Prostate Stromal Cells Research Articles

Androgen Receptor Expression in Epithelial and Stromal Cells of Prostatic Carcinoma and Benign Prostatic Hyperplasia.

BACKGROUND:Prostatic carcinoma (PCa) derives from prostatic epithelial cells. However stromal microenvironment, associated with malignant epithelium, also plays a role in prostatic carcinogenesis. Alterations in prostatic stromal cells contribute to the loss of growth control in epithelial cells that lead to progression of PCa.AIM:To analyse the differences between Androgen Receptor (AR) expression in both epithelial and stromal cells in PCa and the surrounding benign prostatic hyperplasia (BPH) and to compare the results with tumour grade.MATERIAL AND METHODS:Samples from 70 cases of radical prostatectomy specimens were used. The expression and intensity of the signal for AR was analysed in the epithelial and stromal cells of PCa and BPH, and the data was quantified using histological score (H-score).RESULTS:AR showed significantly lower expression in both epithelial and stromal cells of PCa compared to BPH. In PCa a significant positive correlation of AR expression was found between stromal and epithelial cells of PCa. AR expression showed a correlation between the stromal cells of PCa and tumour grade.CONCLUSION:AR expression is reduced in epithelial and stromal cells of PCa. Expression of AR in stromal cells of PCa significantly correlates with tumour grade.

Lack of adiponectin and adiponectin receptor 1 contributes to benign prostatic hyperplasia.

PURPOSEThe incidence of benign prostatic hyperplasia increases among obese individuals, but few studies have fully explained the underlying mechanisms. Adiponectin has drawn much attention in recent years due to its protective role in obesity-related diseases. Here we aimed to investigate the possible molecular mechanisms and clinical significance of adiponectin in relation to benign prostatic hyperplasia.METHODSWe analyzed data from 98 Chinese men, including 48 BPH cases and 50 controls in a case-control study. Then, we utilized a tissue microarray analysis to examine expression of AdipoR1 and p-p90RSK in normal and hyperplastic prostate tissues. These studies were followed by various in vitro approaches to examine the anti-proliferation effect and signaling pathways of adiponectin involved in benign prostatic hyperplasia.RESULTSLower serum adiponectin levels were independently associated with larger prostate volume and an increased risk of benign prostatic hyperplasia. Benign prostatic hyperplasia tissues had a decreased expression of AdipoR1 and increased expression of p-p90RSK compared with normal prostate tissues. in vitro, adiponectin inhibited the proliferation of prostatic epithelial and stromal cells and arrested cells in the G0/G1 phase by decreasing phosphorylation of the MEK-ERK-p90RSK axis.CONCLUSIONSOur results suggest a possible negative regulatory mechanism in which adiponectin signaling antagonizes ERK-mediated cell proliferation, and a deficiency in adiponectin could facilitate the proliferation of prostate cells and consequently contribute to benign prostatic hyperplasia.

Abstract 5910: Influence of 3D- cultured prostate cancer and stromal cells on drug response

Abstract Background: Response to chemotherapeutic drugs presents a significant challenge to effective treatment of advanced prostate cancer. Exploration of therapeutic response has focused largely on the tumor cell. However, evidence suggests mechanisms that involve the tumor microenvironment mediate response to therapeutics. Therefore, it is imperative to mimic the in vivo tumor microenvironment, to bridge the gap between in vitro studies and the development of therapeutics. The concept of three-dimensional (3D) cell culture and co-culture of multiple cell types is critical to predict therapeutic efficacy and outcome. Thus, these studies sought to determine the distinct responses to anti-cancer drugs in 3D cell spheroids. Methods: In this study, we utilized metastatic prostate cancer cells (PC3) and fluorescently labeled prostate bone stromal cell line (HS27a) to generate tumor spheroids. Tumor spheroid viability was measured at 72 and 120 h using the CellTiter-Glo 3D assay after treatment with three common anti-cancer drugs, Docetaxel (4ηM), Enzalutamide (30μM), and Bicalutamide (30μM).Treatments were compared with spheroids originated from HS27a and PC3 cells alone and in co-culture. The cell viability percentage was normalized using the untreated cells as 100% cell survival. Results: Spheroid formation increased resistance to Docetaxel, Enzalutamide, and Bicalutamide. However, PC3 spheroid cells was significantly higher compared to HS27a and co-culture spheroids. For all three spheroids, as the size of the spheroids increase, cellular resistance to anti-cancer and hormone drugs increased. Conclusion: The findings in this study demonstrated that the use for 3D-cell cultures influence many aspects of PCa behavior including, proliferation rates, and response to chemotherapeutics. Note: This abstract was not presented at the meeting. Citation Format: Dominique N. Gales, Sonni Miller, Temesgen Samuel, Clatyon Yates. Influence of 3D- cultured prostate cancer and stromal cells on drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5910. doi:10.1158/1538-7445.AM2017-5910

