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Centre for Urological Research (S.J.M., S.J.E., G.P.R.), Monash Institute of Medical Research, Monash University, Clayton 3168, Australia; Prince Henry’s Institute (E.R.S.), Melbourne 3168, Australia; and Schering AG, CRBA Gynecology and Andrology (V.P., K.-H.F.), 13342 Berlin, Germany
Address all correspondence and requests for reprints to: Gail P. Risbridger, Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au.
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Abstract |
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and ß, exert direct and indirect actions on prostate growth and differentiation. Previous studies using animal models to determine the role of ERß in the prostate have been problematic because the centrally mediated response to estrogen results in reduced androgen levels and prostatic epithelial regression, potentially masking any direct effects via ERß. This study overcomes this problem by using the estrogen-deficient aromatase knockout mouse and tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Homo- and heterotypic aromatase knockout tissue recombinants revealed stromal aromatase deficiency induced hyperplasia in normal prostatic epithelium due to disruption of paracrine interaction between stroma and epithelia. Treatment of tissue recombinants with an ERß-specific agonist demonstrated that stimulation of ERß elicits antiproliferative responses in epithelium that are not influenced by alterations to systemic androgen levels or the activation of ER. Additionally, work performed with intact aromatase knockout mice demonstrated that the administration of an ERß-specific agonist ablated preexisting prostatic epithelial hyperplasia, whereas an ER-specific agonist did not. Therefore, failed activation of ERß, resulting from local stromal aromatase deficiency, in conjunction with increased androgen levels, results in increased epithelial cell proliferation and prostatic hyperplasia. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguishes them from those that adversely alter prostate growth and differentiation. This highlights the potential of selective estrogen-receptor modulators, rather than aromatase inhibitors, for the management of dysregulated prostate growth. |
Introduction |
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within the prostatic stroma, estrogens stimulate aberrant epithelial cell differentiation and proliferation, leading to squamous metaplasia (6, 7). More recently, an antiproliferative action of estrogen was suggested to occur via activation of the epithelial ERß (8, 9, 10). However, those studies used intact wild-type (wt) or transgenic male mice, which remain sensitive to the inhibition of pituitary function by estrogen. This outcome, mediated by ER, can result in prostate glandular regression, making antiproliferative effects caused by the activation of ERß difficult to identify.
Aromatase deficiency results in hypertrophy and hyperplasia of the prostate gland at maturity (11), providing a novel way of examining whether ERß has antiproliferative activity within the prostate gland. Because aromatase is expressed in the stroma and ERß receptors are located predominantly in the epithelia of the prostate (8, 12), we have proposed that the action of estrogen via ERß involves stromal-epithelial cell signaling (13). Additionally, we believe that the action of estrogen via ERß, like ER, permanently and irreversibly alters prostate epithelial cell differentiation during development (6, 7).
Mesenchymal-epithelial cell interactions are vital for the correct development of the male reproductive tract, including the prostate gland (14). Tissue recombination techniques have successfully been used to define mechanisms of stromal signaling during development and differentiation of the epithelia, particularly the role of androgens acting via the stromal androgen receptor (AR) to induce epithelial differentiation and proliferation (15, 16). Taking a similar approach, we used prostate tissue from aromatase knockout (ArKO) mice to test the effect of a deficiency of prostatic stromal aromatase on prostate development and the subsequent activation of epithelial ERß using a selective ERß agonist.
This study shows that aromatase deficiency, and therefore the absence of local estrogen and failure to activate ERß, has a significant impact on prostate development. It alters the inductive and instructive properties of the neonatal prostatic stroma, leading to perturbation of stromal-epithelial cell signaling and aberrant prostatic growth. In the absence of ERß signaling, increased cell proliferation results in non-neoplastic increases in epithelial tissue identified as epithelial hyperplasia (17).
This study demonstrates that although androgens are essential for the coordinated growth of the prostate, local estrogenic activity is equally essential for the modulation of normal prostate development. Estrogen, acting via ERß, has a definite antiproliferative effect on prostatic epithelium that is able to prevent and ablate prostatic epithelial hyperplasia. Therefore, estrogens, acting in synergy with androgens and ERß, are required to regulate the proliferative and antiproliferative changes that occur during normal prostate development and differentiation.
