Benign prostatic hyperplasia (BPH) epithelial cell line BPH-1 induces aromatase expression in prostatic stromal cells via prostaglandin E2

Estradiol (E2) level in stroma of benign prostatic hyperplasia (BPH) increases with age, and this increase was associated with an elevated expression of aromatase in prostatic stromal cells (PrSCs). Here, we showed that conditioned medium (CM) of BPH-1 (a benign hyperplastic prostatic epithelial cell line), but not of prostate cancer cell lines (LNCaP, DU-145, and PC-3), stimulates aromatase expression in PrSCs. Cyclooxygenase-2 (COX-2) mRNA level in BPH-1, as well as prostaglandin E2 (PGE2) concentration in BPH-1 CM, was significantly higher than that of prostate cancer cell lines. CM of BPH-1 treated with NS-398 (a specific inhibitor of COX-2) failed to stimulate aromatase expression in PrSCs. And PGE2 can stimulate aromatase expression in PrSCs. Our data suggested that BPH-1 induced aromatase expression in PrSCs through the production of PGE2 in a paracrine mechanism.     

Zone-dependent expression of estrogen receptors alpha and beta in human benign prostatic hyperplasia

Estrogen, which acts through estrogen receptors (ERs) alpha and beta, has been implicated in the pathogenesis of benign and malignant human prostatic tumors, i.e. benign prostatic hyperplasia and prostate cancer, thought to originate from different zones of the prostate [the transition zone (TZ) and peripheral zone (PZ), respectively]. Here, we examined the cellular distribution of ERalpha and ERbeta in human normal and hyperplastic prostate tissues, using in situ hybridization and immunohistochemistry. ERalpha expression was restricted to stromal cells of PZ. In contrast, ERbeta was expressed in the stromal cells of PZ as well as TZ. ERbeta-positive epithelial cells were evenly distributed in PZ and TZ of the prostate. Our results suggest that estrogen may play a crucial role in the pathogenesis of benign prostatic hyperplasia through ERbeta.     

Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.     

Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault

The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote "It is not the cell itself that is disorderly, but its relationship with the rest of the tissue". We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.     

Essential role for estrogen receptor beta in stromal-epithelial regulation of prostatic hyperplasia

Estrogens, acting via estrogen receptors (ER) alpha and beta, exert direct and indirect actions on prostate growth and differentiation. Previous studies using animal models to determine the role of ERbeta 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 ERbeta. 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 ERbeta-specific agonist demonstrated that stimulation of ERbeta elicits antiproliferative responses in epithelium that are not influenced by alterations to systemic androgen levels or the activation of ERalpha. Additionally, work performed with intact aromatase knockout mice demonstrated that the administration of an ERbeta-specific agonist ablated preexisting prostatic epithelial hyperplasia, whereas an ERalpha-specific agonist did not. Therefore, failed activation of ERbeta, 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.     

Androgen receptor signalling in prostate: effects of stromal factors on normal and cancer stem cells

The prostate gland is the most common site for cancer in males within the developed world. Androgens play a vital role in prostate development, maintenance of tissue function and pathogenesis of prostate disease. The androgen receptor signalling pathway facilitates that role in both the epithelial compartment and in the underlying stroma. Stroma is a key mediator of androgenic effects upon the epithelium and can regulate both the fate of the epithelial stem cell and potentially the initiation and progression of prostate cancer. Different groups of growth factors are expressed by stroma, which control proliferation, and differentiation of prostate epithelium demonstrating a critical role for stroma in epithelial growth and homeostasis. Paracrine stromal proteins may offer the possibility to control tumour stem cell growth and could permit prostate specific targeting of both therapies and of androgen responsive proteins. The effect of 5alpha-dihydrotestosterone, the more potent metabolite of testosterone, on expression of androgen-regulated genes in stroma from benign prostatic hyperplasia is a key mediator of epithelial cell fate. Global gene expression arrays have recently identified new candidate genes in androgen responsive stroma, some of which have androgen receptor binding sites in their promoter regions. Some of these genes have direct androgen receptor binding ability.     

Androgen-stimulated human prostate epithelial growth mediated by stromal-derived fibroblast growth factor-10.

