Androgen Regulated Genes in Intact Human Prostate Tissues: Relation to Benign Prostatic Hyperplasia and Prostate Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17862 | GEO | 2010/06/14
SECONDARY ACCESSION(S): PRJNA120109
REPOSITORIES: GEO
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Project description:To investigate gene expression profiling in intact human prostate tissue xenografts in mice, following the addition or subtraction of androgens. 58 prostate samples were implanted into castrated or testosterone-treated mice for 5 different lengths of time. Samples were compared to a control pool created by combining day zero tissue samples from all patients
2010-06-14 | E-GEOD-17862 | biostudies-arrayexpress
Project description:The role of molecular changes in the androgen receptor (AR) as AR variants (AR-Vs) is not clear in the pathophysiology of benign prostatic hyperplasia (BPH) and hormone-naïve PCa. The aim of the current work was to identify the presence of AR isoforms in benign tissue and primary PCa, and to evaluate the possible association with tumor aggressiveness and biochemical recurrence in primary PCa. The mRNA levels of full length AR (AR-FL) and AR-Vs (AR-V1, AR-V4 and AR-V7) were measured using RT-qPCR. The protein expression of AR-FL (AR-CTD and AR-NTD) and AR-V7 were evaluated by the H-Score in immunohistochemistry (IHC). All investigated mRNA targets were expressed both in BPH and PCa. AR-FL mRNA levels were similar in both groups. AR-V4 mRNA expression showed higher levels in BPH, and AR-V1 and AR-V7 mRNA expression were higher in PCa. The AR-V7 protein showed a similar H-Score in both groups, while AR-CTD and AR-NTD were higher in nuclei of epithelial cells from BPH. These results support the assumption that these constitutively active isoforms of AR are involved in the pathophysiology of primary PCa and BPH. The role of AR-Vs and their possible modulation by steroid tissue levels in distinct types of prostate tumors needs to be elucidated to help guide the best clinical management of these diseases.
| S-EPMC6054396 | biostudies-literature
Project description:Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9(®), led to the reduction of prostate size, which could be used in future therapy.
| S-EPMC3787128 | biostudies-literature
Project description:Treatment of prostate stroma with dihydrotestosterone to examine differential gene expression. Isolation of androgen receptor fraction of stroma using cd49a antibody, RNA extraction, one cycle cDNA synthesis and IVT labelling standard protocols same for each microarray
2011-10-01 | E-MTAB-402 | biostudies-arrayexpress
Project description:Treatment of prostate stroma with dihydrotestosterone to examine differential gene expression. Isolation of androgen receptor fraction of stroma using cd49a antibody, RNA extraction, one cycle cDNA synthesis and IVT labelling standard protocols same for each microarray
2011-10-01 | E-MTAB-600 | biostudies-arrayexpress
Project description:Infiltrated macrophages may play important roles in the development and progression of benign prostatic hyperplasia (BPH), but the underlying mechanisms remain largely unknown. We found increased macrophages infiltration in human and mouse BPH tissues. By establishing a co-culture transwell system, we found increased migration of macrophages and proliferation of prostate stromal cells during co-culture. Importantly, stromal androgen receptor (AR) could enhance the migration of macrophages and macrophage-mediated stromal cell proliferation. We identified CCL3 as an AR downstream player, and found CCL3 levels were notably increased in human and mouse BPH prostates. Ablation of prostate stromal AR in a mouse BPH model significantly reduced CCL3 expression levels in prostates. Consistently, targeting AR via an AR degradation enhancer, ASC-J9®, or neutralization of CCL3 with an antibody, resulted in suppression of macrophage migration and prostate stromal cell growth. Our study provides mechanistic insights on the regulation of prostate stromal cells by macrophages via stromal AR/CCL3 signaling pathways, which could potentially allow the development of therapeutic approaches for battling BPH with persistent inflammation.
| S-EPMC3365773 | biostudies-literature
Project description:Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-?2, were increased, and administration of anti-TGF-?2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.
| S-EPMC3458217 | biostudies-literature
Project description:An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH).Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics.By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively.The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH.
| S-EPMC4702000 | biostudies-literature
Project description:BackgroundAmong various treatment options for benign prostatic hyperplasia (BPH), surgical therapy is the most invasive. As Switzerland has the highest transurethral prostatectomy rate among OECD countries, we assessed the regional variation in prostate surgery for BPH and explored potential determinants of variation.MethodsWe conducted a population-based analysis using discharge data for men aged ≥40 years with transurethral or simple prostatectomy from all Swiss hospitals during 2013-2018. After excluding patients with genitourinary/prostate cancer, we derived hospital service areas (HSAs) by analyzing patient flows. We calculated age-standardized mean procedure rates and variation indices (extremal quotient [EQ] and systematic component of variation [SCV]). We estimated the reduction in variance across HSAs of prostatectomy rates in multilevel regression models, with incremental adjustment for age, regional cultural and socioeconomic factors, disease burden, density of urologists, and the time since urologists' graduation.ResultsOverall, 44,253 prostatectomies (42,710 transurethral and 1543 simple) from 44 HSAs were analyzed. The mean age-standardized prostate surgery rate was 314 (range 166-500) per 100,000 men aged ≥40 years per year. The EQ was 3.01 and the SCV 5.53, indicating a high regional variation. In multivariate models, men aged 75-79 years had an 11.6-fold higher prostatectomy rate than those aged 50-54 years. French/Italian language areas had a 21% lower rate than Swiss German speaking areas. Socioeconomic factors, disease burden, and density of urologist/time since graduation were not associated with prostatectomy rates. After full adjustment, 80% of the variance in prostate surgery across HSAs remained unexplained.ConclusionWe found a remarkably high regional variation in prostate surgery rates for BPH within Switzerland.
| S-EPMC8297757 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH.Levels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter.Human BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls.Oxidative stress and oxidative DNA damage are important in the pathogenesis of BPH.
| S-EPMC5469601 | biostudies-literature