Normal Ventral Prostate Research Articles

A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model

Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.

Androgen‐insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen‐dependent prostate environment

Castration-induced involution of the normal prostate is caused by primary effects in the prostate stroma and vasculature, but if this is the case also in tumors is unknown. Androgen-independent AT-1 prostate tumor cells were therefore injected into the ventral prostate (VP) in Copenhagen rats. Seven days later when the growing tumor was surrounded by normal VP tissue the rats were castrated and the effect examined 3 and 7 days later. Castration reduced vascular density in the surrounding VP tissue and this was accompanied by tumor cell hypoxia, apoptosis, and temporarily retarded tumor growth. Castration-induced VP tissue regression occurred more rapidly in the contra-lateral than in the tumor-bearing lobe. Androgen-independent tumor cell respond to castration when growing in an androgen-dependent environment. The presence of a tumor influences the castration response in the surrounding normal tissue. The microenvironment determines how prostate epithelial cells respond to castration.

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

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. 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. 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. 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.

Expression and androgen regulation of C-CAM cell adhesion molecule isoforms in rat dorsal and ventral prostate.

C-CAM is an epithelial cell adhesion molecule with two major splice variants that differ in the length of the cytoplasmic domain. C-CAM1 (long (L)-form) strongly suppresses the tumorigenicity of human prostate carcinoma cells. In contrast, C-CAM2 (short (S)-form) does not exhibit tumor-suppressive activity. In the present study we have investigated the functional significance of L-form and S-form C-CAM in rat prostate by examining their expression and distribution in different prostate lobes and their response to androgen deprivation. RNase protection assays with a probe for both C-CAM isoforms detected high levels of C-CAM messages in the rat dorso-lateral prostate (DLP). L- and S-form proteins, localized by indirect immunofluorescence using isoform-specific antipeptide antibodies, were co-expressed on the apical surface of prostate epithelial cells in normal DLP. Androgen depletion did not significantly change the steady state levels of C-CAM message and protein expression in the DLP, although there was a change in the pattern of protein expression in these lobes. In contrast, C-CAM isoform messages and proteins were undetectable in normal ventral prostate (VP) but increased markedly in this lobe in response to castration, producing isoform ratios similar to those in DLP. These results demonstrate that coordinate expression of C-CAM isoforms is maintained in the VP following androgen depletion and suggest that androgen suppresses C-CAM expression in VP but not in DLP. These results suggest that balanced expression of L- and S-form C-CAM is important for normal prostate growth and differentiation.

Expression of gonadotropin‐releasing hormone receptor mRNA in the rat ventral prostate and Dunning R3327 PAP adenocarcinoma before and after castration

BACKGROUND Continuous administration of gonadotropin-releasing hormone (GnRH) agonists in prostate cancer patients results in involution of the tumors due to suppression of androgen production. In addition to the effect of GnRH at the hypothalamic-pituitary level, experiments in vitro on breast, ovary, and prostatic cells have shown an inhibition of cell proliferation, indicating the presence of local GnRH receptors (GnRH-R). The aim of the present study was to investigate the expression of GnRH-R mRNA in the normal rat ventral prostate (VP) and Dunning R3327 PAP adenocarcinoma and to evaluate the effects of castration on receptor mRNA expression. METHODS RNA was prepared from ovaries, pituitaries, VP, and Dunning tumors from both intact and castrated animals. GnRH-R mRNA levels were quantified by a competitive reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS GnRH-R mRNA was detected in normal VP and Dunning tumors. Normal VP showed lower amounts of GnRH-R mRNA compared to Dunning tumors. An elevation of mRNA expression was observed 7 days after castration in Dunning tumors. CONCLUSIONS GnRH-R mRNA was found in both VP and Dunning tumors, indicating the presence of a local GnRH system. Normal VP showed lower amounts of GnRH-R mRNA when compared to malignant tissues. GnRH-R mRNA levels were elevated in Dunning tumors following castration. Prostate 39:101–107, 1999. © 1999 Wiley-Liss, Inc.

Expression of gonadotropin-releasing hormone receptor mRNA in the rat ventral prostate and dunning R3327 PAP adenocarcinoma before and after castration.

