Stromal Androgen Receptor Roles in the Development of Normal Prostate,Benign Prostate Hyperplasia,and Prostate Cancer

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.The prostate contains mainly the stromal cells and epithelial cells that are separated by base members and merged in extracellular matrix. Stromal cells include fibroblasts, smooth muscle cells (SMCs), and other minor inflammatory cells, nerve cells, and endothelial cells.The prostate is developed from the endodermal urogenital sinus¹ that contains an outer layer of embryonic connective tissue urogenital sinus mesenchyme (UGM) and an inner layer of urogenital sinus epithelium (UGE).¹ The initial step of prostate development in UGM involves the differentiation of fibroblasts and SMCs,¹ and in response to the UGM androgen/androgen receptor (AR) signals, UGE can grow into the surrounding stromal cells and develop into the prostate epithelial cells as part of the normal prostate development.The ability of the UGM to induce epithelial development and the developed epithelial cells, in return, to direct UGM to undergo differentiation, suggesting that the reciprocal developmental interactions between UGM and UGE might be governed by androgen/AR signals, which are essential for the development of normal prostate, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Prostate development factors, including its proliferation, differentiation, morphogenesis, and functional maintenance, are all influenced by androgen/AR signals.² Androgen/AR signals also play vital roles in the initiation and progression of BPH and PCa,^3,4 which may require the proper interaction with various AR coregulators.²AR is a member of the nuclear receptor superfamily that can be activated and translocated from cytoplasm to nucleus after binding the testosterone or dihydrotestosterone.^5–7 In prostate, AR is expressed in both epithelial and stromal tissues. The transactivated AR in nucleus may then function through modulation of various downstream target genes to influence the development and maintenance of the prostate. In addition to influencing cell growth directly, epithelial AR and stromal AR can also function through epithelial-mesenchymal transition (EMT) to influence prostate development. EMT is a process by which epithelial cells lose their cell-cell adhesion and gain migratory properties to become mesenchymal-like and/or mesenchymal stem cells. These potent mesenchymal cells may then differentiate into different cell types to influence the progression of BHP⁸ and PCa.⁹This review will focus on the discussion of the roles of stromal AR in the development of normal prostate and prostate diseases.     

雄激素受体异常激活与激素非依赖性前列腺癌的形成机制

前列腺癌进展的晚期常转变为激素非依赖性 ,包括雄激素受体拮抗剂在内的多种细胞外因子能够刺激其增殖。雄激素受体基因突变、多种途径引起的异常磷酸化激活和共激活物的调节失控等是激素非依赖性前列腺癌形成的主要促成因素。以雄激素受体为靶标可能成为晚期前列腺癌的有效治疗途径。     

Androgen Receptor Roles in the Development of Benign Prostate Hyperplasia

Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell–stromal cell interaction with alterations of epithelial–mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development.Benign prostatic hyperplasia (BPH) is the most common male benign proliferative disease, and approximately 8 million patients are estimated to visit physicians with the diagnosis of primary or secondary BPH.¹ The incidence of gross enlargement of the prostate gland has been reported as 40% in 70-year-old men, and microscopic foci of the prostate gland are present in up to 80% of these men.² BPH patients often have lower urinary tract symptoms, and need to be treated with surgery or medication. Although transurethral resection of the prostate is the most common surgical treatment for BPH worldwide, the procedure can lead to complications (eg, bleeding, urethral stricture, incontinence) and may have limitations for people of advanced age.^3–5 Although α-blockers are frequently prescribed for treatment of BPH and have a quick onset of action, within 3 to 5 days,⁶ these drugs alone fail to shrink BPH volume and are often insufficient to eliminate symptoms.⁷ In contrast, 5-α reductase inhibitors (5-ARIs), which suppress testosterone conversion into dihydrotestosterone (DHT), have greater efficacy in reducing BPH volume, and clinical data indicate that the combination of 5-ARIs with α-blockers leads to the best symptomatic response to date.^8,9The above clinical data suggest that androgen/androgen receptor (AR) signaling plays key roles in development of BPH and that targeting androgen/AR signaling could be a major therapeutic approach for BPH. Nevertheless, the detailed mechanisms of androgen/AR signaling, and especially the pathogenic roles of AR in BPH,¹⁰ are still unclear.In this review, we focus on the roles of AR in promoting prostate stromal cell growth¹¹ and prostate epithelial cell growth with increased epithelial–mesenchymal transition (EMT).¹² We also discuss how AR regulates development of BPH through the inflammatory environment with macrophage infiltration, and address potential new therapeutic approaches, such as targeting AR with the newly identified AR degradation enhancer ASC-J9 and/or targeting specific inflammatory cytokines downstream of AR.     

