Farnesoid X receptor is a tumor suppressor linking intestinal self-renewal and bile acid homeostasis.
Major finding: Farnesoid X receptor is a tumor suppressor linking intestinal self-renewal and bile acid homeostasis.
Mechanism: Bile acids antagonize FXR function to drive transformation of intestinal stem cells.
Impact: Pharmacologic activation of FXR is a potential therapeutic strategy to delay CRC progression.
Among the many risk factors for colorectal cancer (CRC) is elevated serum levels of toxic bile acids (BA) caused by a high-fat diet. Erosion of the crypt-villi architecture is the driving force behind increased BA exposure of Lgr5+ intestinal stem cells (ISC), the cell of origin of colonic neoplasias caused by mutation of the APC tumor suppressor, but how precisely this exposure contributes to initiation and progression of CRC remains unclear. Fu and colleagues showed that increased BA exposure in the APCmin/+ mouse model inactivates farnesoid X receptor (FXR)–mediated control of Lgr5+ proliferation and contributes to malignant transformation and CRC progression. Mice subjected to a high-fat diet exhibited multiple intestinal abnormalities and increased serum levels of the BAs tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA). T-βMCA inhibited FXR activity, decreased intestinal integrity, increased DNA damage and chromosomal aberrations, and accelerated tumor growth in the intestine and colon. Deletion of FXR in ISCs increased growth and enhanced expression of proliferation marker genes; conversely, treatment with the FXR agonist FexD inhibited basal WNT signaling. Treatment of organoids or APCmin/+ mice with FexD abrogated T-βMCA–induced proliferation, reduced expression of ISC genes, and derepressed genes in the p53 tumor suppressor pathway. FexD also reduced serum levels of T-βMCA and DCA, restored intestinal integrity and function, increased cellular differentiation, and significantly reduced tumor frequency and delayed tumor progression in both adenoma and adenocarcinoma models. Collectively, these findings identify BAs as antagonists of FXR signaling, whose disruption is critical for intestinal stem cell proliferation and disease progression. Moreover, they highlight the potential for FXR agonists as effective therapeutic agents in limiting CRC initiation and progression.
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