Continuous administration of gonadotropin-releasing hormone (GnRH) agonists in prostate cancer patients results in involution of the tumors due to suppression of androgen production. In addition to the effect of GnRH at the hypothalamic-pituitary level, experiments in vitro on breast, ovary, and prostatic cells have shown an inhibition of cell proliferation, indicating the presence of local GnRH receptors (GnRH-R). The aim of the present study was to investigate the expression of GnRH-R mRNA in the normal rat ventral prostate (VP) and Dunning R3327 PAP adenocarcinoma and to evaluate the effects of castration on receptor mRNA expression. RNA was prepared from ovaries, pituitaries, VP, and Dunning tumors from both intact and castrated animals. GnRH-R mRNA levels were quantified by a competitive reverse transcription-polymerase chain reaction (RT-PCR) method. GnRH-R mRNA was detected in normal VP and Dunning tumors. Normal VP showed lower amounts of GnRH-R mRNA compared to Dunning tumors. An elevation of mRNA expression was observed 7 days after castration in Dunning tumors. GnRH-R mRNA was found in both VP and Dunning tumors, indicating the presence of a local GnRH system. Normal VP showed lower amounts of GnRH-R mRNA when compared to malignant tissues. GnRH-R mRNA levels were elevated in Dunning tumors following castration.

CRYOSURGICAL ABLATION OF THE NORMAL VENTRAL PROSTATE PLUS ADJUVANT DOES NOT PROTECT COPENHAGEN RATS FROM DUNNING PROSTATIC ADENOCARCINOMA CHALLENGE

We wished to determine if cryosurgical ablation of the normal ventral prostate of Copenhagen rats confers protective immunity against a subsequent challenge with Dunning R3327 MatLyLu prostatic adenocarcinoma. In human melanoma, tumor antigens have been characterized as normal cellular proteins. We reasoned that cryosurgical ablation of the normal prostate along with immunostimulatory adjuvants might release prostatic antigens to the immune system engendering an immune response and rendering rats immune to prostatic cancer cells. On day 0, Copenhagen rats underwent cryosurgical ablation of the normal ventral prostate, cryosurgery and intraprostatic injection of Complete Freund's Adjuvant (CFA), CFA injection alone, or laparotomy alone. On day 21, animals received a subcutaneous challenge of MatLyLu tumor cells. Tumor dimensions were recorded at regular intervals by a single blinded investigator. Animals receiving cryosurgical ablation of the normal ventral prostate or intraprostatic CFA developed tumors more frequently than animals receiving laparotomy alone and the effect was statistically significant if animals received both cryosurgical ablation of the prostate and intraprostatic CFA (3 experiments, 1 x 10(4) MatLyLu cells), total number with tumors/total number challenged: laparotomy alone 3/17, cryosurgical ablation 7/17, cryosurgery plus CFA 10/16 (p = 0.013 versus laparotomy, Fisher's exact test), CFA alone 9/17. Cryosurgical ablation of the normal rat ventral prostate and intraprostatic CFA does not protect against and can enhance the tumorigenicity of MatLyLu prostatic cancer cells at distant sites. This could be occurring through specific immunologic effects or non-specific mechanisms induced by cryosurgery and CFA.

Effects of castration on plasminogen activator activities and plasminogen activator inhibitor type I in the rat ventral prostate

The involution of the prostate gland after castration is an active process which requires the induction of new proteins. The plasminogen activator urokinase has been proposed to be a gene repressed by androgen which is activated upon castration and thus participating in the atrophy of the gland. However, urokinase is secreted by the ventral lobe of the rat prostate and this should be positively affected by androgens. The purpose of this study was to examine further the effects of castration upon plasminogen activator (PA) activities in the rat prostate and to determine possible explanations to this apparent dilemma. Castration of young sexually mature adult rats resulted in a substantial increase in PA activities at 4 days after castration in the ventral prostate, but then the activities returned to within the range of untreated animals with a longer duration of castration. Urokinase was the predominant molecular form of PA in the normal ventral prostate and it was the molecular form increased after castration; based upon its sensitivity to amiloride and its molecular size determined in zymograms. In contrast to the effect of castration, there was no increase in PA activities in the ventral prostate with treatment of rats with the antiandrogen flutamide, but rather a decrease when specific activity was expressed per unit DNA. In addition, the effect of castration was specific for the ventral lobe for there was no change in the PA activity in the dorsolateral prostate after androgen ablation. The diminished PA activities in the ventral prostates of rats castrated for 7 days or longer appeared to be due at least in part to an increase in plasminogen activator inhibitor type-1 (PAI-1). Immunoreactive PAI-1 was found predominantly in high molecular weight forms which indicates that the inhibitor was complexed with PA. Daily treatment of rats upon castration with agents known to retard the rate of regression of the involuting prostate gave dichotomous results. Hydrocortisone prevented the increase in PA activity, whereas treatment with actinomycin D, an inhibitor of RNA synthesis, not only did not prevent an increase in PA activity, but actually produced a superinduction in PA activity at 4 days orchiectomy. These data may be interpreted to mean that hydrocortisone stimulated PAI activity and that actinomycin D treatment blocked its induction. However, the actinomycin D data may also indicate that an increase in urokinase protein and mRNA after castration may result from some mechanism to conserve these molecules suggesting that this inhibitor of RNA synthesis prevented the transcription of messages for proteins involved in the degradation of urokinase message.

