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PubMed1997

Immunohistochemical localization of human protein 1 in the female prostate (Skene's gland) and the male prostate.

Mouse monoclonal anti-urine protein 1 antibody and the biotin-streptavidin-peroxidase technique were used for the immunohistochemical demonstration of human protein 1 in prostatic tissue of both sexes. In the female prostate (Skene's gland), like the male prostate, high expression of human protein 1 was observed on the luminal surface and in the apical cytoplasm of secretory cells of prostatic glands, as well as on the luminal surface of the epithelium of the large ducts of the female prostate and urethra. Expression was also found in the membranes of secretory and basal cells of the glands, in membranes of the urethral uroepithelium and of the female prostate ducts, in the content of glands and ducts, as well as in vascular endothelium and smooth muscle. Human protein 1 (urine protein 1) expression in the secretory cells of the male and female prostate and its incorporation into the surface of cells lining the lumina of the female urethroprostatic complex is indicative not only of the secretory role of protein 1 but also of its potential protective properties operative in shielding the uroepithelium from the aggressive urinary environment. All genito-urinary tissue, and especially the female prostate, were found to be a potential source of urine protein 1 (human protein 1), refuting the notion held so far that it is exclusively the genito-urinary prostatic tissue of the male that participates in its production. The corresponding immunohistochemical distribution of human protein 1 in the same structures of the male and female prostate provides yet another analogous functional-morphological parameter of prostatic tissue in both sexes and further evidence supporting the non-vestigial concept of the prostate in the female.

Adolescent↗

PubMed2003

Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase.

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.

Adipocytes↗

PubMed2004

Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model.

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.

Adenocarcinoma↗

PubMed2006

EZC-prostate models offer high sensitivity and specificity for noninvasive imaging of prostate cancer progression and androgen receptor action.

In vivo imaging advances have greatly expanded the use of animal cancer models. Herein, we describe two new models that permit prostate imaging ex vivo, in vivo, and in utero. Further, we show the use of these models for detecting small metastasis and testing reagents that modulate the androgen receptor (AR) axis. A luciferase reporter gene was directed to the prostate epithelium using three composite promoters called human kallikrein 2 (hK2)-E3/P, PSA-E2/P, and ARR2PB, derived from hK2, PSA, and rat probasin regulatory elements, to generate the EZC1, EZC2, and EZC3-prostate mice, respectively. EZC2 and EZC3-prostate display robust expression in the prostate with only minimal detectable expression in other organs, including testes and epididymis. Luciferase expression was detected as early as embryonic day 13 (E13) in the urogenital track. To image prostate cancer progression, lines of EZC mice were bred with prostate cancer models TRAMP and JOCK1, and imaged longitudinally. When crossed with prostate cancer models, EZC3 facilitated detection of metastatic lesions although total prostate luciferase expression was static or reduced due to weakening of AR-regulated promoters. Castration reduced luciferase expression by 90% and 97% in EZC2 and EZC3 mice, respectively, and use of GnRH antagonist also led to extensive inhibition of reporter activity. The EZC-prostate model permits prostate imaging in vivo and should be useful for imaging prostate development, growth, metastasis, and response to treatment noninvasively and longitudinally. These models also provide powerful new reagents for developing improved drugs that inhibit the AR axis.

Animals↗

PubMed2006

Expression of novel molecules, MICAL2-PV (MICAL2 prostate cancer variants), increases with high Gleason score and prostate cancer progression.

