Stromal androgen signaling governs essential niches in supporting prostate development and tumorigenesis

Abstract

Androgens and androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, growth, and regeneration. Early tissue recombination experiments showed that AR-deficient urogenital sinus mesenchyme combined with intact urogenital sinus epithelium failed to develop into a prostate, demonstrating a stem cell niche for mesenchymal AR in prostatic development. Androgen signaling remains critical for prostate maturation and growth during postnatal stages. Importantly, most primary prostate cancer (PCa) cells express the AR, and aberrant activation of AR directly promotes PCa development, growth, and progression. Therefore, androgen deprivation therapy (ADT) targeting the AR in PCa cells is the main treatment for advanced PCa. However, it eventually fails, leading to the development of castration-resistant PCa, an incurable disease. Given these clinical challenges, the oncogenic AR action needs to be reevaluated for developing new and effective therapies. Recently, an essential niche role of stromal AR was identified in regulating prostate development and tumorigenesis. Here, we summarize the latest discoveries of stromal AR niches and their interactions with prostatic epithelia. In combination with emerging clinical and experimental evidence, we specifically discuss several important and long-term unanswered questions regarding tumor niche roles of stromal AR and highlight future therapeutic strategies by co-targeting epithelial and stromal AR for treating advanced PCa.

Fig. 1. Androgen signaling in stromal Gli1-lineage cells plays a niche role in normal and oncogenic prostate tissues.

A In normal prostatic state, AR activation of Shh-responsive, Gli1-lineage stromal cells through the binding of androgens stimulates IGF1R expression in prostatic basal epithelial cells and attenuates SP1-regulated IGFBP3 expression in stromal cells, which in return increases IGF1 bioavailability. Subsequent activation of IGF1 and Wnt/β-catenin axes in basal and luminal epithelial cells promotes prostate development, differentiation, and regeneration. B In prostatic oncogenic state, non-physiologic, aberrant activation of AR and/or IGF1 axes can lead to dysregulated activation of IGF1 and Wnt/β-catenin axes in basal and luminal epithelial cells, promoting prostatic epithelial oncogenesis.