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PubMed1984

Immunocytochemical evaluation of human prostatic carcinomas for carcinoembryonic antigen, nonspecific cross-reacting antigen, beta-chorionic gonadotrophin, and prostate-specific antigen.

The unlabeled antibody peroxidase-antiperoxidase technique was used to examine human malignant prostatic tissue (primary tumors) for the presence of prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), nonspecific cross-reacting antigen (NCA), and beta-chorionic gonadotrophin (HCG). The results were compared to those obtained with normal and hyperplastic prostate tissue (BPH). All specimens of neoplastic, hyperplastic, and normal prostate tissue showed immunostaining reactions for PSA. Immunostaining for PSA was relatively uniform among samples of normal and BPH tissue, but variations with respect to intensity of PSA immunostaining were noted among prostate tumors as well as between the neoplastic cells of individual tumors. Some areas of normal or hyperplastic prostatic epithelium within tumors showed stronger staining reactions for PSA than the tumor cells themselves. Using an antiserum which was able to detect both NCA and CEA, it was found that 16 of 38 tumors (42%) had positive immunostaining reactions. Of these, 15 were subsequently shown to contain only NCA immunoreactivity, and 1 tumor had both NCA and CEA immunoreactivity. NCA, but not CEA, immunoreactivity was identified in hyperplastic prostate tissue within tumor specimens and in BPH specimens. Neither antigen was detected in normal prostatic epithelium. Three of 38 tumors (8%) were found to contain neoplastic cells with HCG immunoreactivity. HCG immunoreactivity was not identified in BPH or normal prostatic tissue. Therefore, HCG and CEA immunoreactivity appear to be tumor-associated antigens in prostate cancer which are expressed with a low incidence. The results of the study identified prostate tumors with different patterns of immunocytochemical markers: 22 of 38 tumors (58%) contained only PSA immunoreactivity; 13 of 38 tumors (34%) contained PSA and NCA immunoreactivity; 2 of 38 tumors (5%) were positive for PSA, NCA, and HCG immunoreactivity; and 1 of 38 tumors (3%) contained PSA, NCA, HCG, and CEA immunoreactivity. Apart from PSA, which was present in all tumors, the markers studied here appeared to be more frequently expressed in well-differentiated tumors than in less-differentiated tumors. Our results suggest the possibility of subclassifying prostate tumors by means of immunocytochemistry.

Antigens↗
PubMed1999

Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment.

BACKGROUND: Unlike most other malignancies, prostate cancer metastasizes preferentially to the skeleton and elicits osteoblastic reactions. METHODS: We present a hypothesis, based upon results obtained from our laboratory and others, on the nature of progression of prostate cancer cells and their predilection to growth and metastasis in the bone microenvironment. We propose the hypothesis that osseous metastatic prostate cancer cells must be osteomimetic in order to metastasize, grow, and survive in the skeleton. The reciprocal interaction between prostate cancer and bone stromal growth factors, including basic fibroblast growth factor (bFGF), hepatocyte growth factor/scatter factor (HGF/SF), and especially the insulin growth factor (IGF) axis initiates bone tropism, and is enhanced by prostate secreted endothelin-1 (ET-1) and urokinase-type plasminogen activator (uPA). Growth factors and peptides that have differentiating activity, such as transforming growth factor beta (TGF-beta), parathyroid hormone-related protein (PTH-rp), and the bone morphogenetic proteins (BMPs), can shift local homeostasis to produce the characteristic blastic phenotype, via interaction with prostate-secreted human kalikrein 2 (hK2), and prostate-specific antigen (PSA). This proposal asserts that altering the expression of certain critical transcription factors, such as Cbfa and MSX in prostate cancer cells, which presumably are under the inductive influences of prostate or bone stromal cells, can confer profiles of gene expression, such as osteopontin (OPN), osteocalcin (OC), and bone sialoprotein (BSP), that mimic that of osteoblasts. RESULTS AND CONCLUSIONS: Elucidation of common proteins, presumably driven by the same promoters, expressed by both prostate cancer and bone stromal cells, could result in the development of novel preventive and therapeutic strategies for the treatment of prostate cancer skeletal metastasis. Agents developed using these strategies could have the potential advantage of interfering with growth and enhancing apoptosis in both prostate cancer and bone stromal compartments. The selective application of gene therapy strategy, driven by tissue-specific and tumor-restricted promoters for the safe delivery and expression of therapeutic genes in experimental models of prostate cancer metastasis, is discussed.