PURPOSE: The aim of this study is to identify novel molecular targets for development of novel treatment or diagnostic markers of prostate cancer through genome-wide cDNA microarray analysis of prostate cancer cells purified by laser microdissection. EXPERIMENTAL DESIGN AND RESULTS: Here, we identified molecule interacting with CasL-2 prostate cancer variants (MICAL2-PV), novel splicing variants of MICAL2, showing overexpression in prostate cancer cells. Immunohistochemical analysis using an antibody generated specific to MICAL2-PV revealed that MICAL2-PV was expressed in the cytoplasm of cancer cells with various staining patterns and intensities, whereas it was not or hardly detectable in adjacent normal prostate epithelium or prostatic intraepithelial neoplasia. Interestingly, immunohistochemical analysis of 105 prostate cancer specimens on the tissue microarray indicated that MICAL2-PV expression status was strongly correlated with Gleason scores (P < 0.0001) or tumor classification (P < 0.0001). Furthermore, the expression levels of MICAL2-PVs were also concordant to those of c-Met, a marker of tumor progression, with statistical significance (P = 0.0018). To investigate its potential of molecular therapeutic target for prostate cancers, we knocked down endogenous MICAL2-PVs in prostate cancer cells by small interfering RNA, which resulted in the significant reduction of prostate cancer cell viability. CONCLUSIONS: Our findings suggest that MICAL2-PV is likely to be involved in cancer progression of prostate cancer and could be a candidate as a novel molecular marker and/or target for treatment of prostate cancers with high Gleason score.

Adaptor Proteins, Signal Transducing↗

PubMed1984

Hormonal control of prostatic thyrotropin-releasing hormone (TRH) testosterone modulates prostatic TRH concentrations.

The presence of extremely high concentrations of authentic TRH in the rat prostate prompted us to examine whether prostatic TRH concentrations were under hormonal control. Both the immunoreactive TRH content per prostate and TRH immunoreactivity expressed per 100 mg prostatic protein were lower in animals 2 weeks after hypophysectomy than in sham-operated and calorically restricted weight-matched controls. Since many of the prostatic functions are testosterone dependent, we assessed the possibility that testosterone modulated prostatic TRH concentrations. We measured prostatic TRH concentrations in the following four groups of sexually mature male Sprague-Dawley rats: group I, sham operated; group II, castrated; group III, castrated animals with 5-mm Silastic testosterone implants; and group IV, castrated animals with 20-mm testosterone implants. Prostatic TRH concentrations in these four groups 2 weeks after surgery were 600.5 +/- 33.3, 65.1 +/- 22.6, 169.4 +/- 55.3, and 609.5 +/- 144.3 (+/-SE) ng/100 mg protein. There was good linear correlation between prostatic TRH concentrations and serum testosterone concentrations (r = 0.65; P less than 0.01). By subjecting the pooled prostatic extracts from each group to ion exchange chromatography on a SP-Sephadex C-25 column and measuring the proportion of immunoreactivity coeluting with authentic TRH, it was shown that the fall in prostatic TRH immunoreactivity after castration and hypophysectomy was indeed due to a loss of authentic TRH. We conclude that the prostatic TRH concentrations are under hormonal control and appear to be modulated by serum testosterone concentrations. This is the first demonstration of hormonal regulation of a neuropeptide in a mammalian extrahypothalamic site and suggests a physiological role for this neuropeptide at this site.

Animals↗

PubMed1986

Regulation of overgrowth and expression of prostatic binding protein in rat chimeric prostate gland.

Enlargement of the chimeric ventral prostate gland (VP) was induced by directly implanting either fetal urogenital sinus mesenchyme (UGM) or intact fetal urogenital sinus (UGS) into the VP of intact adult rats. The macromolecular content in the chimeric prostate increased from 40-100% (UGM implants) to 200-300% (UGS implants) above control levels. The enlargement of the prostate gland was the result of growth from both the donor tissue and the host gland. Growth of the donor fetal UGS within the host prostate gland may account for the difference observed between the growth induced by fetal UGS and fetal UGM implants. Because fetal UGM regressed when implanted and grown under the renal capsules, the observation of growth in the adult rat VP induced by fetal UGM, either by implanting UGM in situ or forming tissue recombinants of UGM and the adult VP, suggests that fetal UGM requires close association with the VP for the induction of growth to occur. The concentration of an epithelial androgen-dependent protein, the prostatic binding protein (PBP), expressed by the enlarged lobe of the rat VP was similar to that of the control lobe of rat VP. The adult host gland, rather than donor implants, appeared to determine the levels of expression of PBP within the chimeric prostate gland. Immunofluorescence data indicated that PBP was distributed evenly throughout most of the prostatic acini. PBP also accumulated in the lumen of the prostatic acini. Positive immunofluorescence, although less intense, was detected in the UGS remnant, suggesting that fetal UGS was induced by the intact adult VP environment to express PBP. We observed a developmental restriction in the ability of donor prostatic tissues to induce enlargement of the host prostate gland. Fetal UGS was the most effective inducer, whereas neonatal prostatic tissue was marginally effective, and adult prostatic tissue or stromal cells derived from adult VP were completely ineffective.

