Abstract
SummaryResearch shows a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown. We report the roles of androgen in proliferation and differentiation of intestinal stem cells via targeting of the androgen receptor (AR) on intestinal stromal cells by negatively regulating BMP signaling. Orchidectomy (ORX) or the AR antagonist promotes expansion of intestinal epithelium but suppresses intestinal stem cell (ISC) proliferation. Conversely, the AR agonist inhibits ISC differentiation but augments proliferation in ovariectomized mice. Mechanistically, activation of the AR increases expression of BMP antagonists but lowers expression of BMP4 and Wnt antagonists in primary stromal cells, which promotes intestinal organoid growth. Interestingly, the BMP pathway inhibitor LDN-193189 reverses the ORX-induced effects. Our results highlight that stromal cells constitute the intestinal stem cell niche and provide a possible explanation for higher incidence rates of colorectal cancer in men.
Highlights
The intestinal epithelium structure is organized into villi and crypts and rapidly self-renews every 5 days (Barker, 2014; Clevers, 2013)
In vitro experiments have proven that activation of androgen receptor (AR) in response to dihydrotestosterone (DHT) leads to higher expression of bone morphogenetic proteins (BMPs) antagonists while reducing expression of both BMP4 and Wnt antagonists in cultured primary stromal cells, which promotes the expansion of organoids
Androgens Decrease the Population of Differentiated Cells in the Intestinal Epithelium ORX, OVX, and inhibition of AR in male mouse models were done to investigate the effect of androgens on intestinal stem cell (ISC) terminal
Summary
The intestinal epithelium structure is organized into villi and crypts and rapidly self-renews every 5 days (Barker, 2014; Clevers, 2013). Intestinal stem cells (ISCs) localized at the base of the crypts produce progenitors. These progenitors proliferate and differentiate into six separate mature epithelial cell types, comprising enterocytes, M cells, Paneth cells, goblet cells, enteroendocrine cells, and tuft cells (van der Flier and Clevers, 2009). Our data highlight a previously unappreciated role for androgens in the ISC niche, supporting ISC proliferation and restraining epithelium differentiation by negatively regulating BMP signaling in the stromal cells. These findings may help explain the observed higher incidence rates of colorectal cancer in men
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