Bone Neoplasms↗
PubMed1998

Estimation of canine prostatic volume: nomogram based on prostatic cubic volume.

To estimate prostate volume in canines, we demonstrated the nomogram based on prostatic cubic volume. Transrectal ultrasonography (TRUS) was performed in twenty beagle dogs. Prostatic length (L) and height (H) were determined on sagittal image, and prostatic width (W) was determined on transaxial image. Data of one dog, which had asymmetrical shaped prostate, were excluded from the analysis. Prostate volume was estimated by the following nomogram: Gravimetric prostatic volume (g) = 0.642 x prostatic cubic volume (cm3) + 1.84 (prostatic cubic volume = L x H x W cm3, r = 0.997, p<0.001). By substituting the prostatic height to the average of height, prostatic volume of one dog showing asymmetrical shape was successfully estimated. We also showed technical points in evaluating morphology of canine prostate on TRUS. In conclusion, this nomogram is of great use for directly estimating prostatic volume.

Animals↗
PubMed2006

DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process.

Prostate cancer metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer, frequently resulting in significant morbidity and mortality. As the underlying mechanisms are not fully characterized, understanding the biological mechanisms that govern prostate cancer metastases to bone at the molecular level should lead to the determination of new potential therapeutic targets. Receptor activator of NFkappaB ligand (RANKL)/RANK/Osteoprotegerin (OPG) are the key regulators of bone metabolism both in normal and pathological condition, including prostate cancer bone metastases. In the present study, we demonstrated that human prostate cancer cell lines, DU145 and PC3 express biologically functional RANK. Indeed, soluble human RANKL (shRANKL, 100 ng/ml) treatment induced ERK 1/2, p38 and IkappaB phosphorylations in these cells. shRANKL administration also promoted DU145 and PC3 prostate cancer cell invasion in vitro. Whereas human OPG (hOPG) administration alone (100 ng/ml) had no marked effect, combined association of both agents abolished the RANKL-induced DU145 cell invasion. As RANKL had no direct effect on DU145 cell proliferation, the observed effects were indeed related to RANKL-induced cell migration. DU145 human prostate cancer cells promoted osteoclastogenesis of osteoclast precursors generated from mouse bone marrow. Moreover, DU145 cells produced soluble factor(s) that up-regulate the proliferation of MC3T3-E1 pre-osteoblasts through the activation of the ERK 1/2 and STAT3 signal transduction pathways. This stimulation of pre-osteoblast proliferation resulted in an increased local RANKL expression that can activate both osteoclasts/osteoclast precursors and prostate cancer cells, thus facilitating prostate cancer metastasis development in bone. We confirm that RANKL is a factor that facilitates metastasis to bone by acting as an activator of both osteoclasts and RANK-positive prostate cancer cells in our model. Furthermore, the present study provides the evidence that blocking RANKL-RANK interaction offer new therapeutic approach not only at the level of bone resorbing cells, but also by interfering with RANK-positive prostate cancer cells in the prostate cancer bone metastasis development.

3T3 Cells↗
PubMed2001

Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma.

OBJECTIVES: To compare the immunohistochemical properties of the 7E11 anti-prostate-specific membrane antigen (anti-PSMA) monoclonal antibody (mAb) with the recently developed anti-PSMA mAb, PM2J004.5, and with other common immunomarkers in metastatic prostate cancer. PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer cells. The mAb 7E11 is currently used in the radioisotopic evaluation of prostate cancer, and its immunohistochemical properties have been examined in primary prostate cancer specimens. METHODS: We examined 23 formalin-fixed, paraffin-embedded, metastatic prostate carcinoma specimens from various anatomic sites, including bone, lymph node, liver, lung, and soft tissue. Using the biotin-streptavidin method, we performed immunohistochemical reactions with the anti-PSMA mAbs 7E11 and PM2J004.5 and with antibodies to prostate-specific antigen and prostatic acid phosphatase. The immunoreactions were scored by pathologists unaware of the clinical and pathologic data according to a staining intensity scale and the percentage of cells stained. RESULTS: All four mAbs consistently stained the metastatic prostate cancer specimens. In 2 (8.7%) of 23 cases, however, the prostate-specific antigen immunoreaction was negative but the anti-PSMA mAbs had positive staining. Although 7E11 and PM2J004.5 had a similar staining intensity and percentage of cells stained for most specimens, in 3 (13%) of 23 specimens, 7E11 had less intense staining. None of the specimens were negative for all four antibodies. CONCLUSIONS: Anti-PSMA mAbs consistently immunoreacted with metastatic prostate cancer specimens and were positive in instances when prostate-specific antigen staining was negative. The anti-PSMA mAbs demonstrated similar staining patterns; however, in select cases, the PM2J004.5 mAb did show more intense staining. The anti-PSMA mAbs 7E11 and PM2J004.5 are useful in the pathologic evaluation of paraffin-embedded metastatic prostate cancer specimens.