It has been suggested that prostate homeostasis is regulated indirectly by androgens through stromal-epithelial interactions in part by factors from the stromal cells acting on receptors in epithelial cells. In this report, the role of fibroblast growth factor (FGF)-10 in prostatic epithelial proliferation was investigated. The expression of FGF-10 mRNA was apparent in primary-cultured stromal cells, but not in epithelial cells derived from human tissue from patients with benign prostatic hyperplasia (BPH). The mitogenic activity of human recombinant FGF-10 assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation was demonstrated in isolated epithelial cells, but not in cultured stromal cells. No mitogenic activity of dihydrotestosterone (DHT) for either epithelial or stromal cells could be demonstrated, but quantitative PCR (real-time PCR) with a double-labeled fluorogenic probe demonstrated that expression of FGF-10 in stromal cells was enhanced 5.3-fold at a DHT concentration of 100 pM. Androgen receptor mRNA levels showed no significant change with DHT at concentrations less than 100 pM, but were reduced to 50% of control levels at a DHT concentration of 10 nM. These results suggest that stromal-derived FGF-10 stimulates human prostatic epithelial growth and its mRNA expression is induced by androgens, without an increase in the androgen receptor mRNA. Moreover, FGF-10 may be involved in the development or support of human BPH.     

良性前列腺增生组织中雄激素结合位点和表皮生长因子受体的相关性研究

目的评估雄激素结合位点（ＡＢＳ）和表皮生长因子受体（ＥＧＦＲ）在良性前列腺增生症（ＢＰＨ）中的作用及相互调节关系。方法应用免疫组织化学方法（ＳＰ法）在５０例ＢＰＨ组织和９例正常前列腺组织中对ＡＢＳ和ＥＧＦＲ进行免疫定位、半定量表达。结果前列腺增生组织中ＡＢＳ和ＥＧＦＲ表达均增强，ＡＢＳ主要位于腺上皮细胞和基质细胞，ＥＧＦＲ主要位于基底细胞，ＡＢＳ和ＥＧＦＲ呈显著正相关。结论雄激素的作用部位主要在上皮细胞和基质细胞，表皮生长因子的作用部位在基底细胞，二者的密切相关在ＢＰＨ的发病机理中可能是非常重要的。     

Interaction between prostatic fibroblast and epithelial cells in culture: role of androgen

We have established and characterized two cell lines from the ventral prostate gland of normal Nb rats: NbE-1 (prostatic epithelial) and NbF-1 (prostatic fibroblast) cell lines. To identify the direct mitogenic action of dihydrotestosterone (DHT), we incubated these cell lines alone and together (in the presence and absence of cell contact) with various concentrations of DHT (0.1-10,000 ng/ml) for 24-72 h and assayed for the rate of DNA synthesis and the total number of cells in tissue culture at specified time periods. Results demonstrate that the primary target for DHT mitogenic action is the prostatic fibroblasts. DHT inhibited the growth of prostatic epithelial cells by themselves, but stimulated prostatic epithelial cell growth when the epithelial cells were cocultured with prostatic fibroblasts. Furthermore, the cell-conditioned medium obtained from either the fibroblast or the epithelial cells stimulated in an autocrine or a paracrine manner the growth of prostatic cells in culture. These results are consistent with the concept that DHT stimulates the growth of prostatic epithelial cells indirectly via its direct mitogenic action on the prostatic fibroblasts. Because epithelial cells are the cell type principally responsible for converting testosterone to DHT, and the fibroblasts respond to the mitogenic action of DHT, our results support the concept that tight metabolic cooperation exists between prostatic epithelial and fibroblast cells. These data are in agreement with previous in vivo studies in which we have demonstrated that androgen receptors in the mesenchyme are obligatory for androgen-induced prostate growth and development.     

Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression

Colony-stimulating factor-1 receptor (CSF-1R) is the major regulator of macrophage development and is associated with epithelial cancers of the breast and ovary. Immunohistochemistry analysis of murine prostate development demonstrated epithelial expression of CSF-1R during the protrusion of prostatic buds from the urogenital sinus, during the prepubertal and androgen-driven proliferative expansion and branching of the gland, with a decline in older animals. Models of murine prostate cancer showed CSF-1R expression in areas of carcinoma- and tumor-associated macrophages. Several human prostate cancer cell lines and primary cultures of human prostate epithelial cells had low but detectable levels of CSF-1R. Human prostatectomy samples showed low or undetectable levels of receptor in normal glands or benign prostatic hypertrophy specimens. Staining was strongest in areas of prostatic intraepithelial neoplasia or carcinoma of Gleason histological grade 3 or 4. The activated form of the receptor reactive with antibodies specific for phosphotyrosine modified peptide sequences was observed in samples of metastatic prostate cancer. Immunohistochemistry showed strong expression of CSF-1R by macrophage lineage cells, including villous macrophages and the syncytiotrophoblast layer of placenta, Kupper cells in the liver, and histiocytes infiltrating near prostate cancers. These observations correlate CSF-1R expression with changes in the growth and development of the normal and neoplastic prostate.     

Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue

To examine the relationship between whole prostatic dihydrotestosterone (DHT) concentrations and epithelial and stromal protein synthesis, patients awaiting surgery for benign prostatic hypertrophy were given medication to reduce circulating and tissue androgen levels for comparison to levels in untreated patients. The medications, either megestrol acetate, a progestational antiandrogen, or megestrol acetate plus dexamethasone, were given for 1 week before surgery. Aliquots of prostate tissue obtained at surgery were assayed for DHT. The remainder of the tissue was separated into stromal and epithelial cells using enzymatic separation; the incorporation of both [3H] proline into stromal protein and [3H]leucine into epithelial cell protein was then measured. Over a wide range of tissue DHT concentrations, DHT correlated significantly with [3H]proline incorporation into stromal protein (r = 0.58). Likewise, epithelial cell incorporation of [3H]leucine into protein correlated significantly with tissue DHT concentrations, with a r value of 0.79. In the case of stromal cells, no additional effects of dexamethasone given with megestrol acetate were found on stromal protein synthesis. Epithelial cell [3H]leucine incorporation into protein was paradoxically enhanced by dexamethasone plus megestrol acetate compared to the latter alone, despite the fact that tissue DHT and circulating adrenal androgens, dehydroepiandrosterone sulfate and delta 4-androstenedione, were not significantly different from values obtained after treatment with megestrol acetate alone. These studies support the conclusion that there is a dominant role of DHT in regulating protein synthesis in both prostatic epithelial and stromal cells. Dexamethasone appears to have a growth-stimulating effect on prostatic epithelial cells.     

Proliferative disorders of the aging human prostate: involvement of protein hormones and their receptors.

The majority of elderly men is affected by benign and malignant diseases of the prostate. Both proliferative disorders, i.e., benign hyperplasia of the prostate (BPH) and prostate cancer (PCa)-which has recently emerged as the most common male malignancy in industrialized countries-seem to be governed by endocrine factors such as sex steroid hormones, but auto/paracrine factors are involved as well. Age-related changes in levels and ratios of endocrine factors as androgens, estrogens, gonadotropins, and prolactin (PRL) and changes in the balance between auto/paracrine growth-stimulatory and growth-inhibitory factors such as insulin-like growth factors (IGFs), epidermal growth factor (EGF), nerve growth factor (NGF), IGF-binding proteins (IGFBPs), and transforming growth factor beta (TGFbeta) are meant to be responsible for abnormal prostatic growth. We investigated the existence of putative local regulatory circuits involving the protein hormones, human growth hormone (hGH), human placental lactogen (hPL), and hPRL, and their corresponding receptors in prostatic tissue specimens (transurethral resections of the prostate, TURP; n = 11), in the prostatic cancer cell lines PC3, Du145, LnCap, a virus-transformed BPH cell line (BPH-1), and in a normal healthy prostate by RT-PCRs and highly specific and sensitive immunofluorometric assays (IFMA). Neither hPRL nor hGH was detected at the mRNA or protein levels in prostatic tissue and cell lines, with the exception of 2 of 11 prostatic TURP-samples, which showed weak expression of the PL-A/B genes. PRL- and GH-receptors were expressed in all normal and pathological prostatic specimens. Surprisingly, PRL-receptor expression was not detectable in prostatic cancer cell lines. The trophic effects of exogenous hGH, hPL, and hPRL were investigated by cell proliferation assays (WST-I) in prostatic primary cell cultures and PCa cell lines. hGH significantly (p < 0.005) increased cell proliferation up to 138+/-3.2% (1 nM hGH), while hPL and hPRL revealed only moderate effects. Our data suggest that local auto/paracrine networks of protein hormone actions are not involved in the pathology of BPH or prostatic cancer. On the other hand, systemic pituitary-derived hGH can increase the proliferative response of BPH and PCa, acting directly on the target organ prostate, via the hGH-R. In this case, envisaged GH substitution in elderly people must be viewed at with caution because age-related declines in GH/IGF-I could act as a protective mechanism against abnormal cell growth.     