Abstract 5772: Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities

Abstract The prostate is composed of a fibro-muscular stromal and glandular epithelial cells. Cross-talk between these cell populations is essential for normal prostate development and is involved in carcinogenesis. In the past year, an estimated 220,800 new cases of prostate cancer (PCa) were diagnosed and 27,540 died of PCa. PCa in African American men occurs more frequently, develops at a much earlier age, and is more aggressive and lethal compared to men of European descent. Both biological and socioeconomic factors likely contribute to this disparity. There is currently a paucity of relevant preclinical models in which to examine biological mechanisms in African American PCa. Patient-derived organoids are a recently developed in vitro preclinical model which facilitate examination of underlying mechanisms of disease etiology. However, current models of epithelial organoid growth lack the prostate stroma. To address this unmet need, we began development of a 3D organoid model that incorporated both primary human prostatic epithelial (PrE) and stromal (PrS) cells to better mimic the microenvironment of the organ. Prostate organoids were derived from cells collected from radical prostatectomy tissues from patients (UIC IRBs: 2006-0679 (PI Behm), (2013-0341(PI Nonn). Mixtures of single PrE-derived and single PrS-derived cells were seeded in 3D in matrigel. Bright-field microscopy of live organoids and histological examination of fixed organoids showed that the addition of PrS cells to the culture altered the shape of the organoids compared to the spherical phenotype observed in PrE only cultures. Immunofluorescent analysis of the basal cell marker p63 showed increased epithelial differentiation in the co-culture organoids. In summary, these data suggest that inclusion of prostate stroma in co-culture organoid models influences prostatic epithelial organoid development in vitro. Ongoing studies are focused on molecular analysis or organoid phenotypes and comparison of AA and EA-derived organoids. Citation Format: Joseph Marsili, Zachary Richards, Jason Garcia, Cindy Voisine, Larisa Nonn. Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5772. doi:10.1158/1538-7445.AM2017-5772

Abstract 344: Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate stem cells

Abstract The chondroitin sulfatases N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) and N-acetylgalactosamine 6-sulfatase (galactose 6-sulfatase, GALNS) remove the 4-sulfate and 6-sulfate groups of chondroitin sulfates. ARSB acts to remove 4-sulfate groups of chondroitin 4-sulfate (C4S) or dermatan sulfate, and GALNS acts to remove 6-sulfate groups of chondroitin 6-sulfate (C6S) or chondroitin 4,6-disulfate, as well as keratan sulfate. In human prostate cancer tissues, ARSB activity was markedly reduced and GALNS activity increased. By immunohistochemistry of malignant prostate tissue captured by laser microdissection and by assay of human prostate stromal and epithelial cell lines, ARSB was predominant in stromal cells of the extracellular matrix, whereas GALNS predominated in prostate epithelial cells. When ARSB was reduced by silencing in human prostate stem cells or GALNS was increased by overexpression in the stem cells, SHP2 binding to chondroitin 4-sulfate increased, leading to inhibition of phosphatase action and sustained phosphorylation of Erk1,2. Erk activation enabled increase in c-Myc binding to nuclear DNA and increased expression of DNMT 1a, 3a, and 3b. DNMT activation increased following ARSB silencing or GALNS overexpression, and was blocked by ERK inhibition. Increased DNMT activity led to the increased promoter methylation of DKK3, and the subsequent inhibition of nuclear β-catenin nuclear translocation and Wnt signaling. Decline in Wnt signaling was manifested by reduced TCF-LEF nuclear binding, and decline in the mRNA expression of c-Myc and GATA. Since c-Myc activation can lead to increased expression of cell cycle regulators, the changes in chondroitin sulfation mediated by sulfatases can lead to profound effects in cell proliferation. Hence, the modification of sulfatase activity, manifested as increased chondroitin 4-sulfate, provides the platform for an extensive extracellular-intracellular signaling network that can regulate phosphorylation, DNA promoter methylation, and proliferation, and affect development and malignant transformation. Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Leo Feferman. Chondroitin sulfatases regulate Wnt signaling through effects on Shp2, phospho-Erk1,2, c-Myc, and histone methylation of DKK3 in prostate cancer and prostate stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 344. doi:10.1158/1538-7445.AM2017-344