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Materials and Methods |
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Tissue recombination
Tissue recombinants were prepared as previously described (6, 14, 18) using newborn (d 0) wt or ArKO mouse stroma (S) and adult (16-wk-old) wt or ArKO epithelia (E). As indicated in Fig. 1
, tissue recombinants composed of epithelial tissue from adult ArKO or wt prostates recombined with seminal vesicle mesenchyme (SVM) from newborn (d 0) ArKO or wt mice to produce the homotypic combinations wt-S/wt-E and ArKO-S/ArKO-E and heterotypic combinations ArKO-S/wt-E and wt-S/ArKO-E. Up to eight recombinants were grafted under the renal capsules of any one intact host SCID mouse. Because the genotype of neonatal mouse SVM donors was not available until after composition of the tissue recombinants and grafting into host mice recombinants was completed, the homo- and heterotypic grafts were randomly assigned to host mice, thus removing any bias in their positioning. After grafting under the renal capsule of intact male SCID mice, recombinants were harvested after 6 wk and fixed in Bouin’s fixative for analysis. A minimum of eight grafts were obtained for each tissue recombinant group.
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-specific agonist (16-LE2) were obtained from Dr. Fritzemeier (Schering AG, Berlin, Germany). The chemical characteristics and biologic effects of these compounds, demonstrating selective activation of ERs, have been previously described (19, 20, 21). Doses of ER-specific agonists used throughout this study were based on those previously used in male and female rats (19). ERß agonist or placebo was administered to host SCID mice in the form of subcutaneous long-term release pellets (Innovative Research of America, Sarasota, FL) at the time of renal grafting, providing a dose comparable to 300 µg/kg·d. In experiments using intact adult male ArKO mice, the ERß agonist was administered by daily injection at doses of 100 and 30 µg/kg·d. ER agonist was administered to adult ArKO mice at doses of 3 and 0.3 µg/kg·d by daily subcutaneous injection. In all cases, treatment with ER agonists was continued for 6 wk before tissue was collected. A minimum of four host SCID mice were used for treatment with either ERß agonist or placebo to provide at least eight of each homo- or heterotypic tissue recombinant type. For treatment of intact animals, a minimum of six animals was used per treatment group.
Serum hormones
Measurement of serum testosterone levels was performed by ANZAC Research Institute (Sydney, Australia) using methods previously described by Ly et al. (22). Briefly, after organic extraction with a 3:2 mixture of hexane and ethyl acetate, the organic fraction was dried overnight and then reconstituted with a 1% gelatin PBS buffer before being processed in a radioimmunoprecipitation assay with a specific antibody raised to testosterone (T3-125; Endocrine Sciences Laboratories, Calabasas, CA) and a liquid chromatography-purified tritiated testosterone. After 16-h incubation at 4 C, free and bound hormones were separated with dextran T70-coated charcoal. The testosterone standard was calibrated against a World Health Organization testosterone preparation (coefficient of variation, 3.1–7.5%).
Immunohistochemistry
After fixation, tissue recombinants were embedded and serially sectioned at 5 µm. Uniform systematic random sampling was used to select every 10th section for hematoxylin-eosin staining or immunohistochemical analysis. Immunohistochemistry was conducted with antibodies for AR (N-20; Santa Cruz Biotechnology, Santa Cruz, CA), ER (ID5) and proliferating cell nuclear antigen (PCNA) (PC10; Dako Corp., Carpinteria, CA), and ERß (Novocastra, Newcastle upon Tyne, UK) using previously described protocols (11, 23). Analyses of AR and PCNA immunolocalization were conducted using CAST software (version 2.1.4; Olympus Corp., Albertslund, Denmark) as previously described (11, 23).
Quantitation of epithelial hyperplasia
Epithelial hyperplasia in tissue recombinants was identified according to morphologic criteria specifically defined by Shappell et al. (17) as a non-neoplastic increase in epithelial tissue compared with age-matched controls. Practically, epithelial hyperplasia was identified as increased epithelial folding within tissue recombinants and the extent of this epithelial folding was accurately estimated using CAST software, counting frames, and systematic uniform random sampling methods adapted from those used to estimate epithelial morphology in gut (24). Briefly, the incidence of epithelial folds ("branches") projecting into the prostatic lumen, away from the basement membrane, was counted for every 10th section of a graft (minimum of six sections per graft) with eight grafts analyzed per group (n 
8). Counts were expressed per unit of section area for each graft with the mean for each tissue graft used for comparison.