Basic fibroblast growth factor: a potential mediator of stromal growth in the human prostate.

Studies were undertaken, using isolated prostatic epithelial and stromal cells, to evaluate the role of basic fibroblast growth factor (bFGF) in the regulation of benign prostatic growth. bFGF was detected in lysates, but not the conditioned media, of cultured prostatic epithelial and stromal cells by Western immunoblotting and immunoprecipitation of metabolically labeled proteins. Immunofluorescence analysis of benign human prostate localized the majority of bFGF to the prostatic stroma. In addition, bFGF was a potent stimulator of stromal cell proliferation in vitro, but was not mitogenic to cultured epithelial cells. Further studies demonstrated bFGF receptors (Kd = 258 pM; 61,400 receptors/cell) on stromal cells, but not epithelial cells. Epithelial cell-conditioned medium was mitogenic for stromal cells, suggesting the presence of paracrine interactions. However, bFGF does not appear to be the mediator of this interaction, since the mitogenic effect of epithelial cell-conditioned medium on stromal cells was not significantly reduced by the addition of anti-bFGF. Additional studies showed that concentrated stromal cell-conditioned medium was not mitogenic to cultured stromal cells under serum-free defined conditions, indicating the lack of an external autocine mechanism. These studies demonstrate that bFGF is actively synthesized by isolated prostatic epithelial and stromal cells, but is largely not secreted. Prostatic stroma, but not epithelia, are responsive to the mitogenic effect of bFGF in vitro. However, because of the limited secretion of bFGF by prostatic cells, the mechanism(s) of bFGF-mediated regulation of stromal growth remains unclear.     

Human prostate specific and shared differentiation antigens defined by monoclonal antibodies.

Splenic lymphocytes of BALB/c mice immunized with membrane-enriched fractions of human benign prostatic hyperplasia tissues were fused with the NS-1 light chain-secreting murine myeloma cell line. This generated hybridoma cultures that secreted immunoglobulins reactive in solid-phase radioimmunoassays with membrane preparations of prostatic tissues but not with membrane preparations of apparently normal human liver, spleen, thymus, or erythrocytes. After further screening of immunoglobulin reactivities and cloning of cultures, eight monoclonal antibodies were chosen that demonstrated reactivity with human prostate tissues. These monoclonal antibodies could be placed into at least three major groups--epithelium-specific, polyepithelial, and stroma-specific--on the basis of differential binding to the surfaces of various component cells in the prostate and other epithelia. Two antibodies defined unique protein antigens specific for prostate epithelia that were not crossreactive with prostatic acid phosphatase or the recently described "prostatic antigens." These antibodies also detected antigens on malignant prostate tissues as well as other malignant tissues. Four antibodies defined three unique polyepithelial protein antigens (two of the antibodies were different isotypes defining the same protein). Each of the polyepithelial antigens was expressed on a different spectrum of normal epithelial tissues. Two displayed brain tissue crossreactivity, one was present on pancreas, and one was present on platelets. The two antibodies that detected prostatic stromal protein antigens showed different spectra of reactivities. One antibody reacted with apparently all prostatic stromal cells as well as endothelial cells in the prostate and other organs. The other antibody apparently reacted with all prostatic stromal cells as well as myoepithelial and muscle cells in other organs.     

Androgen receptor is a tumor suppressor and proliferator in prostate cancer

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo. Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.     

Benign prostatic hyperplasia: age-related tissue-remodeling

Aging and androgens are the two established risk factors for the development of benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE), which can lead to lower urinary tract symptoms (LUTS) in elderly men. BPH, consisting of a nodular overgrowth of the epithelium and fibromuscular tissue within transition zone and periurethral areas, is first detectable around the fourth decade of life and affects nearly all men by the ninth decade. The pathogenesis of BPH is still largely unresolved, but multiple partially overlapping and complementary theories have been proposed, all of which seem to be operative at least to some extent. In addition to nerve-, endocrine- and immune system, local para- and luminocrine pleiotrope mechanisms/factors are implicated in the prostatic tissue-remodeling process. Prostate tissue-remodeling in the transition zone is characterized by: (i) hypertrophic basal cells, (ii) altered secretions of luminal cells leading to calcification, clogged ducts and inflammation, (iii) lymphocytic infiltration with production of proinflammatory cytokines, (iv) increased radical oxygen species (ROS) production that damages epithelial and stromal cells, (v) increased basic fibroblast (bFGF) and transforming growth factor beta (TGF-beta 1) production leading to stromal proliferation, transdifferentiation and extracellular matrix production, (vi) altered autonomous innervation that decreases relaxation and leads to a high adrenergic tonus, (vii) and altered neuroendocine cell function and release of neuroendocrine peptides (NEP). This review summarizes the multifactorial nature of prostate tissue remodeling in elderly men with symptomatic BPH with a particular focus on changes of cell-cell interactions and cell functions in the human aging prostate.     

