, and the substrates were also tested for activity against a panel of purified proteases. Previously, a variety of chymotrypsin substrates have been used to assay the enzymatic activity of PSA. The present studies have identified a peptide sequence with a high degree of specificity for PSA (ie., no detectable hydrolysis by chymotrypsin) and improved K(m)s and k(cat)s over previously used substrates. On the basis of these parameters, the best peptide substrate for PSA has the amino acid sequence HSSKLQ. Using PC-82 human prostate cancer xenografts and human prostate tissues, this PSA substrate was used to document that prostate cancer cells secrete enzymatically active PSA into the extracellular fluid but that once in the blood, PSA is not enzymatically active. On the basis of this information, it should be possible to use the HSSKLQ peptide as a carrier to target peptide-coupled prodrugs for selective activation within sites of PSA-secreting, metastatic prostate cancer cells and not within the blood or other nonprostatic normal tissues.

Enhanced expression of prostate-specific membrane antigen gene in prostate cancer as revealed by in situ hybridization.

Abstract: Recently, the cDNA encoding a novel candidate for prostate cancer-specific antigen, named prostate-specific membrane antigen (PSM), was cloned from the LNCaP prostate cancer cell line (R S Israeli, C T Powell, W R Fair, and W D W Heston, Cancer Res, 53: 227-230,1993) More recently, they also identified an alternatively spliced variant of PSM in normal prostate tissues (S L Su, I-P Huang, W R Fair, C T Powell, and W D W Heston, Cancer Res, 55: 1441-1443, 1995) The cDNA of this variant, named PSM', lacks 266 nucleotides present in PSM cDNA, so the transcripts derived from this particular nucleotide sequence can be regarded as PSM-specific transcripts In this study, we investigated the expression of PSM-specific transcripts in 15 specimens of prostate cancer obtained by needle biopsy using in situ hybridization with a newly developed RNA probe PSM-specific transcripts were detected in most of the carcinoma cells in all of the specimens examined, and the level of expression was higher in carcinoma cells from hormone-refractory patients than in the cells of those who showed a good response to hormonal therapy In addition, increased expression of PSM-specific transcripts was also associated with an increased Gleason score In the normal prostate, on the other hand, PSM-specific transcripts were limited to the basal cells of the prostate glands These results clearly show that expression of PSM-specific transcripts is closely associated with malignant transformation of the prostate; thus, in situ hybridization for detection of the transcripts is useful for the diagnosis of prostate cancer

Loss of the cyclin-dependent kinase inhibitor p27(Kip1) protein in human prostate cancer correlates with tumor grade.

Abstract: Loss of expression or mutational deletion of the cyclin-dependent kinase inhibitor p27(Kip1) has recently been implicated in malignant development. In this study, we investigated the relationship between p27(Kip1) protein expression and tumor grade in human prostate cancer by conducting an immunohistochemical analysis in a series of normal prostate, benign prostatic hyperplasia, and malignant prostate cancer specimens. The proliferative activity of prostatic tumors was determined on the basis of the Ki-67 nuclear antigen staining. A uniformly intense immunoreactivity for p27(Kip1) was localized to the nuclei of glandular epithelial cells of normal prostates. The benign glandular epithelia exhibited moderate immunostaining. In the malignant prostate tissue, however, a heterogeneous pattern of substantially reduced p27(Kip1) immunoreactivity was found among the glandular epithelial cells. The majority of primary prostate cancer specimens (68%) were totally negative for p27(Kip1) immunoreactivity, whereas the rest exhibited a significantly decreased p27(Kip1) expression, compared with the normal prostate (P < 0.01). Moreover, there was progressively diminished p27(Kip1) immunostaining with increased tumor grade. This loss of p27(Kip1) was associated with an increase in the proliferative index of prostatic tumors (r = 0.88). There was no significant relationship between p27(Kip) loss and the transforming growth factor beta receptor status of prostatic adenocarcinomas. These results indicate that frequent loss of the cyclin-dependent kinase inhibitor p27(Kip1) in human prostate cancer cells correlates with advancing histological aggressiveness, implicating deregulation of p27(Kip1) in prostate tumor progression.

Prolactin and prolactin receptors are expressed and functioning in human prostate.

Abstract: Prolactin is widely expressed in different tissues, and it is presumed to have both local and systemic actions. In males it is known to influence reproductive functions but the significance and mechanisms of prolactin action in male accessory reproductive tissues are poorly understood. Here we show that prolactin acts as a direct growth and differentiation factor for human prostate, as measured by changes in DNA synthesis and epithelial morphology of organ cultures. Furthermore, we report the expression in human prostate of a short prolactin receptor form in addition to the long form, based upon ligand cross-linking studies and RT-PCR analysis of mRNA expression. The highest density of prolactin receptors was detected in the secretory epithelial cells by immunohistochemistry. Finally, we report that prolactin is locally produced in human prostate epithelium, as evidenced by marked prolactin immunoreactivity in a significant portion of prostate epithelial cells, with parallel expression of prolactin mRNA in human prostate. Collectively, these data provide significant support for the existence of an autocrine/paracrine loop of prolactin in the human prostate and may shed new light on the involvement of prolactin in the etiology and progression of neoplastic growth of the prostate.