New Therapeutic Approach to Suppress Castration-Resistant Prostate Cancer Using ASC-J9 via Targeting Androgen Receptor in Selective Prostate Cells

Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten^+/− mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.Androgen/androgen receptor (AR) signaling plays essential roles in prostate cancer (PCa) progression and results in castration resistance.^1–4 Currently, most, if not all, androgen deprivation therapy (ADT) targets androgens via surgical and/or medical castration to reduce/prevent androgen binding to AR.⁵ However, few, if any, of these ADTs with various antiandrogens, including the recently developed enzalutamide,⁶ have the capacity to eliminate all PCa cells in the later castration-resistant stage. Therefore, degradation of AR during/after ADT can be considered to have clinical benefits for patients with advanced PCa with substantial AR.⁶ These conclusions suggest that identifying a novel compound(s) that could degrade/diminish AR protein in the castration-resistant stage, unlike currently used antiandrogens, may yield better therapeutic efficacies to battle PCa in the castration-resistant stage.Early studies via isolation of three PCa primary cells (PCa1, PCa2, and PCa3) from the same patient found that androgen/AR signaling could function differentially to either suppress or promote PCa growth.⁷ Using the cre-loxP strategy in mice to selectively knockout AR in various PCa cells, Niu and colleagues^3,4,8 observed that the loss of AR in cytokeratin 5/cytokeratin 8–positive basal intermediate epithelial cells led to increased PCa metastasis, yet loss of AR in cytokeratin 8–positive luminal epithelial cells resulted in suppressed PCa progression with increased cell apoptosis. In contrast, loss of AR in stromal fibroblasts and smooth muscle cells resulted in suppression of prostate/PCa growth.^9,10 These results conclude that AR can either promote or suppress PCa progression in different types of PCa cells.Because only one AR gene has been identified,¹¹ we hypothesized that these differential AR roles in various PCa cells in the same patient could be due to the existence of different AR-AR coregulator complexes. This hypothesis led us to screen the AR degradation enhancer 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) from natural products and their derivatives by selectively interrupting the interaction between AR and selective AR coregulators, such as AR–AR-associated protein (ARA) 70 and AR-ARA55, which are expressed mainly in luminal epithelial cells and stromal cells, respectively, in which AR may function with positive roles to either maintain cell survival or promote cell proliferation. Results from four different human PCa cell lines and eight different in vivo mouse models concluded that ASC-J9 could function as a promising AR degradation enhancer to suppress PCa progression before and after castration resistance with few adverse effects.     

The Expression of the Androgen Receptor and Estrogen Receptor 1 is Related to Sex Dimorphism in the Gerbil Prostate Development

The development of the prostate gland in females has not yet been clearly elucidated, and the sexual dimorphism associated with such gland development in general is far from being understood. In the present study, we used tridimensional (3D) reconstructions and histochemical and immunohistochemical techniques to describe the sexual dimorphism and its causes in the early postnatal development of the prostate in male and female Mongolian gerbils (Meriones unguiculatus). We observed that the female prostate was smaller, had fewer branches throughout the development, and underwent differentiation earlier than that in males. Also, the expression of the estrogen receptor 1 (ESR1 or ER‐alpha) and fibroblast growth factor 10 (FGF10) was decreased in the periductal region, and the expression of the androgen receptor (AR) was increased in the epithelium. All together, these changes decreased proliferation and branching and led to an earlier prematuration of the female prostate. These new data shed light on the underlying mechanisms involved with the sexual dimorphism in the development of the prostate. Anat Rec, 299:1130–1139, 2016. © 2016 Wiley Periodicals, Inc.     

Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 +/- 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 +/- 0.08). Cellular proliferation measured using Ki-67 revealed <1% immunostained cells on day 6. Androgen receptor immunostained cells increased to 63% on day 6 and 84% on day 32 although immunostaining remained weak. Cellular proliferation was undetectable beyond day 6 after castration until multiple foci of 5 to 20 proliferating cells became apparent on day 120. These foci expressed increased levels of prostate-specific antigen, an androgen receptor-regulated gene product. In tumors recurrent 150 days after castration androgen receptor-immunostaining intensity was similar to CWR22 tumors from intact mice although the percentage of cells immunostained was more variable. The appearance of proliferating tumor cells that expressed androgen receptor and prostate-specific antigen 120 days after castration suggests that these cells represent the origin of recurrent tumors.     