Antibodies, Monoclonal↗
PubMed1999

Polymerase chain reaction amplification of bacterial 16s rRNA genes in prostate biopsies from men without chronic prostatitis.

OBJECTIVES: A previously reported study using nested polymerase chain reaction (PCR) analysis indicated the presence of DNA from a variety of prokaryotic microorganisms in 77% of transperineal prostate biopsies from patients with chronic nonbacterial prostatitis. Because that study did not include a control group, we investigated whether microbial DNA could also be found in transperineal prostate biopsies obtained from men who did not have a history of prostatitis. METHODS: Transperineal biopsies of both lobes of the prostate were obtained under ultrasound guidance from 9 patients with localized adenocarcinoma of the prostate. DNA was extracted from the prostatic tissue and two-round amplification performed using nested primers from a highly conserved region of the bacterial 16s rRNA gene. Amplified DNA was purified and sequenced, and sequences obtained were compared to bacterial rRNA genes recorded in GenBank. Results. Eleven of 18 biopsy specimens from 8 of 9 patients were positive for bacterial DNA by PCR. Sequence data indicated a predominant organism in 8 of 11 specimens, with greater than 95% homology to DNA from several different genera of bacteria, including Escherichia and Bacteroides. All 9 control samples from the instruments before biopsy were negative. CONCLUSIONS: The presence of bacterial 16s rRNA genes in prostatic tissue is not specific for chronic prostatitis and occurred in most of our patients with localized prostate cancer. Whether the presence of such bacteria is related to the development of prostatic diseases such as prostatitis or prostatic cancer will require carefully controlled trials, including appropriate control groups examined identically.

Aged↗
PubMed2000

Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer.

Prostate stem cell antigen (PSCA) is a recently defined homologue of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA mRNA is expressed in the basal cells of normal prostate and in more than 80% of prostate cancers. The purpose of the present study was to examine PSCA protein expression in clinical specimens of human prostate cancer. Five monoclonal antibodies were raised against a PSCA-GST fusion protein and screened for their ability to recognize PSCA on the cell surface of human prostate cancer cells. Immunohistochemical analysis of PSCA expression was performed on paraffin-embedded sections from 25 normal tissues, 112 primary prostate cancers and nine prostate cancers metastatic to bone. The level of PSCA expression in prostate tumors was quantified and compared with expression in adjacent normal glands. The antibodies detect PSCA expression on the cell surface of normal and malignant prostate cells and distinguish three extracellular epitopes on PSCA. Prostate and transitional epithelium reacted strongly with PSCA. PSCA staining was also seen in placental trophoblasts, renal collecting ducts and neuroendocrine cells in the stomach and colon. All other normal tissues tested were negative. PSCA protein expression was identified in 105/112 (94%) primary prostate tumors and 9/9 (100%) bone metastases. The level of PSCA expression increased with higher Gleason score (P=0.016), higher tumor stage (P=0.010) and progression to androgen-independence (P=0. 021). Intense, homogeneous staining was seen in all nine bone metastases. PSCA is a cell surface protein with limited expression in extraprostatic normal tissues. PSCA expression correlates with tumor stage, grade and androgen independence and may have prognostic utility. Because expression on the surface of prostate cancer cells increases with tumor progression, PSCA may be a useful molecular target in advanced prostate cancer.

Antibodies, Monoclonal↗
PubMed2001

Expression and regulation of prostate androgen regulated transcript-1 (PART-1) and identification of differential expression in prostatic cancer.