Statistics
Data were analyzed to determine normality and significant differences were determined by either t test or one-way ANOVA. Significance was accepted at P < 0.05. Analyses were conducted using Prism 4.00 software (GraphPad Software Inc., San Diego, CA). Data are expressed as mean ± SEM unless otherwise noted.
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Results |
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). Using this technique of tissue recombination, Cunha and Risbridger (6, 15, 16) made seminal contributions to our understanding of stromal-epithelial interactions in prostate development and disease, including the elucidation of the roles of the androgen and ER receptors.
To demonstrate the importance of locally synthesized estrogen on local stromal-epithelial cell interactions, we used tissue recombination to study the effects of estrogen deficiency. First, we compared homotypic tissue recombinants derived from wt mice with those derived from ArKO mice (i.e. wt-S/wt-E, ArKO-S/ArKO-E; Fig. 1, A and B). The wt recombinants gave rise to normal prostate tissue morphology as expected (Fig. 2A), but those derived from ArKO tissues generated prostate tissue with extensive epithelial infolding (Fig. 2B), characteristic of in vivo epithelial hyperplasia, previously reported in the prostates of adult ArKO mice (11). Quantitation showed that epithelial infolding in the ArKO-S/ArKO-E homotypic recombinants was significantly increased, being approximately 3-fold greater compared with wt-S/wt-E recombinants (Fig. 2E). These data demonstrate that the difference in epithelial hyperplasia must be due to the effects of local estrogen deficiency and perturbation of stromal-epithelial cell interactions, because ArKO and wt homotypic recombinants were exposed to the same host environment and hormone levels.
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, C and D) with the homotypic recombinants. Epithelial hyperplasia was morphologically identifiable in ArKO-S/wt-E recombinants (Fig. 2C), being significantly greater than that seen in wt-S/wt-E recombinants and comparable to that seen in ArKO-S/ArKO-E grafts (Fig. 2E). These data indicate that the absence of aromatase from the prostatic stroma, and thus estrogen synthesis, is necessary for the initiation of epithelial hyperplasia in mature (wt) epithelia.
A further comparison was made of heterotypic wt-S/ArKO-E recombinants (Fig. 2D) with homotypic recombinant tissues. This recombinant is composed of neonatal inductive stroma from wt mice and adult ArKO epithelia that exhibit epithelial hyperplasia as we have previously described (11). Thus, this heterotypic recombinant tested the ability of the wt neonatal stroma to redirect hyperplasia in adult epithelial tissue (Fig. 1). The data obtained from heterotypic wt-S/ArKO-E tissue recombinants show that the inductive and instructive capacity of normal wt stroma was unable to reverse the hyperplastic phenotype at least within the 6-wk time frame of this experiment (Fig. 2E). It is possible that wt stroma may be able to ablate the hyperplastic pathology of the ArKO epithelium if the duration of epithelial exposure to signals from the wt stroma is extended; however, this remains to be determined.
Overall, these data demonstrate that homotypic ArKO-S/ArKO-E recombinations accurately reconstitute the pathology observed in the prostates of intact ArKO mice. Furthermore, these data demonstrate that the absence of aromatase activity from the stroma results in the induction of prostatic epithelial hyperplasia within normal prostatic epithelium. The recombinant tissues were exposed to identical systemic hormones from the host mice in which the grafted tissues were maintained; thus, these results show that there is a perturbation in local stromal epithelial-cell signaling related to estrogen deficiency.
Immunohistochemical localization of steroid hormone receptors and proliferation in tissue recombinants
To further examine the local cell-cell signaling in these tissue recombinants, we investigated whether differences in hormone receptor expression could account for the different tissue responses to the same systemic hormone levels. The presence of AR is essential for normal prostatic differentiation (25) and initial examination identified AR immunoreactivity in all tissue recombinants; however, there were no obvious differences in the pattern of AR localization (Fig. 3, A–D). Although AR was localized to both stroma and epithelium, subsequent quantitation confirmed no significant differences in AR localization between tissue recombinants (Table 1). Localization of ERß showed immunoreactivity was almost completely confined to the epithelial tissue of each graft (Fig. 3, E–H). Unlike ERß, ER could not be detected in any tissue recombinant nor was there any evidence of PR (data not shown).