Androgen-Binding Protein↗

PubMed2002

Finasteride-induced prostatic involution by apoptosis in dogs with benign prostatic hypertrophy.

OBJECTIVE: To determine the effect of finasteride on programmed cell death (apoptosis) of prostatic cells during prostatic involution in dogs with benign prostatic hypertrophy (BPH). ANIMALS: 9 dogs with BPH. PROCEDURE: Dogs were randomly assigned to treatment or control groups. Treatment dogs (n = 5) were administered finasteride (0.1 to 0.5 mg/kg, PO, q 24 h) for 16 weeks, whereas the 4 control dogs were administered an inert compound. Prostatic cells from the prostatic fluid portion of the ejaculate of treatment and control dogs were obtained before and 1, 2, 3, 4, 8, and 16 weeks after initiation of treatment. Cells were concentrated by use of centrifugation. Prostatic cells were examined for indications of apoptosis by use of a terminal deoxyribonucleotidyl transferase-mediated deoxyuracil triphosphate nick-end labeling technique. After receiving the inert compound for 16 weeks, the 4 control dogs were administered finasteride for 16 weeks, and evaluations were repeated. RESULTS: Percentage of apoptotic prostatic cells in ejaculated prostatic fluid of treatment dogs increased significantly (from 9% before treatment to 33, 31, 26, and 27% after 1, 2, 3, and 8 weeks of treatment, respectively). There was no significant change in percentage of apoptotic prostatic cells in the ejaculated prostatic fluid of control dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Finasteride-induced prostatic involution appears to be via apoptosis in dogs with BPH. Finasteride treatment of dogs with BPH causes prostatic involution by apoptosis rather than necrosis.

Animals↗

PubMed1999

Castration induces acute vasoconstriction of blood vessels in the rat prostate concomitant with a reduction of prostatic nitric oxide synthase activity.

PURPOSE: Previous studies demonstrating a rapid and drastic reduction of blood flow to the rat prostate gland resulting from castration caused us to consider the influence of castration on the state of vascular constriction and on the activity of the vascular tone-regulating factors (nitric oxide synthase and cyclic GMP) in the rat prostate. MATERIALS AND METHODS: Sections of ventral prostate glands obtained from intact and castrated rats were analyzed for the mean areas within smooth muscle-coated blood vessels using a computerized microscopic image analysis system. Nitric oxide synthase (NOS) levels were measured in prostatic extracts from unoperated or castrated rats using an enzyme assay system that measures conversion of 3H-L-arginine to citruline. Cyclic GMP levels were measured in prostatic extracts from unoperated or castrated rats using a competitive radioimmunoassay system. RESULTS: The mean area within ventral prostate smooth muscle-coated blood vessels was reduced 39% at 24 hours after castration (p = 0.039) and 47.7% at 48 hours after castration (p = 0.039). NOS activity measured in prostatic extracts was reduced 38% at 24 hours (p = 0.0012) and 51.6% at 36 hours after castration (p = 0.0001) compared with the control group of noncastrated rats. Finally, prostatic cGMP levels were reduced 55.8% (p = 0.0018) at 36 hours after castration when compared with controls rats. CONCLUSION: Within 24 hours after castration, the lumenal areas of smooth muscle-coated blood vessels in the rat prostate gland were found to be significantly reduced. This vasoconstriction was associated with a significant reduction of prostatic NOS activity as well as a reduction in the prostatic levels of the NOS co-factor, cGMP. Thus, acute vasoconstriction is a prominent early event associated with rat prostate regression in response to castration and likely contributes to the regression of the tissue.