Abstract SY07-02: Adipose stromal cells: A player in cancer progression and a therapeutic target

Abstract Prostate cancer (PCa) is promoted by white adipose tissue (WAT) overgrown in obesity. As an underlying mechanism, we have discovered the recruitment of adipose stromal cells (ASC) by tumors. We reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing its receptor CXCR1. As a candidate upstream mechanism, we identified interleukin 22 secreted by WAT-infiltrating leukocytes and signaling through IL-22R in cancer cells. Our experiments in Hi-Myc mice indicate that obesity promotes epithelial-mesenchymal transition (EMT). We show that ASC directly induce EMT in adenocarcinoma cells. To test whether cancer progression can be blocked by ASC targeting, we have used a hunter-killer peptide D-WAT composed of an ASC-homing and a pro-apoptotic domain. D-WAT administration depleted prostate stromal cells expressing a chemokine SDF1α and suppressed the EMT. Our results indicate that ASC promote the EMT, at least in part, via SDF1a paracrine signaling and validate ASC as a therapeutic target. Citation Format: Mikhail Kolonin. Adipose stromal cells: A player in cancer progression and a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY07-02. doi:10.1158/1538-7445.AM2017-SY07-02

The androgen receptor plays different roles in macrophage-induced proliferation in prostate stromal cells between transitional and peripheral zones of benign prostatic hypertrophy.

Macrophages play a critical role in the process of excessive stromal proliferation of benign prostatic hyperplasia (BPH). In our previous study, we used a BPH mouse model to elucidate a potential mechanism whereby macrophage infiltration promotes stromal cell proliferation in the prostate via the androgen receptor (AR)/inflammatory cytokine CCL3-dependent pathway. In our present study, we used the co-culture system of human macrophages and various prostatic zone stromal cells to further demonstrate that infiltrating macrophages promote prostatic stromal cell proliferation through stromal AR-dependent pathways, and we show that the stroma of TZ and PZ respond to macrophages differently because of differences in stromal AR signaling; this could possibly be one of the key pathways for stromal expansion during BPH development and progression. We hypothesize that AR and different downstream inflammatory mediators between TZ and PZ could serve as potential targets for the future design of therapeutic agents for BPH and our results provide significant insights into the search for targeted therapeutic approaches to battle BPH.

Inhibition of chronic prostate inflammation by hyaluronic acid through an immortalized human prostate stromal cell line model.

Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. A well-established in vitro cell model is required to determine the therapeutic mechanism of BPH inflammation. In this study, we attempted to establish an immortalized human prostate stromal cell line by transfecting with HPV-16 E6/E7 and designated as ihPSC. No significant difference was found in fibroblast-like morphology between primary hPSC and ihPSC. The ihPSC possessed a significantly higher cell proliferation rate than primary hPSC. The prostate-specific markers and proteins including cytoskeleton (α-SMA and vimentin) and smooth muscle (calponin), especially the androgen receptor (AR) were also examined in ihPSC, almost identical to the primary hPSC. To create an in vitro model featuring chronic prostatic inflammation, ihPSC was stimulated with IFN-γ+IL-17 and then treated with the high molecular weight hyaluronic acid hylan G-F 20 as an alternative strategy for inhibiting BPH inflammation. Hylan G-F 20 could dose-dependently diminish the inflammation-induced proliferation in ihPSC. The enhanced expressions of inflammatory molecules including IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), inducible nitrogen oxide synthase (iNOS), and Toll-like receptor 4 (TLR4) were all abolished by hylan G-F 20. For inflammatory signaling, hylan G-F 20 can also diminish the IFN-γ+IL-17-increased expression of iNOS and p65 in ihPSC. These findings suggest that ihPSC could provide a mechanism-based platform for investigating prostate inflammation. The hylan G-F 20 showed strong anti-inflammatory effects by decreasing inflammatory cytokines and signalings in the ihPSC, indicating its therapeutic potentials in BPH treatment in the future.