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, I–L). Quantitation of PCNA localization demonstrated significantly increased expression in all recombinants containing ArKO stroma and/or epithelium compared with the homotypic wt-S/wt-E controls (Table 2). Proliferation was significantly increased in wt epithelium after recombination with ArKO-S (ArKO-S/wt-E). In contrast, the proliferation in hyperplastic ArKO-E was unaffected by wt-S (wt-S/ArKO-E), exhibiting similar levels of proliferative activity to that seem in ArKO-S/wt-E and ArKO-S/ArKO-E recombinants (Table 2).
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and ERß are believed to promote different proliferative responses in prostatic tissues. ER is required for epithelial differentiation and proliferation (6), whereas ERß is believed to be antiproliferative (8, 9, 10). However, the levels of androgens were not reported in these latter studies and if reduced would lower epithelial cell proliferation and induce apoptosis.
The results of the recombination experiments presented here did not show squamous metaplasia and implicate ERß rather than ER in mediating aberrant stromal-epithelial cell signaling leading to epithelial hyperplasia. In the absence of stromal aromatase activity and with reduced estrogen synthesis within the tissue, we postulated that a failure to locally activate ERß caused epithelial hyperplasia in the tissue recombinants.
To test this postulate, we again used the aromatase-deficient prostatic tissue recombination model to reveal the cell-cell interactions, independent of systemic hormone levels. The tissue recombinants composed of neonatal stroma from ArKO mice (ArKO-S) with either wt or ArKO epithelium show epithelial hyperplasia so we administered an ERß-specific agonist to the host SCID mice bearing these homotypic tissue recombinants (ArKO-S/ArKO-E and wt-S/wt-E). Compared with placebo-treated controls (Fig. 4A), exposure to ERß agonist had no obvious effect on the morphology of wt-S/wt-E tissues (Fig. 4B). However, compared with placebo treated ArKO-S/ArKO-E controls (Fig. 4C), treatment with an ERß agonist abrogated epithelial hyperplasia in ArKO-S/ArKO-E recombinants (Fig. 4D) so that tissues were indistinguishable from wt-S/wt-E tissue recombinants. This inhibition of hyperplasia was also observed in heterotypic ArKO-S/wt-E and wt-S/ArKO-E tissues (data not shown). The total level of PCNA expression was significantly reduced in all ArKO-S/ArKO-E, ArKO-S/wt-E, and wt-S/ArKO-E tissue recombinants (Table 2). This significant response reflected changes observed in proliferation within the epithelial compartments of each of these grafts confirming the reduction in epithelial hyperplasia after exposure to the ERß agonist was due to reduced proliferation of prostatic epithelial cells.
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) and is probably due to the reciprocal epithelial-stromal cell signaling from the hyperplastic epithelium. Treatment with ERß agonist did not suppress proliferation in the stromal tissue of any recombinant consistent with ERß being predominantly localized in the epithelium.
These data provide further evidence that the stimulation of epithelial ERß is a major factor in regulating prostatic epithelial proliferation, but this occurs at a local tissue level and involves stromal-epithelial cell interactions within prostatic tissue. Although the systemic administration of ERß agonist was able to ablate epithelial hyperplasia resulting from local deficiency in estrogen synthesis, it had no significant effect on homotypic wt/wt recombinants; neither did it alter the weight of SV, testis, or prostate lobes in the host mice (Table 3).
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-specific agonist.
Histologic comparison to wt tissue (Fig. 5D) showed that epithelial hyperplasia normally present in ArKO prostate (Fig. 5E) was attenuated and areas of ArKO tissue were morphologically indistinguishable from wt controls (Fig. 5F). In contrast, ArKO mice receiving an ER agonist showed no attenuating influence on prostatic hyperplasia (Fig. 5G) and exposure to this compound resulted in an inflammatory response evident from the infiltration of inflammatory cells into tissues, a response not seen in ArKO prostate tissue itself (data not shown). Neither ER nor ERß agonist showed significant effects on serum testosterone levels compared with control levels, although the responses were highly variable, as is commonly observed (Fig. 5A). Administration of both agonists reduced prostate weight (Fig. 5B), but only ER agonist treatment reduced SV weight (Fig. 5C). The weight of the seminal vesicles is a good indicator of androgen levels and suggests the ER agonist, rather than the ERß agonist, lowered systemic androgen levels, although this was not detected in the serum assay.