Minireview: regulation of prostatic stem cells by stromal niche in health and disease

The isolation and characterization of prostatic stem cells has received significant attention in the last few years based on the belief that aberrant regulation of adult stem cells leads to prostate disease including cancer. The nature of the perturbations in stem cell regulation remains largely unknown. Although adult stem cells are can be governed by autonomous regulatory mechanisms, the stromal niche environment also provides essential cues to direct directing differentiation decisions and can lead to aberrant proliferation and/or differentiation. Elegant tissue recombination experiments, pioneered by Gerald Cunha and colleagues, provided evidence that quiescent epithelial tissues containing adult stem cells were capable of altered differentiation in response to inductive and instructive mesenchyme. In more recent times, it has been demonstrated that embryonic mesenchyme is sufficiently powerful to direct the differentiation of embryonic stem cells into mature prostate or bladder. In addition, prostatic tumor stroma provides another unique niche or microenvironment for stem cell differentiation that is distinct to normal stroma. This review highlights the importance of the appropriate selection of the stromal cell niche for tissue regeneration and implies plasticity of adult stem cells that is dictated by the tissue microenvironment.     

Proliferation of prostate epithelia induced by IL‐6 from stroma reacted with Trichomonas vaginalis

Benign prostatic hyperplasia (BPH) is characterized by the proliferation of stromal and epithelial cell types in the prostate, and interactions between the two types of cells. We demonstrated previously that proliferation of prostate stromal cells was induced by BPH epithelial cells in response to Trichomonas vaginalis (Tv) infection via crosstalk with mast cells. In this study, we investigated whether IL‐6 released by the proliferating stromal cells in turn induce the BPH epithelial cells to multiply. When culture supernatants of the proliferating prostate stromal cells were added to BPH epithelial cells, the latter multiplied, and expression of cyclin D1, FGF2 and Bcl‐2 increased. Blocking the IL‐6 signalling pathway with anti‐IL‐6R antibody or JAK1/2 inhibitor inhibited the proliferation of the BPH epithelial cells and reduced the expression of IL‐6, IL‐6R and STAT3. Also, epithelial‐mesenchymal transition was detected in the proliferating BPH epithelial cells. In conclusion , IL‐6 released from proliferating prostate stromal cells induced by BPH epithelial cells infected with Tv in turn induces multiplication of the BPH epithelial cells. This result provides first evidence that the inflammatory microenvironment of prostate stromal cells resulting from Tv infection induces the proliferation of prostate epithelial cells by stromal‐epithelial interaction.     

Estrogen receptors alpha and beta in the normal, hyperplastic and carcinomatous human prostate

Two different estrogen receptors (ER-alpha and ER-beta) have been described, which are differentially involved in regulating the normal function of reproductive tissues. ER-alpha was considered for a long time to be the only estrogen receptor, and it has been detected in the stromal cells of the human prostate but not in the epithelium. To obtain new information about the differential effects of both receptor types, we have investigated their localization in normal prostates, benign prostatic hyperplasia (BPH), and prostatic cancer (PC) by immunohistochemistry, ELISA and Western blot. Epithelial immunostaining was absent in normal prostates and was present in BPH (10% of cells) and PC (80% of cells), whereas about 15% of stromal cells were positively immunostained for ER-alpha in the three types of prostatic specimens studied. Epithelial immunostaining for ER-beta was detected in normal prostates (13% of cells), BPH (30% of cells) and PC (79% of cells), whereas stromal immunostaining for ER-beta was absent in normal and hyperplastic prostates and was present in PC (12% of cells). The complementary presence of both receptor types in the normal prostate (ER-beta in the epithelium and ER-alpha in the stroma) might explain the mechanism of estrogen action in the development of BPH. The increased epithelial immunostaining for both ER-alpha and ER-beta in BPH and PC suggests that the involvement of estrogen receptors in hyperplasia and cancer concerns mainly the epithelium.