Instructive induction of prostate growth and differentiation by a defined urogenital sinus mesenchyme.

Instructive influences of fetal mesenchyme were examined in heterotypic tissue recombinants consisting of urogenital sinus mesenchyme (UGM) from male and female rats and distal ductal tips from adult rat prostate. Tissues were grown under the renal capsule of male hosts for periods up to 28 days. Resultant growths exhibited typical prostate histology. Expression of lobe-specific proteins for the ventral (prostatic steroid binding protein [PSBP]) lateral (seminal vesicle secretion II [SVS II]), and dorsal prostate (secretory transglutaminase [TGase]) were examined by immunocytochemistry. Male or female UGM combined with terminal segments of the ventral or dorsal prostate and immunolabeled with antibodies to lobe-specific proteins demonstrated expression of all three secretory products. The pattern of staining was consistent with a compound inductive response from the UGM. Unique to this study was our ability to use a defined mesenchymal tissue (female ventral mesenchymal pad [VMP]). This tissue is specifically associated with ductal branching morphogenesis and cytodifferentiation of the ventral prostate. Distal ductal tips from the dorsal lobe of the adult male prostate when recombined with female VMP and grown in vivo exhibited transformation of secretory phenotype, and the epithelium expressed mRNAs for PSBP. Immunocytochemistry of serial sections did not demonstrate labeling for TGase in the new epithelial growth. Ultrastructural analysis of the heterotypic recombinants indicated that the epithelium had similar characteristics to those of normal ventral prostate. Early stages of the mesenchymal-epithelial interactions resulted in dedifferentiation of the adult epithelium to solid cords of stratified cells. These findings illustrate the potent instructive capacity of a defined fetal UGM to influence development and cytodifferentiation of adult prostate epithelium.

Stimulation of Androgen-Dependent Gene Expression by the Adrenal Precursors Dehydroepiandrosterone and Androstenedione in the Rat Ventral Prostate*

Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels. The present results demonstrate that circulating levels of the adrenal steroids DHEA and delta 4-dione comparable to those found in man cause an important stimulation of androgen-dependent gene expression in the rat, probably after their conversion to DHT in the prostatic tissue itself.

Testosterone Dose‐Dependency of Sexual and Nonsexual Behaviors in The Gonadotropin‐Releasing Hormone Antagonist‐Treated Male Rat

The testosterone dose-dependency of several mating and nonmating behaviors was examined in the male rat, chemically castrated with a GnRH antagonist analog. Graded doses of testosterone enanthate (TE) were given to male rats to reinstate behaviors abolished by GnRH antagonist treatment. GnRH antagonist treatment alone markedly lowered serum LH, FSH and T concentrations and ventral prostate and testis weights. Open field behaviors were not significantly affected by GnRH antagonist treatment or castration. Scent-marking behavior was markedly suppressed by both castration and GnRH antagonist and restored by the lowest dose of TE (0.05 mg). All measures of male sexual behavior were impaired by GnRH antagonist treatment and castration and restored by the lowest dose of TE (0.05 mg). The doses of TE required to restore normal ventral prostate weights and testis weights were higher than those required to maintain scent marking and mating behaviors. No direct behavioral effects of the GnRH antagonist, other than those that can be explained by GnRH antagonist-induced suppression of testosterone were observed. The finding that sexual and nonsexual behaviors in the male rat have different testosterone requirements from those maintaining spermatogenesis and fertility may have significant implications for contraception.