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Discussion |
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) suppresses androgen levels which in turn reduces epithelial cell proliferation. Consequently, this will mask any putative antiproliferative effects that may be mediated directly by ERß. To overcome this, we have used the estrogen-deficient, ArKO mouse in addition to ERß and ER SERMs to unequivocally demonstrate that ERß is a key factor in the regulation of prostatic epithelial proliferation and growth. This study reveals that a failure to activate prostatic ERß leads to epithelial hyperplasia, is specifically the result of altered stromal epithelial cell signaling, is independent of systemic hormones, and is reversible after administration of an ERß SERM.
Elevated levels of systemic estrogen in aging men are associated with the onset of benign and malignant prostate disease (27, 28, 29). Estrogen action, mediated via ER, will cause aberrant cellular differentiation and proliferation with progression to prostatic hyperplasia, neoplasia, and dysplasia (1, 2, 3). Aromatase inhibitors have been tested as treatments for prostate disease, particularly cancer, yet have been surprisingly ineffective in reducing disease progression (30, 31, 32). Aromatase inhibition, however, will eliminate all estrogen action in the prostate, both direct and indirect, beneficial and adverse. Thus, any beneficial effects of estrogen acting via ERß will be lost (8, 9, 10), which may account for the ineffectiveness of aromatase inhibitors in treating prostate disease. Therefore, suppression of estrogenic activity in the prostate may be detrimental, rather than beneficial, in combating prostate disease.
Unlike ER, the stimulation of ERß has been suggested to be antiproliferative. However, this effect has not been demonstrated independent of altered systemic androgen levels, which may also cause a reduction in proliferation. This study provides the first evidence that the ERß-mediated effects on prostate epithelial cell proliferation are independent of systemic hormone levels. The absence of aromatase activity in both the stroma and epithelium of prostate tissue recombinants results in epithelial hyperplasia comparable to that seen in intact ArKO mice and in men with benign prostatic hyperplasia (17). These data demonstrate that the absence of local aromatase expression in the prostate is a key factor in determining epithelial cell hyperplasia. Based on our prior report demonstrating aromatase expression in the stroma, but not epithelia, of nonmalignant human prostate (13), it was assumed that the stroma was the major site of aromatase activity in the rodent prostate. Consistent with this assumption, tissue recombinants comprising wt epithelium and aromatase-deficient stroma (ArKO-S + wt-E) developed epithelial hyperplasia, whereas wt stroma recombined with wt epithelia (wt-S + wt-E) did not. This directly implicates the stroma as a key determinant of epithelial pathology with the loss of stromal aromatase causing epithelial hyperplasia.
The ability of the stroma to direct epithelial development is not a new concept and has been studied and reported previously (34, 35, 36, 37). Abnormal stromal characteristics lead to abnormalities in epithelial cell differentiation such as the lack of stromal AR expression contributing to aberrant epithelial cell differentiation during development or in cancer (34, 35, 36, 37). The converse situation, in which normal stroma may reverse and/or abrogate an existing abnormal epithelial pathology, has not been reported nor was it observed in the current study. When normal stroma was recombined with hyperplastic ArKO epithelia (wt-S + ArKO-E), hyperplasia persisted. Although it is possible that a longer experimental time frame was required for the reversal of hyperplasia, this is unlikely. Additionally, Cunha and colleagues have demonstrated that the signaling between the stroma and the epithelium is reciprocal, and once deregulated, a vicious cycle of miscommunication ensues that serves to exacerbate the pathology (35, 36). This was readily apparent in the current study in which increased cell proliferation was observed in the stroma of tissue recombinants composed of wt stroma and ArKO epithelium (wt-S/ArKO-E).