Animals↗

PubMed2000

Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.

PURPOSE: NKX3.1, a member of the family of homeobox genes, exhibits prostate tissue specific expression and appears to play a role in mouse prostate development. Rapid induction of NKX3.1 gene expression in response to androgens has also been described. On the basis of the established role of androgens in prostatic growth and differentiation and studies showing an association of aberrant homeobox gene expression with the neoplastic process, we hypothesize that alterations of NKX3.1 gene expression play a role in prostate tumorigenesis. MATERIALS AND METHODS: NKX3.1 expression was analyzed in matched, microdissected normal and tumor tissues from 52 primary prostate cancer specimens from radical prostatectomy by semiquantitative RT-PCR and in situ hybridization and correlated with the clinicopathologic features. NKX3.1 expression was quantified as differential expression between matched tumor and normal tissues and was grouped as overexpression in tumor tissue, reduced expression in tumor tissue and no change between tumor and normal tissues. Androgen regulation of NKX3.1 expression was also studied in LNCaP cells. Androgen receptor (AR) expression in prostate tumor and normal tissue was correlated with NKX3.1 expression. RESULTS: Comparison of NKX3.1 expression between normal and tumor tissues revealed overexpression in 31% tumor specimens (16 of 52), decreased expression in 21% tumor specimens (11 of 52) and no change in 48% specimens (25 of 52). When these expression patterns were stratified by organ confined and non-organ-confined tumor, a higher percentage of patients exhibited NKX3.1 overexpression in non-organ confined tumor (40%) versus organ confined tumor (22%). Elevated NKX3.1 expression significantly correlated with tumor volume and serum prostate specific antigen (PSA) level in the NKX3.1 overexpression group (p<0.05). Metastatic prostate cancer cell lines did not exhibit mutations in the protein coding sequence of NKX3.1. Additionally, the NKX3.1 expression correlated with AR expression (p<0.01) in vivo in human prostate tissues. Comparison of PSA and NKX3.1 expression in response to androgen revealed a rapid androgen mediated induction of NKX3.1 expression in LNCaP cells. In situ hybridization analysis of representative specimens confirmed RT-PCR observations. CONCLUSIONS: These results suggest an association of NKX3.1 with a more aggressive phenotype of carcinoma of the prostate. Correlation of AR expression with NKX3.1 in human prostate tissues underscores the androgen regulation of NKX3.1 in the physiologic context of human prostate tissues.

Androgens↗

PubMed2001

Alternative pathways to prostate carcinoma activate prostate stem cell antigen expression.

Prostate Stem Cell Antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface protein that is expressed in normal human prostate and overexpressed in human prostate cancers. To test whether different pathways that generate prostate cancer would affect PSCA expression, a murine model system was developed. Monoclonal antibodies were generated against murine PSCA (mPSCA). mPSCA is expressed on approximately 20% of cells in normal prostate epithelium, and this number decreases with increasing age. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer, tumors develop between 19 and 25 weeks of age. Murine PSCA was strongly expressed on approximately 60% of the cells of TRAMP tumors, at an age where the number of PSCA+ cells and the level of expression of PSCA is very low in the normal prostate. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) +/- mice develop a number of different cancers, including prostate cancer. The incidence of prostate cancer is low and occurs after a relatively long latency. Fluorescence-activated cell sorter analysis of prostatic tissue from 11-18-month-old PTEN +/- mice showed elevated numbers of PSCA+ cells in the prostate, and immunohistochemical analysis showed high mPSCA expression in the tumors of these mice. Together, these results show that two distinct mechanisms of carcinogenesis lead to expression of a common target antigen.

Adenocarcinoma↗

PubMed2003

A novel human prostate-specific gene-1 (HPG-1): molecular cloning, sequencing, and its potential involvement in prostate carcinogenesis.