Ginsenoside Rg3 inhibits the senescence of prostate stromal cells through down-regulation of interleukin 8 expression.

Senescent stromal cells support the development of prostate cancer and are considered potential therapeutic targets. This research evaluated the regulatory effects of ginsenoside Rg3 on the senescence of prostatic stromal cells pre-incubated in medium supplemented with 0.5% fetal bovine serum. The results revealed that ginsenoside Rg3 decreased the number of stromal cells positively stained with a senescent cell marker (senescence-associated β-galactosidase). Ginsenoside Rg3 also increased the viability of stromal cells and promoted cell cycle transition from G0/G1 to S phase, as well as inhibited the carcinoma-associated fibroblast-like phenotype in prostate stromal cells, through the up-regulation of smooth muscle cell markers SM22 and smooth muscle myosin heavy chain. Conditioned medium collected from stromal cells treated with ginsenoside Rg3 exhibited an attenuated effect on the promotion of prostate cancer cell migration compared with conditioned medium from stromal cells without Rg3 treatment. Down-regulation of interleukin 8 (IL-8) in a dose- and time-dependent manner was observed in ginsenoside Rg3-treated stromal cells, and over-expression or addition of IL-8 reversed the anti-senescence role of Rg3 in prostate stromal cells. Furthermore, ginsenoside Rg3 down-regulated IL-8 expression by decreasing the reactive oxygen species level in prostatic stromal cells and reducing the transcriptional activity of IL-8 promoter by damping the transcription factors C/EBP β and p65 binding to IL-8 promoter. Our research revealed that ginsenoside Rg3 was able to inhibit prostate stromal cell senescence by down-regulating IL-8 expression. The results suggest a potential value for ginsenoside Rg3 in prostate cancer treatment through the targeting of pro-carcinogenic senescent stromal cells.

A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness.

MP17-18 PERI-PROSTATIC FAT (PPF) SECRETOME IN BPH PROGRESSION

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2017MP17-18 PERI-PROSTATIC FAT (PPF) SECRETOME IN BPH PROGRESSION Omar Franco, Rodrigo Javier, Mathew Brady, Susan Crawford, and Simon Hayward Omar FrancoOmar Franco More articles by this author , Rodrigo JavierRodrigo Javier More articles by this author , Mathew BradyMathew Brady More articles by this author , Susan CrawfordSusan Crawford More articles by this author , and Simon HaywardSimon Hayward More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.607AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Periprostatic fat (PPF) is a well-vascularized adipose tissue that encloses the prostate containing resident adipose tissue macrophages (ATM) that are mobilized and recruited to areas with high tissue remodeling. PPF can secrete a wide range of adipokines involved in physiologic and pathologic processes. It is well established that the unbalanced production of pro-inflammatory adipokines is a key component to the development of the metabolic syndrome, a risk factor for lower urinary tract symptoms (LUTS) and BPH progression. However, the link between PPF and BPH pathogenesis has not been previously addressed. In this study, we hypothesize that during BPH progression, PPF secretes a pro-inflammatory cytokine profile leading to chronic activation of NF-κB signaling pathway METHODS PPF was collected from patients undergoing prostatectomy. The thickness of PPF was determined (distance between the pubic symphysis and prostate) in 205 patients using MRI and classified based on their BMI (lean vs. obese). The composition of PPF was characterized histopathologically with emphasis on the immune/inflammatory infiltrates. To determine the factors secreted by PPF, a short in vitro culture was used to generated conditioned medium and adipocytokine array analysis performed. Proliferation of benign prostate epithelial and stromal cells exposed to PPF-CM was assessed. Upon exposure to PPF-CM, activation of the NF-κB pathway was determined by western blot analysis. In vivo experiments were performed xenografting PPF and human prostate tissues under the kidney capsule of SCID mice to determine the effects of PPF on prostate histology and recruitment of inflammatory cells RESULTS Histological analysis of human PPF samples showed an increased ratio of multilocular/unilocular phenotype composed mainly of macrophages and mononuclear infiltrates in obese individuals compared to the unilocular pattern and lack of inflammatory infiltrates in lean patients. Obese patients showed a significantly increased PPF thickness (more than double) compared to lean patients. Interestingly MRI showed that PPF only partially surrounds the prostate in lean patients, while fat tissue almost completely encased the prostate in obese individuals. Adipokine array assays from PPF-CM samples show the expression of a profile of pro-inflammatory factors. Addition of androgens modulated the secretion of IL11, TGFβ1, IL16 and SDF1α, among oth CONCLUSIONS Our preliminary studies suggest a potential role for the PPF pro-inflammatory secretome in BPH pathogenesis © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e218 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Omar Franco More articles by this author Rodrigo Javier More articles by this author Mathew Brady More articles by this author Susan Crawford More articles by this author Simon Hayward More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Antiangiogenic Agent Nintedanib (BIBF 1120) Effectiveness in vitro and in vivo Against Prostate Cancer

