Stromal Androgen Receptor in Prostate Cancer Development and Progression

Abstract

Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression.

Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

“…During carcinogenesis, the composition of the stroma changes, characterized by a loss of well‐differentiated smooth muscle cells and appearance of so‐called myofibroblasts (Tuxhorn et al ., ). Activated myofibroblasts, or CAFs are the principal components of the PCa microenvironment and are involved in PCa cell growth and invasion (Leach and Buchanan, ; Tuxhorn et al ., ). We established short‐term cultures of prostate CAFs with CAF‐like features.…”

“…In agreement with others (Olapade‐Olaopa et al ., ; Wikstrom et al ., ), we report that AR is expressed in the PCa stroma and that levels of AR staining in the stroma are inversely related with the malignancy grade of the tumor and presence of pelvic lymph node metastases. Stromal cells expressing AR, such as CAFs, might undergo clonal selection upon pressure of AR action, or limited ligand availability during androgen deprivation therapy might lead to destabilization of less AR sensitive cells, such as stromal cells (Leach and Buchanan, ). Alternatively, epigenetic regulation could also be involved, as alterations in methylation state are known to control AR expression (Keil et al ., ).…”

“…Despite the clear relationship between poor outcome and loss of stromal AR, the underlying mechanism involving AR signaling in CAFs and consequences in cancer progression and outcome remains largely unknown. Several mechanisms have been proposed, including AR‐regulated secretion of factors by CAFs, affecting PCa cell proliferation, and modification of the extracellular matrix (Leach and Buchanan, ). Here, we present an unbiased, genomic, and functional assessment of AR actions in human prostate‐derived CAF‐like cells in relation to PCa behavior.…”

Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre‐clinical study

“…It has become increasingly clear that the stroma within a tumor plays a critical role in its growth and in disease progression. In the prostate, AR is expressed both in epithelial cells and in fibroblasts, where changes in AR signaling considerably alter the biology and behavior of the epithelial tumor cells (reviewed in Ref …”

“…In the prostate, AR is expressed both in epithelial cells and in fibroblasts, where changes in AR signaling considerably alter the biology and behavior of the epithelial tumor cells (reviewed in Ref. 45 ). Genetic loss of AR in stromal myofibroblasts in a mouse model of prostatic intraepithelial neoplasia (PIN) delayed the appearance of PIN, inhibited the proliferation of epithelial cells and decreased inflammation-related changes in the microenvironment that would support tumor formation.…”