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

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.