Prostate-specific genes that have a role in normal and abnormal prostate growth are needed for early and specific diagnosis and treatment of prostate cancer. In the present study, the differential display-PCR technique was used to obtain a prostate-specific approximately 339-bp cDNA fragment. On screening the human-prostate lambdagt10 library with this fragment, a full-length 1468-bp human prostate-specific gene (HPG-1) with an open reading frame of 127 amino acids (aa) was retrieved. Extensive database search revealed that the HPG-1 has novel nucleotide/aa sequences. It was localized on Homo sapiens 3q26 chromosomal locus, a region that has been shown to be involved in prostate carcinoma. The computer-generated translated protein has a calculated molecular mass of 14.8 kDa with several potential glycosylation and phosphorylation sites including two N-linked glycosylation, one tyrosine phosphorylation, and one N-myristoylation sites. The in vitro transcription and translation procedures using HPG-1 cDNA yielded a protein of similar molecular mass of approximately 15 kDa. Hydrophilicity analysis of the deduced aa sequence indicated that HPG-1 is a membrane-anchored/attached protein. Analysis for tissue specificity by using the Northern blot and reverse transcription-PCR-Southern blot procedures using 19 different human tissues revealed that HPG-1 is expressed specifically only in prostate tissue. To examine its involvement in prostate carcinogenesis, three prostate cancer epithelial cell lines, one androgen-responsive (LNCaP) and two androgen-nonresponsive (DU-145 and PC-3), were examined for the expression of HPG-1. Using the Northern blot and quantitative reverse transcription-PCR procedures it was found that LNCaP and DU-145 cells and not the PC-3 cells have HPG-1 expression, with LNCaP cells having approximately 2-3-fold higher levels of HPG-1 mRNA transcripts compared with DU-145 cells. In vitro culture of LNCaP cell with antisense and not the sense oligonucleotide decreased the HPG-1 mRNA levels and inhibited the cell growth in a concentration-dependent manner; at 72 h there was an 86% inhibition of cell growth. HPG-1 mRNA expression in LNCaP cells was found to be responsive to androgen. Thus, the novel androgen-responsive HPG-1, which has prostate-specific expression and seems to be involved in carcinogenesis, may have applications in the specific diagnosis and treatment of prostate cancer.

Amino Acid Sequence↗

PubMed1989

[Studies on prostatism of males fifty years of age and older--analysis on results of a second mass screening for prostatic diseases in Tanno town].

We conducted a second mass screening for prostatism on males 50 years of age and older in the Tanno town area, to determine the incidence of benign prostatic hypertrophy (BPH) and prostatic carcinoma. We also studied how often elderly males had symptoms related to prostatism according to their age. The incidence of BPH was 10.0% in these males who were received the first and/or second mass screening as well as those treated previously, when BPH was defined as the prostate with a moderately or greater enlarged size upon digital palpation. The incidence of BPH was 8.9% in males fifty years of age and older who lived in Tanno town. The figures tended to elevate with the advance of age. Two new patients with prostatic carcinoma were discovered during this second mass screening, which resulted in a total of 8 patients discovered in this area. Of these 8 patients, 6 had been found in the first screening. The incidence of prostatic carcinoma was 1.4% in those males who received the first or second mass screening as well as those treated previously, and that in all the males who lived in the town was 1.0%. Further efforts will be necessary to establish a more convenient system that can provide less costly screening procedures and more effective diagnostic procedures to detect localized prostatic carcinoma. With advance in age the male tended to have a higher incidence of prostate with a moderately or markedly enlarged size, and symptoms related to prostatism. In addition, the urinary flow rate tended to decrease, irrespective of the prostate size. The results supported the significance of mass screening for prostatism.

Age Factors↗

PubMedDate not supplied

Separation and characterization of epithelial cells from prostates and prostatic carcinomas: a review.