Race and Time to Receipt of Androgen Deprivation Therapy Among Men With Metastatic Prostate Cancer

BackgroundThe Medicare Modernization Act (MMA) drastically reduced reimbursement for androgen deprivation therapy (ADT) in 2005. One unintended consequence of the MMA may be an increase in the racial disparities in receipt of ADT. Given these policy changes, it becomes increasingly important to assess racial disparities in timely receipt of ADT.MethodsThe purpose of this study is to evaluate the associations between race and median time to receipt of ADT among men with metastatic prostate cancer before and after the passage of the MMA. A population-based retrospective cohort was created from the Surveillance, Epidemiology, and End Results-Medicare.ResultsA total of 1,846 African-American and 9,462 Caucasian men diagnosed with metastatic prostate cancer from 2000 through 2011 were included. An accelerated failure time regression model was used to examine factors associated with racial differences in median time to receipt of ADT. Results indicate that African-American men had a longer median time to receipt of ADT both before the MMA (Time Ratio (TR): 1.15; 95% Confidence Interval (CI) [1.05, 1.27]) and after the MMA (TR: 1.29; 95% CI [1.10, 1.53]) as compared to Caucasian men. In addition to race, men residing in South had longer median time to receipt of ADT (TR: 1.26, 1.52; 95% CI [1.01, 1.52; 1.24, 1.87] before and after MMA, respectively) compared to the Northeast region.ConclusionConsidering the palliative benefits of ADT, it is important to develop effective strategies to address racial differences in receipt of treatment for metastatic prostate cancer.     

Unrecognized Kinetics of Serum Testosterone: Impact on Short-Term Androgen Deprivation Therapy for Prostate Cancer

Purpose

To evaluate the kinetics of serum testosterone (T) recovery following short-term androgen deprivation therapy (ADT), as the understanding thereof is essential for the proper management of prostate cancer (PCa), especially intermittent ADT.

Materials and Methods

This prospective analysis included male sex offenders who voluntarily received leuprolide acetate in order to alleviate sexual aberrance. Thirty-three and 25 patients who received 3 and 6 months of ADT were assigned to Group A and Group B, respectively. Serum T levels were obtained every week during the on-cycle period, then monthly during the off-cycle period for at least 12 months.

Results

The kinetics of serum T during the on-cycle period were similar in both groups. After flare reaction at week 2, a nadir of 0.45±0.29 ng/mL was achieved. In Group A, an abrupt rebound-upsurge was observed during the first 2 month off-cycle period, which surpassed the baseline level and reached a plateau level of 8.74±2.11 ng/mL during the flare (p<0.001). This upsurge was followed by a gradual decline back to baseline over the following 10 months. In Group B, a gradual increase was observed, and a baseline level of 7.26±1.73 ng/mL was reached at 5 months. Thereafter, an ongoing upsurge that surpassed baseline levels was observed until 12 months (8.81±1.92 ng/mL; p=0.002).

Conclusion

The kinetics of serum T recovery during the off-cycle period varied according to the duration of ADT. Serum T should be monitored beyond normalization, as an excessive rebound may improve quality-of-life, but hamper the treatment efficacy of PCa.     

Relationship between Androgen Deprivation Therapy and Normal-Tension Glaucoma in Patients with Prostate Cancer: A Nationwide Cohort Study

PurposeThis study assessed the relationship between newly developed normal-tension glaucoma (NTG) and androgen deprivation therapy (ADT) in patients with prostate cancer.Materials and MethodsA retrospective population-based cohort study was performed. During the period between 2008 and 2017, a total of 218203 prostate cancer patients were identified in a nationwide claims database in the Republic of Korea. The final analysis included 170874 patients (42909 in the ADT group, 127965 in the control group) after applying the inclusion and exclusion criteria. The incidences of NTG according to ADT duration were compared with controls. Exact matching was conducted to adjust comorbidities between cohorts. Cox proportional hazard regression models were performed after controlling for latent confounding factors, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of NTG according to ADT were obtained.ResultsIn the matched cohort, the ADT group was associated with a significantly reduced risk of NTG in multivariable analysis compared to the control group. The risk of NTG decreased in patients who underwent ADT for less than 2 years (HR=0.824; 95% CI, 0.682–0.995; p=0.0440) and in those using ADT over 2 years (HR=0.796; 95% CI, 0.678–0.934; p=0.0051), compared to the controls.ConclusionMedical castrations for patients with prostate cancer results in a lower incidence of newly diagnosed NTG compared to no ADT. These findings suggest that testosterone may be involved in the pathogenesis of NTG.     

