Myofibroblast androgen receptor expression determines cell survival in co-cultures of myofibroblasts and prostate cancer cells in vitro

Abstract

Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells.In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR-negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5α-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth.These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo, providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome.

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

“…Experimental models support the idea that AR mediates, in part, the complex molecular interaction between CAFs and prostate cancer. Altered AR target genes in CAFs could affect AR-mediated regulation of growth, adhesion, motility and invasion of prostate cancer cells [ 78 ]. AR function in prostate CAFs was shown to be regulated by hydrogen peroxide-inducible gene 5 (Hic-5), an AR co-regulator, involved in the regulation of a limited number of genes activated via both genomic and non-genomic AR-dependent mechanisms [ 79 ].…”

The Androgen Regulation of Matrix Metalloproteases in Prostate Cancer and Its Related Tumor Microenvironment

“…By contrast, AR knockdown downregulates the adhesion proteins and upregulates ECM-degrading enzymes [86,87] and stemness markers in PC cocultures [11]. Consistent with the protective role of AR, it has been reported that the receptor activation delays PC cell growth [88], further corroborating the idea that AR blockade might paradoxically foster PC progression. Nevertheless, different studies support an oncogenic role for stromal AR.…”

Evaluation of myofibroblasts in superficial and deep layers of oral squamous cell carcinoma; an immunohistochemical study

“…Myofibroblasts have been recognized as the main component in the stroma of many solid malignant tumors such as breast cancer (18), prostate cancer (19), and hepatocellular carcinomas (20). However, few studies published in recent years have evaluated the presence of myofibroblasts in OSCC and the possible role of myofibroblasts in tumor invasion (10).…”