Our investigation of normal, hyperplastic, and neoplastic prostatic tissue during the past 2 1/2 years has produced several findings which have been published or accepted for publication. (a) Cells from hamster prostates with intense histochemically demonstrable acid phosphatase activity (HDAP) after fixation with formaldehyde which we believe to be epithelial cells can be obtained in 97.2% +/- 0.8% purity by velocity sedimentation in a previously described isokinetic density gradient; (b) similarly, cells with HDAP, many of which contain lipofuscin granules, can be obtained as 81.0% +/- 12.2% of nucleated cells from hyperplastic human prostates and as 86.4% +/- 9.4% of nucleated cells from human prostatic carcinomas; (c) more cells were obtained from human hyperplastic prostates and prostates with prostatic carcinoma per gram of tissue with the aid of Pronase than were obtained with trypsin, collagenase, or mechanical methods; (d) more cells per gram of tissue were obtained from surgically removed prostates than from prostates obtained at even very rapid autopsies, and a much larger proportion of the cells from surgically removed prostates were viable as assessed both by dye exclusion and by plating efficiency; (e) none of several substrates and inhibitors which we tested were highly specific for acid phosphatase from purified prostatic epithelial cells compared with several other kinds of purified human cells; and (f) purified hamster prostatic epithelial cells incorporate large amounts of tritiated thymidine in 72-hour cultures.

Adenocarcinoma↗

PubMed1998

Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer.

Probasin (PB) gene product is prostate-specific, epithelial cell in origin, and androgen-regulated. A large 12-kb promoter fragment of the PB gene (LPB) was linked to the simian virus 40 (SV40) large T antigen (Tag) deletion mutant (that removes the expression of the small t antigen) to deliver consistently high levels of transgene expression to the transgenic mouse prostate. Seven male founders, their male offspring, and all the male offspring from two female founders developed at least prostatic epithelial cell hyperplasia by 10 weeks of age, indicating that the incidence of transformation was 100%. Tumorigenesis in the LPB-Tag animals progressed in a manner similar to that observed in the human prostate. Initially, multifocal proliferating lesions were detected in the prostatic epithelium, which continued to progress into hyperplasia involving the entire epithelium and then low-grade dysplasia. Reactive stromal proliferation was induced and continued to develop throughout the progression to high-grade dysplasia, carcinoma in situ, and adenocarcinoma. Immunohistochemical studies indicated that most stromal cells stained positively for both androgen receptor and smooth muscle alpha-actin, suggesting that stromal overgrowth largely represented mesenchymal cells that had differentiated into smooth muscle cells. Epithelial cell transformation was accompanied by the down-regulation of differentiated function, as suggested by the loss of dorsolateral prostate-specific secretory proteins. Tumor growth was regarded as androgen-dependent because tumors regressed in animals castrated at 11 weeks of age, and androgen treatment restored both epithelial/stromal cell ratio and tumor growth. Furthermore, small populations of prostatic epithelial cells in castrated animals continued to proliferate, suggesting the potential for androgen-independent growth. Although prostatic metastasis to other organs was not observed, local invasion was detected. In summary, the LPB-Tag animal model is unique in that it is the only model generated with the Tag alone, thereby eliminating any influences of the small t antigen on prostate tumor formation. Moreover, this model undergoes molecular changes similar to those found in human prostate including: (a) the multi-focal nature of tumorigenesis, (b) the progressive histopathologic changes from low- to high-grade dysplasia similar to human prostatic intraepithelial neoplasia, (c) stimulation of reactive stromal proliferation, and (d) the androgen-dependent growth of the primary tumor. Thus, the LPB-Tag prostate tumor model will be useful for studying the sequential mechanisms underlying the development of multistep tumorigenesis.

Androgen-Binding Protein↗

PubMed1998

Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer.

Androgen-Binding Protein↗

PubMed1998

An open study on the efficacy and safety of transurethral needle ablation of the prostate in treating symptomatic benign prostatic hyperplasia: the University of Florida experience.