Prostate androgen regulated transcript 1 (PART-1), is a gene predominantly expressed in the prostate gland and is regulated by androgens in human prostate cancer cell lines. Here, we report additional characteristics of PART-1 tissue expression and hormonal regulation and study its expression profile in human normal and matched prostate cancer tissues. Since PART-1 shows similarity to prostate-specific antigen (PSA) in prostate specificity and regulation, we hypothesized that it may be implicated in prostate carcinogenesis or may be a potential new biomarker. We used reverse transcriptase polymerase chain reaction (RT-PCR) to further characterize PART-1 tissue expression and hormonal regulation in the LNCaP prostate cancer cell line. RT-PCR analysis revealed that PART-1 is expressed not only in the prostate and salivary gland, but also in other tissues, including the thymus and placenta. In addition to androgen stimulation, PART-1 is also up-regulated by progestins, oestrogens and glucocorticoids. We further studied the expression of PART-1 in 27 paired (from the same patient) cancerous and non-cancerous prostatic tissues, with qualitative and quantitative RT-PCR (LightCycler technology), in order to examine whether PART-1 is overexpressed or underexpressed in cancer. Our results indicated that PART-1 is more frequently overexpressed in the cancerous prostatic tissue. We conclude that this gene is overexpressed in prostate cancer and may represent a novel prostate cancer tumour marker.

Aged↗
PubMed1953

Quantitative studies of prostatic secretion. III. Simultaneous measurement of size and secretion of the canine prostate and the interaction of androgenic and estrogenic substances thereon.

The prostate of the dog was relocated permanently in the perineum where its size could be measured and correlated with the output of prostatic secretion during many months. The secretion of a submaxillary gland obtained through a fistula was utilized as an internal biologic standard of the effects of pilocarpine, the secretory stimulus employed, because the amount and route of administration of the alkaloid are critical factors in inducing secretion. Prostatic secretion was found to be profoundly affected by androgenic and estrogenic compounds, in contrast to salivation. The curves of the secretory response of the prostate and submaxillary glands to pilocarpine proved to be similar and a mathematical formula has been constructed to represent them. When testosterone propionate was administered in increasing quantities for periods of weeks at each level, the volume of the prostate increased in a series of flattened curves. This volume, under the conditions mentioned, was found to stand in a simple arithmetic relationship to the amount of testosterone propionate administered. Moderate quantities of testosterone propionate masked the effects of small amounts of stilbestrol on the prostate. The reverse was also true and the critical amounts of these compounds were defined. The amounts of stilbestrol were determined which lowered the quantity of prostatic secretion resulting from the simultaneous administration of moderate amounts of testosterone propionate in castrate dogs, the result being a level and flat secretory curve which was maintained for many weeks. We designate this effect the plateau phenomenon. When this amount of estrogen was continued, and the dosage of testosterone propionate greatly augmented, the prostatic secretion did not increase in volume. Very slight increases above the critical amount of stilbestrol, however, caused the secretory curve to fall to new and still lower levels though the secretion was never completely suppressed. The acid phosphatase content of the prostatic secretion in the regions of secretory plateaus was similar to that of castrate dogs injected with androgen alone. The plateau phenomenon is due to simultaneous physiologic action of androgenic and estrogenic compounds on the prostatic cells. The depression of prostatic secretion resulting in the plateau phenomenon is due to both functional and structural changes in the prostatic epithelium. They are best explained on the assumption that differences in steroid threshold exist in groups of cells within the prostate, those of the anterior rim of the gland being least susceptible to estrogenic activity.

Androgens↗
PubMed2002

Prostatic tissue in mature cystic teratomas of the ovary: a report of four cases, including one with features of prostatic adenocarcinoma, and cytogenetic studies.

