Abstract
Androgens regulate the proliferation and differentiation of prostatic epithelial cells, including prostate cancer (PCa) cells in a context-dependent manner. Androgens and androgen receptor (AR) do not invariably promote cell proliferation; in the normal adult, endogenous stromal and epithelial AR activation maintains differentiation and inhibits organ growth. In the current study, we report that activation of AR differentially regulates the proliferation of human prostate epithelial progenitor cells, NHPrE1, in vitro and in vivo. Inducing AR signaling in NHPrE1 cells suppressed cell proliferation in vitro, concomitant with a reduction in MYC expression. However, ectopic expression of AR in vivo stimulated cell proliferation and induced development of invasive PCa in tissue recombinants consisting of NHPrE1/AR cells and rat urogenital mesenchymal (UGM) cells, engrafted under renal capsule of adult male athymic mice. Expression of MYC increased in the NHPrE1/AR recombinant tissues, in contrast to the reduction seen in vitro. The inhibitory effect of AR signaling on cell proliferation in vitro were reduced by co-culturing NHPrE1/AR epithelial cells with prostatic stromal cells. In conclusion, these studies revealed that AR signaling differentially regulates proliferation of human prostatic epithelia cells in vitro and in vivo through mechanisms involving stromal/epithelial interactions.
Highlights
Androgen deprivation therapy is the gold standard treatment for advanced stage prostate cancer (PCa) [1]
In order to study the role of androgen receptor (AR) in prostatic cells, we stably integrated full-length AR cDNA into NHPrE1 cells (NHPrE1/AR); NHPrE1 cells stably transduced with empty vector (EV) served as control cells
Our results showed that the presence of prostate stromal cells (PrSC) diminishes the inhibitory effects of androgen, suggesting that factors secreted from PrSC stimulate proliferation of NHPrE1/AR cells
Summary
Androgen deprivation therapy is the gold standard treatment for advanced stage PCa [1]. PCa responds to the treatment, resulting in tumor regression These tumors almost invariably progress to castration-resistant PCa (CRPCa) in which androgen ablation can no longer suppress disease progression [2]. It does not lead to a complete regression of the gland, and mechanisms such as Wnt/ß-catenin signaling seem to play a protective role, maintaining the viability of some portion of the tissue [8]. This maintenance of tissue is important in seasonally breeding animals [9], but is problematic in the context of cancer therapy in humans, where it allows the preservation of cancer cells from androgen deprivation therapy
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