The data presented provide new insight into the pivotal role of estrogen in stromal-epithelial cell signaling during prostate development. The disruption of stromal aromatase activity (and consequently estrogen synthesis) perturbs regulatory signals acting on the epithelium, resulting in epithelial hyperplasia that is independent of systemic hormone levels. However, the mechanism behind this effect is unclear. ER induces atrophy via the suppression of androgen synthesis as well as promoting aberrant proliferation of the prostatic epithelium (squamous metaplasia). Loss or suppression of ER activity, therefore, would be more likely to result in a normal epithelium than a hyperplastic one. Alternately, if ERß is a negative regulator of prostate growth (8, 9, 10), then the loss of local estrogen metabolism would result in reduced ERß activation and consequently increased cell proliferation. Consistent with this idea, the administration of an ERß-specific agonist (ERß SERM) inhibited the development of epithelial hyperplasia (ArKO-S/wt-E recombinants) and abrogated the existing hyperplasia in recombinants prepared with ArKO epithelia (ArKO-S/ArKO-E and wt-S/ArKO-E recombinants). Administration of the ERß SERM also resulted in the ablation of existing epithelial hyperplasia in intact ArKO mice. Significantly, this occurred without any suppression of serum testosterone levels or other adverse affects on the hormone-sensitive tissues of the reproductive tract. This in vivo response is in direct contrast to the effects of an ER agonist which, despite reducing the weight of the prostate and other reproductive organs, had no effect on the hyperplastic pathology of the epithelia.
These data strongly implicate ERß stimulation as a major regulatory factor of prostatic epithelial cell proliferation. However, it is not yet clear exactly which endogenous ligands activate ERß in vivo. It has been previously suggested that metabolites of reduced androgens such as 5-androstane-3ß,17ß-diol (3ßAdiol) may act as preferred ligands for ERß, yet the results of the current study are inconsistent with this premise (9). The metabolism of testosterone results in both reduced androgens as well as estrogens via the reductase and aromatase enzymes respectively. As demonstrated, the failed ERß activation in the ArKO mouse leads to the development of epithelial hyperplasia. Because reductase activity is not affected in this model (11), it would appear that locally synthesized estrogens are the preferred ligand for ERß and are crucial for the prevention of epithelial hyperplasia. Although reduced androgens (like 3ßAdiol) may bind to ERß, they would appear to be much less effective in this role than estrogens.
Studies using exogenous estrogens have demonstrated both direct and indirect effects on prostatic differentiation and proliferation (Fig. 6A). Indirectly, estrogenic suppression of LH release results in reduced systemic androgen levels and epithelial atrophy. Thus, the normal influence of androgens is reduced at the same time as an aberrant response to estrogen is stimulated. By using a murine model of aromatase deficiency, the current study adds essential new information to the existing paradigm (Fig. 6B). First, it demonstrates an essential role for aromatase in stromal-epithelial cell signaling whereby locally synthesized estrogen activates ERß to prevent epithelial hyperplasia. Second, it provides direct evidence that ERß is antiproliferative without the complicating factor of altered systemic androgen levels.
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, respectively. This study suggests that ERß-specific agonists may be of considerable benefit in the treatment of prostate disease together with antagonists to ER.
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Footnotes |
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First Published Online October 26, 2006
Abbreviations: AR, Androgen receptor; ArKO, aromatase knockout; ER, estrogen receptor; PCNA, proliferating cell nuclear antigen; SCID, severe combined immunodeficient; SERM, selective ER modulator; SVM, seminal vesicle mesenchyme; wt, wild type.
Received July 7, 2006.
Accepted for publication October 16, 2006.
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References |
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mediates effects of estrogen on prostatic epithelium. Dev Biol 229:432–442[CrossRef][Medline] and ß in adult rat accessory sex glands and lower urinary tract. Mol Cell Endocrinol 164:109–116[CrossRef][Medline]- and ERß-selective estrogens. Ernst Schering Res Found Workshop 127–150 and ß with potent selective ligands from structure-based design. Mol Endocrinol 18:1599–1609 and ß selective compounds. Ernst Schering Res Found Workshop:47–62-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J Clin Endocrinol Metab 77:375–381[Abstract]: studies with ERKO and ßERKO mice. Cancer Res 61:6089–6097This article has been cited by other articles:
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