Four cases of mature cystic teratoma that contained prostatic tissue are reported. The ovarian tumors occurred in patients from 17 to 38 (mean 31) years of age and had no unusual clinical or gross aspects. The microscopic findings for the most part were typical of a mature cystic teratoma, but they also contained foci of prostatic tissue that ranged from 0.2 to 1.9 cm in greatest dimension. In these areas there was a lobular arrangement of medium-sized acini lined by cuboidal to columnar cells with pale cytoplasm and round nuclei with inconspicuous nucleoli except focally in one case as noted below. Basal cells were seen focally. The prostatic acini lay in a paucicellular fibromuscular stroma. In two cases thick layers of disorganized smooth muscle covered by transitional-like pseudostratified epithelium, resulting in an appearance resembling fetal bladder wall, were present next to the prostatic glands. One tumor also contained prostatic-type acini, which haphazardly infiltrated the stroma over an area approximately 5 mm in maximal dimension. The acini, a few of which contained intraluminal flocculent eosinophilic material, were lined by cells with eosinophilic to amphophilic focally granular cytoplasm and had nuclei that were enlarged compared with the benign-appearing, prostatic-type acini in the four cases and had focally prominent nucleoli. Basal cells were not identified in these infiltrating glands. Grading this focus according to the approach in the prostate, the morphology was that of a Gleason grade 3 of 5 adenocarcinoma. Immunohistochemical stains of the putative prostatic epithelial cells confirmed their nature by showing immunoreactivity for prostatic-specific antigen in the lining epithelial cells in all four cases and for prostatic-specific acid phosphatase in the one case tested. The high molecular cytokeratin stain, 34betaE12, highlighted basal cells to a variable extent in the three cases containing only benign prostatic tissue. Material was not available to immunostain for basal cells in the case with carcinoma. Cytogenetic studies were performed in two cases and showed that the great majority of the nuclei of the nonprostatic and prostatic tissue had an XX karyotype but from 3% to 5% of the nuclei displayed trisomy for the X chromosome. A small number of cases of prostatic tissue in ovarian teratomas have previously been documented but none had morphologic features of carcinoma.

Adenocarcinoma↗
PubMed2006

Tyrosine kinase Etk/BMX is up-regulated in human prostate cancer and its overexpression induces prostate intraepithelial neoplasia in mouse.

The nonreceptor tyrosine kinase Etk/BMX was originally identified from the human prostate xenograft CWR22. Here, we report that Etk is up-regulated in human prostate tumor specimens surveyed. Knocking down Etk expression by a specific small interfering RNA (siRNA) in prostate cancer cells attenuates cell proliferation, suggesting an essential role of Etk for prostate cancer cell survival and growth. Targeted expression of Etk in mouse prostate epithelium results in pathologic changes resembling human prostatic intraepithelial neoplasia, indicating that up-regulation of Etk may contribute to prostate cancer development. A marked increase of luminal epithelial cell proliferation was observed in the Etk transgenic prostate, which may be attributed in part to the elevated activity of Akt and signal transducers and activators of transcription 3 (STAT3). More interestingly, the expression level of acetyltransferase cyclic AMP-responsive element binding protein-binding protein (CBP) is also increased in the Etk transgenic prostate as well as in a prostate cancer cell line overexpressing Etk, concomitant with elevated histone 3 acetylation at lysine 18 (H3K18Ac). Down-modulation of Etk expression by a specific siRNA leads to a decrease of H3 acetylation in prostate cancer cell lines. Our data suggest that Etk may also modulate chromatin remodeling by regulating the activity of acetyltransferases, such as CBP. Given that Etk may exert its effects in prostate through modulation of multiple signaling pathways altered in human prostate cancer, the Etk transgenic mouse model may be a useful tool for studying the functions of Etk and identification of new molecular markers and drug targets relevant to human diseases.

Animals↗
PubMed1996

Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle.