Effectiveness of Adding Docetaxel to Androgen Deprivation Therapy for Metastatic Hormone-Sensitive Prostate Cancer in Korean Real-World Practice

PurposeEvidence in favor of adding docetaxel in treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has led to docetaxel in conjunction with androgen deprivation therapy (ADT) as standard therapy. The aim of this study was to examine the effectiveness of docetaxel with ADT for Korean patients with mHSPC in real-world practice.Materials and MethodsA retrospective cohort study was performed at six Korean hospitals for patients with mHSPC treated with docetaxel plus ADT. Patients were treated every 3 weeks for up to six cycles with 75 mg/m² of docetaxel. The primary endpoint was time to castration resistant prostate cancer (CRPC).ResultsThis study included 46 eligible patients from June 2016 to February 2021. Median age was 68.5 years (range, 52–84) and all patients present with de novo M1 with high-volume disease. The median prostate-specific antigen (PSA) level at ADT initiation was 205.4 (7.7–1933) ng/mL, and time from ADT to docetaxel was 2.4 months (0–5.3). All six planned cycles of docetaxel were delivered in 36 patients (78%), 7 patients (15%) discontinued treatment due to adverse events, and 3 patients (7%) discontinued due to progression. At the time of the analysis, CRPC had developed in 34 patients (74%), and the median time to CRPC was 18.0 (95% confidence interval, 14.1–21.9) months. PSA <0.2 ng/mL was achieved in 11 patients (24%) after 6 months of ADT and in 10 patients (22%) after 12 months. At last follow-up, 35 patients (76%) were alive; the median overall survival was not reached.ConclusionThe effect of docetaxel combined with ADT for Korean patients with mHSPC is comparable with prior results in Western studies.     

Immunolocalization of Androgen Receptor and Estrogen Receptors in Skin Tags

Abstract

Skin tags (STs) are benign connective tissue tumors of the dermis. Several clinical observations suggested the involvement of sex steroids in their development. This study aimed at investigating the possible role of androgen receptor (AR) and estrogen receptors (ERs) in STs pathogenesis through their immunohistochemical (IHC) localization in skin biopsies of this disease and to correlate their expression with different clinical and histopathological parameters. Using IHC techniques, we examined 62 cases with STs and 30 gender- and age-matched, healthy subjects, representing the control group. ERα, ERβ, and AR were upregulated in STs compared to normal skin in epidermis and dermis (p?<?.001 for all). Higher AR H score was significantly associated with axillary STs (p?=?.02), skin colored tags (p?=?.03), acanthosis, and papillomatosis (p?=?.04 for both). Higher ERα H score was significantly associated with hyperpigmented tags (p?<?.001) and positive family history (p?=?.003). Higher ERβ H score was significantly associated with female gender and obesity (p?=?.004 for both). Higher ERα and AR H scores were significantly associated with loose collagen arrangement (p?=?.02, p?=?.004, respectively). Higher AR, ERα, and ERβ H scores were significantly associated with the presence of mast cells (p?=?.01, p?=?.04, p?=?.002, respectively) and dilated blood vessels (p?=?.006, p?=?.04, p?=?.04, respectively). In conclusion, AR and ERs may share in STs pathogenesis through their effect on keratinocytes, fibroblasts, and mast cells.     

Immunoexpression of Androgen Receptor in the Nontumorous Pituitary and in Adenomas

Little information is available regarding androgen receptor immunoexpression (AR) in the normal and neoplastic human pituitary. Available experimental data links it to primarily gonadotroph cells. We undertook an immunohistochemical study of 41 autopsy-derived normal glands from patients of both sexes and all ages as well as 79 fully characterized pituitary adenomas of all types, the focus being upon AR expression in normal and neoplastic gonadotrophs. Nuclear AR immunoreactivity was noted in gonadotrophs and other normal adeno- and neurohypophysial cells. In addition to its presence in 74% of gonadotroph and 55% of null cell adenomas, lesser proportions of other adenoma types (adrenocorticotropic hormone 50%, prolactin 38%, growth hormone 33%) also exhibited AR immunoreactivity. No staining of thyroid-stimulating hormone adenomas was noted. The physiologic significance of our findings remains to be explored. The literature regarding AR expression in animal and human pituitaries is reviewed.