Nintedanib is a compound capable of inhibiting angiogenesis, preventing cell proliferation and decreasing tumor volume. This study was aimed at evaluating Nintedanib efficacy in prostate cancer (PCa) cell lines, besides morphological and molecular features in PCa development in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. PC3 and LNCaP cells were treated with either DMSO alone or Nintedanib (2.5, 5.0, 10 or 25 μM) in DMSO and assessed for viability and clonogenicity. Furthermore, male TRAMP mice were divided into control (Tween 20 (10%)) and treatment groups receiving Nintedanib (10mg/Kg/day) for 4 weeks. The animals were treated either from 8 to 12 weeks of age and euthanized both at 12 and 22 weeks of age or treated from 12 to 16 weeks of age and euthanized both at 16 and 22 weeks of age. At the end of the study, prostate ventral lobes were collected for structural, immunohistochemical and protein analyses for AR, ERα, FGF‐2, VEGF, microvessel density and proliferative index. Nintedanib treatment effectively decreased the total cell number and the survival of colonies. Morphological evaluation of TRAMP mouse prostate showed reduced number of lesions and the stromal hypertrophy after Nintedanib exposure. The treatment also caused a significant reduction in AR levels in epithelial cells and FGF‐2 in both prostatic stromal and epithelial cells. This was accompanied by a decrease in the microvessel density and VEGF immunolocalization. Furthermore, the proliferative index was also diminished by drug treatment. Nintedanib is effective against PCa in vitro and in vivo, due to the delayed neoplastic development in the glandular microenvironment and downregulation of multiple pathways involved in prostate tumorigenesis.Support or Funding InformationFunding: FAPESP 2013/26677‐7Ethics Committee 3285‐1

Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5

BackgroundVirtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported.MethodsCell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay.ResultsCyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block cyproterone acetate-induced CHOP and DR5 up-regulation. More importantly, siRNA silencing of CHOP significantly reduced cyproterone acetate-induced DR5 up-regulation and TRAIL sensitivity in prostate cancer cells.ConclusionsOur study shows a novel effect of cyproterone acetate on apoptosis pathways in prostate cancer cells and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration-resistant prostate cancer.

Adiponectin deficiency contributes to the development and progression of benign prostatic hyperplasia in obesity

The incidence of benign prostatic hyperplasia (BPH) is increasing among obese individuals, but few studies have fully explained the underlying mechanisms. We aimed to elucidate the relationship between obesity and BPH. Herein, we show that in prostatic epithelial and stromal cells, adiponectin exerts multifunctional effects including anti-proliferation, blocking of G1/S-phase progression and the promotion of apoptosis via inhibiting the MEK-ERK-p90RSK axis. Furthermore, we found that a high-fat diet (HFD) led to adiponectin deficiency and microscopic BPH in a mouse model of obesity. And an adiponectin supplement protected the obese mice from microscopic BPH. The present study provides evidence that adiponectin is a protective regulator in the development and progression of BPH and that adiponectin deficiency causally links BPH with obesity.

Long noncoding RNA LINC01296 is associated with poor prognosis in prostate cancer and promotes cancer-cell proliferation and metastasis.