PURPOSE: We determine the safety and efficacy of transurethral needle ablation of the prostate in patients with moderate to severe symptoms of benign prostatic hyperplasia. MATERIALS AND METHODS: Transurethral needle ablation of the prostate was performed on 45 consecutive patients. For an average prostate of 2.5 to 3 cm. long treatments were performed in 2 separate planes at 4 quadrants (2, 4, 8 and 10 o'clock positions) each. The 2 planes were 1 cm. below the bladder neck and 1 cm. proximal to the verumontanum. For prostatic urethral lengths longer than 3 cm. a treatment plane was added for each additional centimeter of prostatic urethra. The procedure was performed in 26 patients under local anesthesia using 20 cc 2% intraurethral lidocaine gel (11) or supplemented with intravenous 1.25 to 5 mg. midozolam (15). Of these patients 2 had a supplemental perineal block using a mixture of equal amounts of 15 cc 2% lidocaine without epinephrine and 0.25% bripivacaine, 10 underwent the procedure under general anesthesia, 2 had epidural and 4 had spinal anesthesia, and 3 had managed anesthesia care. Mean length of each procedure was 79 minutes (range 50 to 240). All procedures were done on an outpatient basis and patients were released on the same operative day. RESULTS: Mean prostatic volume on transrectal ultrasound was estimated at 48.1 cc (range 20 to 185). Following treatment the International Prostate Symptom Score decreased from a mean of 20.9 at baseline to 15.4 at 1 month, 16.1 at 3 months, 10.7 at 6 months and 9.9 at 1 year. The peak flow rate improved from a baseline mean of 8.3 to 13.4 at 3 months, 13.1 at 6 months and 14.9 at 1 year. The quality of life score improved from a baseline of 4.8 to 3.5, 2.2, 2.5 and 1.03 at 1, 3, 6 and 12 months, respectively. Of the 2 patients in whom the procedure failed; 1 required a bladder neck incision at 3 months and the other transurethral resection of the prostate. Foley catheters were left in place in all patients for an average of 4.85 days. CONCLUSIONS: After a followup of up to 12 months we conclude that transurethral needle ablation of the prostate is an effective treatment for symptomatic benign prostatic hyperplasia. This procedure has minimal morbidity, is less costly than conventional transurethral resection of the prostate and can be performed as an outpatient office procedure under local anesthesia in a significant number of patients.

Aged↗

PubMed2000

Structural changes and alteration in expression of TGF-beta1 and its receptors in prostatic intraepithelial neoplasia (PIN) in the ventral prostate of noble rats.

BACKGROUND: Prostatic intraepithelial neoplasia (PIN) is the most likely pre-cancereous lesion and represents the major target for chemoprevention of prostate cancer. The multi-functional role of TGF-beta1, together with its receptors, in normal prostate and development of prostatic neoplasia remains controversial and requires further investigation. METHODS: Ventral prostates were removed from Noble rats treated with a combination of testosterone (T) and estradiol (E(2)) for various periods of time, and processed for ultrastructural examination and histopathological grading. To evaluate the role of TGF-beta1 and TGFbeta receptor types I and II in normal prostate and high-grade PIN development, expression pattern of TGF-beta1 and TGFbeta-RI and TGFbeta-RII were studied on prostate samples with PIN lesions. RESULTS: Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) were observed in ducts or alveoli after three and five months of T + E(2) treatment, respectively. EM study revealed that HGPIN cells were characterized by a reduction in abundance of secretory apparatus and the nucleus with highly irregular and undulated membrane and often with inclusion bodies although the basal lamina remained largely normal. This was associated with a high level of expression of TGF-beta1 in stromal tissue subjacent to foci of HGPIN. No definite positive reactivity of TGF-beta1 was identified in glandular epithelial cells of HGPIN. These results implicated that the major site for the TGF-beta1 production remained to be restricted to stromal compartment at the stage of HGPIN, and a paracrine regulation of TGF-beta1 might be involved in the development of HGPIN. Positive staining for the TGFbeta-RI was found in the cytoplasm of luminal epithelial cells of normal ventral prostate. The intense positive reactivity for TGFbeta-RI was also identified in prostates with HGPIN lesions. Similar expression pattern of TGFbeta-RII was also observed. CONCLUSIONS: Based on the EM study, we concluded that HGPIN in ventral prostate was accompanied with alterations in nuclear morphology together with a change in secretory activity. The over expression of TGFbeta-RI and RII in HGPIN cells as well as TGF-beta1 in stromal tissue subjacent to HGPIN implicated a growth-stimulating role instead of inhibiting role of this peptide growth factor during the early stage of prostatic neoplasia.

Animals↗