A × C Rat Prostate Adenocarcinoma: Initial Characterization of Testosterone Regulation of Hormone Receptors of Cultured Cancer Cells and Derived Tumors<xref ref-type="fn" rid="FN2">2</xref><xref ref-type="fn" rid="FN3">3</xref>

A x C rat prostate cancer cells were established in continuous culture. The polygonal epithelial cells had granular cytoplasm and well-defined cell margins, contained round to oval nuclei with prominent nucleoli, and were tumorigenic when inoculated into A x C male rats. The tumors produced by the injected prostate cancer cells grew as well-vascularized, solid, cribriform adenocarcinomas. The rat prostate cancer cells and derived tumors contained cytoplasmic and nuclear androgen receptors and prolactin receptors. Androgen regulation of prolactin receptor content and androgen receptor distribution in A x C rat prostate cancer cells were comparable to those of the normal ventral prostate gland. These studies suggest that the A x C rat prostate cancer cells and tumors may represent a unique model for studies of hormonal regulation of prostate cancer cell behavior.

Prostatic carcinoma: Castration alters the metabolism of catecholamine and 5-hydroxytryptamine

1. 1. The presence of tyrosine hydroxylase, monoamine oxidase and catechol- O-methyltransferase as well as the putative transmitters, dopamine, 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, has been demonstrated in the methylcholantherene-induced prostatic carcinoma of rats. 2. 2. Although norepinephrine was present in the normal ventral prostate, it was non-detectable in the epithelial cells of neoplastic prostate. 3. 3. Castration of rats implanted with tumour cells significantly reduced the activity of tyrosine hydroxylase, transmitters and the metabolite, 5-hydroxyindoleacetic acid suggesting that the metabolism of these monoamines is androgen-dependent.

Remission of Metastatic Lesions Following Cryosurgery in Prostatic Cancer: Immunologic Considerations

No AccessJournal of Urology1 Jul 1970Remission of Metastatic Lesions Following Cryosurgery in Prostatic Cancer: Immunologic Considerations Ward A. Soanes, R.J. Ablin, and Maurice J. Gonder Ward A. SoanesWard A. Soanes More articles by this author , R.J. AblinR.J. Ablin More articles by this author , and Maurice J. GonderMaurice J. Gonder More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(17)61690-2AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail © 1970 by The American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited ByFriedman E, Orth C, Brewton K, Ponniah S and Alexander R (2018) CRYOSURGICAL ABLATION OF THE NORMAL VENTRAL PROSTATE PLUS ADJUVANT DOES NOT PROTECT COPENHAGEN RATS FROM DUNNING PROSTATIC ADENOCARCINOMA CHALLENGEJournal of Urology, VOL. 158, NO. 4, (1585-1588), Online publication date: 1-Oct-1997.Schurmans J, Blijenberg B, Mickisch G and Schroder F (2018) Spontaneous Remission of a Bony Metastasis in Prostatic AdenocarcinomaJournal of Urology, VOL. 155, NO. 2, (653-653), Online publication date: 1-Feb-1996.Wieder J, Schmidt J, Casola G, VanSonnenberg E, Stainken B and Parsons C (2018) Transrectal Ultrasound-Guided Transperineal Cryoablation in the Treatment of Prostate Carcinoma: Preliminary ResultsJournal of Urology, VOL. 154, NO. 2, (435-441), Online publication date: 1-Aug-1995.Droller M (2018) Immunotherapy in Genitourinary NeoplasiaJournal of Urology, VOL. 133, NO. 1, (1-5), Online publication date: 1-Jan-1985.Milleman L, Weissman W and Culp D (2018) Serum Protein, Enzyme and Immunoglobulin Responses Following Perineal Cryosurgery for Carcinoma of the ProstateJournal of Urology, VOL. 123, NO. 5, (710-712), Online publication date: 1-May-1980.Petersen D, Milleman L, Rose E, Bonney W, Schmidt J, Hawtrey C and Culp D (2018) Biopsy and Clinical Course After Cryosurgery for Prostatic CancerJournal of Urology, VOL. 120, NO. 3, (308-311), Online publication date: 1-Sep-1978.Catalqna W and Scott W (2018) Carcinoma of the Prostate: A RevivewJournal of Urology, VOL. 119, NO. 1, (1-8), Online publication date: 1-Jan-1978.Gursel E, Roberts M and Veenema R (2018) Regression of Prostatic Cancer following Sequential Cryotherapy to the ProstateJournal of Urology, VOL. 108, NO. 6, (928-932), Online publication date: 1-Dec-1972. Volume 104Issue 1July 1970Page: 154-159 Advertisement Copyright & Permissions© 1970 by The American Urological Association Education and Research, Inc.MetricsAuthor Information Ward A. Soanes More articles by this author R.J. Ablin More articles by this author Maurice J. Gonder More articles by this author Expand All Advertisement PDF DownloadLoading ...