Androgen Maintains Intestinal Homeostasis by Inhibiting BMP Signaling via Intestinal Stromal Cells

Area of Science:

• Gastroenterology
• Endocrinology
• Cancer Biology

Background:

• Colorectal cancer (CRC) incidence is higher in men, but the underlying molecular mechanisms are unclear.
• Androgen signaling is implicated in various cellular processes, but its role in intestinal stem cell biology and CRC gender disparity is not well understood.

Purpose of the Study:

• To investigate the role of androgens and the androgen receptor (AR) in regulating intestinal stem cell (ISC) proliferation and differentiation.
• To elucidate the molecular mechanisms by which androgens contribute to the gender disparity in colorectal cancer incidence.

Main Methods:

• Utilized orchidectomy (ORX) and androgen receptor (AR) antagonist/agonist treatments in mouse models.
• Analyzed the effects on intestinal epithelium expansion, ISC proliferation, and differentiation.
• Investigated changes in Bone Morphogenetic Protein (BMP) and Wnt signaling pathways in primary stromal cells.
• Employed the BMP pathway inhibitor LDN-193189 to validate findings.

Main Results:

• Orchidectomy (ORX) or AR antagonism promoted epithelial expansion but suppressed ISC proliferation.
• AR agonism inhibited ISC differentiation while augmenting proliferation in ovariectomized mice.
• AR activation in stromal cells increased BMP antagonist expression and decreased BMP4 and Wnt antagonist expression, promoting intestinal organoid growth.
• The BMP pathway inhibitor LDN-193189 reversed ORX-induced effects.

Conclusions:

• Stromal cells function as the intestinal stem cell niche, mediating androgen effects on ISC behavior.
• Androgen receptor signaling negatively regulates BMP signaling in stromal cells, influencing ISC proliferation and differentiation.
• These findings provide a molecular basis for the higher incidence of colorectal cancer observed in men.