The prostate and seminal vesicle (SV) are androgen-dependent secretory glands of the male genital tract. The epithelial cells of these glands produce the bulk of the seminal secretions. The objective of the present study was to examine the ontogeny of cytokeratin and androgen receptor (AR) expression in the rat SV, anterior prostate (AP) and ventral prostate (VP). The study utilized organ culture to examine the effects of androgens on the development of these markers and castration of adult rats to examine androgenic effects on their maintenance. Tissues were examined from 14 days of gestation to adulthood. The SV was a tubular organ from its inception while the prostate formed from solid epithelial cords. These prostatic buds canalized in a proximal to distal manner starting at day 1 postnatal in the VP and day 5 in the AP. The expression of cytokeratins and AR was visualized by immunocytochemistry. In all three glands keratins 5, 7, 8, 14, 18 and 19 were initially uniformly expressed in all epithelial cells. In the SV, segregation of cytokeratins between the luminal and basal cell types started at 4 days postnatally with keratin 7 localizing to basal cells. Five days after birth, keratins 5 and 14 were also localized to the basal epithelium, while keratins 8 and 18 were only expressed by luminal cells, Keratin 19 was expressed in all epithelial cells throughout development and into adulthood. In the VP and AP the same pattern of cytokeratin segregation occurred as in the SV. Epithelial differentiation occurred in a proximal to distal fashion in the prostate. In the proximal VP ducts keratins 7 and 14 were basally localized by 2 days postnatally, while keratin 5 did not clearly segregate to basal cells until day 9 after birth. In the AP keratin 14 was basally localized by 1 day postnatal but keratin 5 and 7 did not colocalize to the basal cells until days 9 and 12, respectively. AR were expressed in the epithelium of the urogenital sinus from 19 days of gestation. At 19 and 20 days of embryonic development AR-negative prostatic buds were seen emerging from the AR-positive urogenital sinus epithelium. By birth AR were detectable in the epithelium of both prostatic lobes and the SV. The role of androgens in the development of the prostatic and SV epithelium was investigated in a serum-free organ culture system. These experiments showed that differentiation of prostatic and SV luminal and basal epithelial cell types was accelerated as compared to the in vivo situation in the presence of androgens, and did not occur in their absence. Following castration of adult animals the prostate and SV regressed with preferential loss of luminal epithelium. The relative numbers of basal cells was increased, though some flattened cells expressing a luminal cell pattern of cytokeratins were still observed. AR were detected in the prostatic and SV epithelium of long-term castrated animals. In summary, the rat prostate was found to be derived from undifferentiated solid epithelial cords. Canalization occurred concurrent with the differentiation of clear epithelial subtypes. Epithelial AR were expressed from around the time of birth and expression levels increased with age. The SV was canalized from its inception but likewise was derived from an undifferentiated epithelial precursor.

Age Factors↗
PubMed1986

Aging in the AXC/SSh rat: diminished prostate L-ornithine decarboxylase (ODC) activity reflects diminished prostate ODC protein and transcript content.

Immunotitration of L-ornithine decarboxylase (ODC) activity in ventral prostates of young mature (6-month-old) and aged (26-month-old) AXC/SSh rats established that the relation between enzyme activity and prostate ODC mass content was age invariant, demonstrating that the 4-fold diminution in prostate ODC activity in aged subjects represents decreased ODC protein content. Testosterone treatment of aged rats increased prostate ODC activity 2-fold and did not affect prostate ODC half-life. These latter findings and the preceding observation established that the testosterone-mediated increase in prostate ODC activity in aged individuals reflected increased ODC mass content. The half-life of prostate S-adenosyl-L-methionine decarboxylase, another prominent enzyme of polyamine biosynthesis, also was not altered by testosterone treatment of 26-month-old animals. The age-related diminution and testosterone-mediated increase in ventral prostate ODC activity occurred in concert with comparable quantitative changes in ventral prostate ODC transcript content. Because plasma testosterone content was age invariant between 3 and 18 months, the age span during which much of the reduction in prostate ODC activity occurs, and then declined by 50% at 26 months, our studies suggest that age-related diminutions in prostate ODC activity and transcript content reflect altered prostate sensitivity to androgen rather than response to diminished plasma testosterone content. Our data imply that age-related alterations in androgen regulation of androgen-responsive genes may be characteristic of the prostate during aging.

Adenosylmethionine Decarboxylase↗
PubMed1997

The expression of receptors for estrogen and epithelial growth factor in the male rabbit prostate and prostatic urethra following castration.

In the lower urinary tract of the male rabbit, estrogen receptors (ERs) are restricted to the urethra and the prostatic stroma. At present, the function of ERs in these tissues is not known. Epithelial growth factor (EGF) stimulates proliferation of epidermal and epithelial tissues, and several animal studies have indicated that EGF is regulated by estrogen. On this background, we have studied the effect of castration on the expression of ERs and EGF receptors in the rabbit prostatic urethra and prostate. Twelve male rabbits were studied fourteen days after castration, and eight normal rabbits were included as controls. In the control group, ERs were found in the urothelial lining and lamina propria of the prostatic urethra, and in the prostatic stroma. EGF receptors were demonstrated in the epithelial lining of the prostatic urethra and the glandular epithelium of the prostate. Following castration, the expression of ERs, assessed as the increase in the number of positively stained specimens, increased significantly in the lamina propria of the prostatic urethra and the prostatic stroma. EGF receptor expression increased significantly in the epithelial lining of the prostatic urethra. In the prostate, the increase was not significant. The results give no support to the view that ERs play role in the regulation of EGF receptors in the rabbit prostatic urethra nor the prostate.

