High Colorectal Cancer Rates in Men Linked to Androgen Levels

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Colon cancer, or colorectal cancer, typically affects older adults, though it can happen at any age. It usually begins as small, benign clumps of cells called polyps that form on the inside of the colon, but over time some of these polyps can become cancerous. Research has shown a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown.

Now scientists have discovered a new potential link between androgens and stem cells that could contribute to colon cancer.

Their findings, “Androgen Maintains Intestinal Homeostasis by Inhibiting BMP Signaling via Intestinal Stromal Cells,” were published recently in Stem Cell Reports.

Many lifestyle-related factors have been linked to colorectal cancer. The links between diet, weight, and exercise and colorectal cancer risk are some of the strongest for any type of cancer. Colorectal cancer is strongly influenced by sex and gender, with mortality rates in males significantly higher than females.

“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 bone morphogenetic proteins (BMPs) signaling,” noted the researchers.

It was previously shown that the arrangement and stem cell microenvironment between intestinal and colonic epithelia are similar. By tuning androgen levels in mice, the scientists found that high androgen levels cause intestinal stem cells (ISCs) to divide more than usual and at the same time produced less mature epithelial cells.

“Orchidectomy (ORX), ovariectomy (OVX), and inhibition of AR in male mouse models were done to investigate the effect of androgens on ISC terminal differentiation. The small intestines were isolated for specific staining and quantification of secretory cells and enterocytes,” noted the scientists.

Their results revealed that the goblet cells, enteroendocrine cells, and Paneth cells were all increased in males after ORX compared with controls, and this phenomenon was reversed by supplementation with dihydrotestosterone (DHT). They found that androgens may decrease the numbers of secretory lineages and enterocytes.

The researchers then generated a selective inhibitor of the BMP pathway, in ORX males. Outcomes were consistent with the reverse effect of exogenous androgens. BMP antagonists reversed the increase of secretory lineages and decrease of cellular proliferation caused by ORX. They also inhibited the upregulation of BMP downstream signals (Id1 and Msx1), further proving that androgens may serve as selective inhibitors of the BMP pathway.

“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 the 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 effect,” explained the researchers.

“The present study investigated the effect of androgens in promoting proliferation and inhibiting differentiation.” The results highlight that stromal cells constitute the intestinal stem cell niche and provide a potential explanation for higher incidence rates of colorectal cancer in men.

Their findings may lead to new therapies or treatments of colon cancers through androgen regulation and may provide a new therapeutic path for those affected even after the adjustment of related risk factors.

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