Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome

Abstract

Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…This showed relatively low overlap with one stromal dataset (GSE20758, [57]) but stronger overlap with another (GSE8218/GSE17951 [58]), and may show low similarity due to the cellular heterogeneity inherent within tumour stroma. In addition, it has been shown that stromal AR expression is decreased with increasing grade of prostate tumour [35,36] and therefore a larger dataset comprised of prostate tumours with microdissected stroma and sufficient numbers of lower grade tumours would be required to formally address this. In all comparisons, we observed a higher degree of overlap of EPF-specific targets with PCa stromal-specific/enriched transcripts than CAF-specific targets.…”

“…It has been shown that human prostate myofibroblast cell lines have a different AR binding profile to prostate cancer epithelium and are not dependent on the classic AR pioneer factors such as FOXA1 [34]. The role of AR in stroma is likely to be important, since stromal expression of AR is prognostic [35,36] and the genes regulated by AR in stroma may themselves be prognostic and control cell proliferation and differentiation. However, no study has addressed the genomic behavior of AR in primary prostate developmental or cancer-associated fibroblasts.…”

Sexual dimorphism in cancer

“…Cancer Associated Fibroblasts (CAFs) can be viewed like persistently activated fibroblasts sharing properties with fibroblasts at wound sites 44 . While well known differences exist in skin wound healing between the two sexes 26,27 , where fibroblasts exert an important role in the first phases of the process, studies on the impact of sex hormones on CAF function have mostly focused on prostate [45][46][47] , breast 48,49 and cervical cancer 50 types.…”

“…While animal model studies indicate that this receptor in stromal fibroblasts promotes initial stages of the disease 46 , clinical evidence points to the opposite possibility that sustained AR expression in this context is linked to less aggressive cancer and better prognosis 47 .…”

Androgen Receptor and Androgen-Responsive Gene FKBP5 Are Independent Prognostic Indicators for Esophageal Adenocarcinoma

“…The activated AR translocates to the nucleus and binds to androgen response elements in the genome. This binding may then result in the up-or down-regulation of transcription of androgen-responsive genes, such as FK506 binding protein 5 (FKBP5) [15][16][17], heme oxygenase 1 (HMOX1) [18], F-box protein 32 (FBXO32) [19], wingless-type MMTV integration site family, member 5A (WNT5A) [20], vascular endothelial growth factor A (VEGFA) [21] and kallikrein-related peptidase 3 (KLK3) [22]. The actual genes whose expression is altered is influenced by the interaction of AR and various co-regulators and is tissue and context dependent.…”