Background/purposeLong noncoding RNAs (lncRNAs) have emerged as important regulators and biomarkers of tumor development and progression. This study investigated the clinical significance, biological functions, and underlying mechanisms of long intergenic non-protein-coding RNA 1296 (LINC01296) in prostate cancer.Materials and methodsLINC01296 expression in prostate cancer tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between LINC01296 expression and clinicopathologic characteristics of prostate cancer was analyzed using Kaplan–Meier analysis and the Cox proportional-hazard model. Small interfering RNA was used to suppress LINC01296, and knockdown efficiency was examined by qRT-PCR. Cell Counting Kit 8 assay, colony-formation assay, migration and invasion assays, and Western blot assay were used to explore the role of LINC01296 in tumor progression further.ResultsLINC01296-expression level was higher in prostate cancer tissues and prostate cancer cells than in adjacent nontumor tissues and immortalized normal prostate stromal WPMY1 cells. LINC01296 expression was correlated with preoperative prostate specific antigen (P=0.002), lymph-node metastasis (P=0.035), Gleason score (P<0.001), and tumor stage (P=0.036). Patients with higher LINC01296 expression displayed advanced clinical features and shorter biochemical recurrence-free survival time than those with lower LINC01296 expression. Multivariate analysis showed that LINC01296 expression was an independent predictor of biochemical recurrence-free survival in prostate cancer. Additionally, LINC01296 knockdown inhibited prostate cancer-cell proliferation, migration, and invasion, demonstrated in an in vitro study involving regulation of PI3K–Akt–mTOR signaling and epithelial–mesenchymal transition.ConclusionThe results demonstrated that LINC01296 is a novel molecule involved in prostate cancer development and progression, and thus is a potential biomarker of prognosis.

Torulene and torularhodin, protects human prostate stromal cells from hydrogen peroxide-induced oxidative stress damage through the regulation of Bcl-2/Bax mediated apoptosis

The current study was designed to elucidate the cytoprotective effects and possible mechanisms of torulene and torularhodin on hydrogen peroxide (H2O2)-induced oxidative stress damage in human prostate stromal cells (WPMY-1). After treated with H2O2, a notable decrease was appeared in cell viability, yet the decrease was attenuated when cells were pretreated with torulene and torularhodin (0.5–10 μM) as evaluated by WST-1 assay. Pretreatment with these two carotenoids significantly attenuated H2O2-induced apoptosis in WPMY-1 cells through the inhibition of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) overproduction, as well as the activation of the activities in catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Finally, pretreatment of cells with carotenoids resulted in the regulation of the mRNA and protein expression of Bcl-2 and Bax in H2O2-exposed prostate stromal cells. The present results indicate that both torulene and torularhodin can protect human prostate stromal cells from oxidative stress damage via Bcl-2/Bax mediated apoptosis.

LMO2 in prostate stromal cells promotes prostate cancer cells proliferation and invasion through paracrine of IL-11 and FGF-9

LMO2 in prostate stromal cells promotes prostate cancer cells proliferation and invasion through paracrine of IL-11 and FGF-9

MicroRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma

Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D–regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126-3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro-dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa.

Retraction of "Tunable Plasmonic Nanoprobes for Theranostics of Prostate Cancer".

[This retracts the article on p. 3 in vol. 1, PMID: 21547151.].

Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment.

Despite the substantial benefit of androgen deprivation therapy (ADT) for metastatic prostate cancer, patients often progress to castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed androgen receptor activity in tumor cells and restoration of tumor androgen levels through acquired intratumoral steroidogenesis (AIS). Although prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize testosterone (T) from an adrenal precursor, DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG. Here, we show exposure of PrSCs to a different Smoothened (Smo) agonist, Ag1.5, or to conditioned medium from sonic hedgehog overexpressing LNCaP cells induces steroidogenic enzyme expression in PrSCs and significantly increases production of T and its precursor steroids in a Smo-dependent manner from 22-OH-cholesterol substrate. Hh agonist-/ligand-treated PrSCs produced androgens at a rate similar to or greater than that of PCa cell lines. Likewise, primary bone marrow stromal cells became more steroidogenic and produced T under the influence of Smo agonist. Treatment of mice bearing LNCaP xenografts with a Smo antagonist, TAK-441, delayed the onset of CRPC after castration and substantially reduced androgen levels in residual tumors. These outcomes support the idea that stromal cells in ADT-treated primary or metastatic prostate tumors can contribute to AIS as a consequence of a paracrine Hh signaling microenvironment. As such, Smo antagonists may be useful for targeting prostate tumor stromal cell-derived AIS and delaying the onset of CRPC after ADT.