Animals↗
PubMed1999

The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy.

BACKGROUND: Extraprostatic extension (EPE) is an unfavorable prognostic factor in patients with prostate carcinoma. Prior studies have reported the linear extent of EPE measured circumferentially along the edge of the prostate. In this study, the authors defined and evaluated a novel measure of EPE in a large series of radical prostatectomy specimens. These results have important clinical implications in the management of localized prostate carcinoma by brachytherapy and other modalities. METHODS: The authors reviewed the preoperative records and biopsy findings from 376 patients who underwent radical retropubic prostatectomy between September 1991 and June 1993. Whole mount radical prostatectomy specimens were examined, and the location of EPE for each specimen was recorded. The radial EPE distance was measured perpendicular to the edge of the prostate. For specimens with multiple EPE sites, the maximum radial EPE distance was recorded. Established eligibility criteria for prostate brachytherapy were evaluated using these results, with emphasis placed on achieving adequate radiation dose coverage 3-5 mm beyond the capsule or the edge of the prostate. RESULTS: EPE was identified in 105 of 376 specimens (28%) at 248 sites. The radial EPE distance in these specimens had a mean of 0.8 mm (range, 0.04-4.4 mm) and a median of 0.5 mm. Of these 105 patients, the median and mean preoperative prostate specific antigen (PSA) concentrations were 11.8 ng/mL and 17.9 ng/mL, respectively. The mean and range of the Gleason score and prostate volume for all specimens were 6.3 (range, 3-9) and 39 cc (range, 8-294 cc), respectively. In 107 patients who met the selection criteria for prostate brachytherapy eligibility of a PSA level < 10 ng/mL, Gleason score < 7, and gland volume < 60 cc, the maximum and mean radial EPE distances were 0.6 mm and 0.03 mm, respectively. CONCLUSIONS: The radial distance of EPE is an important measure that influences treatment strategies for patients with localized prostate carcinoma. Currently described criteria for the treatment of early stage prostate carcinoma by brachytherapy alone appear satisfactory to ensure effective radiation dose coverage of EPE of prostate tumors. Treating the prostate with a 3-5 mm margin by brachytherapy would encompass all known tumor in approximately 99% of the specimens examined in this study.

Aged↗
PubMed2000

A blood-prostate barrier restricts cell and molecular movement across the rat ventral prostate epithelium.

INTRODUCTION: Blood-epithelial barriers have been described in the testis and epididymis, but the possibility of such barriers in other regions of the male genitourinary tract has received little investigation. The purpose of this study was to use in vivo micro-puncture to determine if the blood-epithelial barrier exists in the rat ventral prostate. In addition, using a model of prostatic inflammation, we sought to examine the effect of inflammation on the passage of blood borne molecules and leukocytes into the prostatic ductal lumen. MATERIALS AND METHODS: Adult Sprague-Dawley rats were divided into two groups, control and 24-hour lipopolysaccharide (LPS)-induced inflammation. Both groups were subjected to vascular infusion of radiolabeled 3H dextran, 14C urea, and 3H water. Contemporaneous in vivo micropuncture sampling of prostatic ductal fluid (DF) and arterial blood occurred at multiple time points over 120 minutes. Transepithelial movement of radiolabeled compounds at each sampling time point was quantified by the expression of DF isotope concentrations as a percentage of serum isotope concentrations at that time point. Histology of representative specimens of control and inflamed prostates was used to confirm the inflammatory response and to examine for the presence of leukocytes into the ductal lumen. RESULTS: The transepithelial movement of radiolabeled compounds from blood to prostatic lumen varied in direct relationship to the compound's molecular weight. 3H-water (MW = 18) movement into the ductal lumina was relatively rapid plateauing at 70-80% of serum values. 14C urea (MW = 60) achieved intermediate penetration into ductal fluid (50-60% of serum values) and 3H dextran (MW = 2 x 106) was essentially excluded from entry (<2% of serum). These results were not altered by LPS-induced inflammation. Histology revealed a diffuse leukocyte infiltrate in the inflamed prostatic interstitium, but penetration of inflammatory cells into the ductal lumen was very restricted. CONCLUSIONS: Our findings demonstrate a blood-prostate barrier in the rat ventral prostate with characteristics similar to the blood-testis barrier. This blood-prostate barrier is not affected by LPS-induced acute inflammation. Further, this persistent barrier apparently restricts the passage of leukocytes into prostate DF even in the presence of pronounced interstitial inflammation. This observation may help to explain the observation that expressed prostatic secretions in human males are often free of leukocytes in clinical prostatitis.

Animals↗
PubMed2001

Induction of tumor specific cytotoxic T lymphocytes in prostate cancer using prostatic acid phosphatase derived HLA-A2402 binding peptide.

PURPOSE: Human prostatic acid phosphatase is a prostate specific differentiation antigen. Prostatic acid phosphatase levels increase in the serum of patients with prostate cancer and its peptide from positions 299 to 307 (PAP 299-307) is recognized by HLA-A2 restricted cytotoxic T lymphocytes. We investigated whether HLA-A2402 binding prostatic acid phosphatase derived peptides induce HLA-A2402 restricted, tumor specific cytotoxic T lymphocytes from the peripheral blood mononuclear cells of patients with prostate cancer. MATERIALS AND METHODS: Peptide binding activity was measured with RMA-S-A*A2402 cell lines and flow cytometry. Cytotoxic T-lymphocyte activity of the peripheral blood mononuclear cells of patients with prostate cancer and healthy donors was measured by interferon-gamma and (51)creatinine release assays. Prostatic acid phosphatase expression in the tumor cell lines at the messenger RNA and protein levels was investigated by reverse transcriptase-polymerase chain reaction and immunohistochemical analysis, respectively. RESULTS: An HLA-A2402 binding, prostatic acid phosphatase derived peptide consisting of the prostatic acid phosphatase amino acid sequence from positions 213 to 221 (PAP 213-221, LYCESVHNF) showed the ability to induce HLA-A2402 restricted and tumor specific cytotoxic T lymphocytes, which are cytoxic to prostatic acid phosphatase positive tumor cells from the peripheral blood mononuclear cells of patients with prostate cancer. CONCLUSIONS: PAP 213-221 may be appropriate as a cancer vaccine for specific immunotherapy in patients with HLA-A2402 positive prostate cancer.

Acid Phosphatase↗
PubMed2002

AIbZIP, a novel bZIP gene located on chromosome 1q21.3 that is highly expressed in prostate tumors and of which the expression is up-regulated by androgens in LNCaP human prostate cancer cells.

Androgens play an important role in the development and physiology of the normal prostate as well as in prostate cancer cell proliferation. Comparison of the mRNA expression profiles of control and R1881-treated cultures of LNCaP human prostate cancer cells using cDNA subtraction led to the identification of a novel transcription factor that we named Androgen-Induced bZIP (AIbZIP) protein. AIbZIP is a 395 aa protein with homology to cyclic AMP-responsive element binding protein/activating transcription factor transcription factors. It contains an NH(2)-terminal activation domain, a central bZIP domain, and a COOH-terminal transmembrane domain. The AIbZIP gene is localized on chromosome 1q21.3 and consists of 10 exons. A major 1.7-kb transcript was detected exclusively in the prostate as well as in breast and prostate cancer cell lines. Androgens up-regulate AIbZIP mRNA and protein levels in a dose-dependent manner. The kinetics of AIbZIP mRNA up-regulation and the results of experiments with cycloheximide suggest that AIbZIP may be a delayed response gene. Immunoreactive AIbZIP protein was primarily detected in the cytoplasm of prostatic luminal epithelial cells. Similarly, full-length AIbZIP-green fluorescent protein fusion proteins were localized in the cytoplasm of LNCaP cells, whereas a truncated form of AIbZIP lacking the putative transmembrane domain was exclusively nuclear. Examination of AIbZIP protein and mRNA expression in a series of transurethral resection of the prostate and needle biopsy specimens indicated that AIbZIP is expressed at higher levels in cancerous prostate cells compared with noncancerous prostate cells. The highly tissue-specific expression profile, androgen regulation, chromosomal localization, and expression profile of AIbZIP in prostate tumors suggest that AIbZIP may play an important role in prostate cancer and in androgen receptor signaling in prostate cells. Future studies will confirm a possible relationship between AIbZIP and prostate cancer.

Alternative Splicing↗