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    • Introduction Risk factors for colorectal cancer CRC

    2021-10-18

    Introduction Risk factors for colorectal cancer (CRC) include high-fat diets, sedentary lifestyles, obesity, diabetes, and elevated serum levels of toxic bile acids (BAs) (de Aguiar Vallim et al., 2013, Degirolamo et al., 2011, Downes and Liddle, 2008, Font-Burgada et al., 2016, Kuipers et al., 2015, Thomas et al., 2008). Although the majority of CRC cases are sporadic, ∼85% of patients have mutations in the adenomatous polyposis coli (APC) gene, a crucial negative regulator of Wnt signaling (Fodde et al., 2001, Powell et al., 1992, Rajagopalan et al., 2003). The subsequent accumulation of mutations, including those activating the oncogene Kras and inactivating tumor suppressors, including Smad4 and p53, drive a progression from adenoma to adenocarcinoma and, ultimately, metastatic adenocarcinoma (Rajagopalan et al., 2003, Dow et al., 2015, Drost et al., 2015, Kuipers et al., 2015, Ongen et al., 2014). Notably, restoring APC function can reestablish intestinal homeostasis in vivo, even in the presence of Kras and p53 mutations, confirming the critical regulatory role for APC (Dow et al., 2015). Lgr5+ intestinal stem cells (ISCs) are both the cell-of-origin for early neoplastic lesions caused by loss of the APC gene and necessary for metastasis (Barker et al., 2009). Located at the Hydroxyurea synthesis of the crypt, precisely regulated cycles of renewal and differentiation of Lgr5+ ISCs maintain the intestinal structure (Barker et al., 2009, Sato et al., 2009). This “bottom-top” cell hierarchy positively correlates with a Wnt signaling gradient and inversely correlates with BA exposure. However, it remains unclear how erosion of the crypt-villi architecture and the subsequent increase in exposure of Lgr5+ ISCs to BAs contribute to the initiation and progression of CRC (de Aguiar Vallim et al., 2013, Degirolamo et al., 2011, Thomas et al., 2008). Dietary fatty acids have been implicated in enhancing the self-renewal capacity of ISCs and progenitor cells, as well as the tumor-initiating potential of cancer stem cells (CSCs) (Beyaz et al., 2016). However, high-fat diets (HFDs) lead to commensurate increases in BAs, which are potent inducers of CRC malignancy (Degirolamo et al., 2011, Downes and Liddle, 2008). In the context of CRC, the secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA) are of particular interest, as their hydrophobic nature promotes intestinal permeability and genotoxic effects (Bayerdörffer et al., 1995, Imray et al., 1992, Mahmoud et al., 1999). The farnesoid X receptor (FXR) serves as a primary sensor of nutritional cues, translating stimuli into transcriptional programs (Degirolamo et al., 2011, Downes and Liddle, 2008, Forman et al., 1995, Makishima et al., 1999, Parks et al., 1999). In particular, FXR is the master regulator of BA homeostasis, governing synthesis, efflux, influx, and detoxification throughout the gut-liver axis (Thomas et al., 2008). Strong evidence suggests a role for FXR in intestinal tumorigenesis, with expression levels inversely correlating with CRC progression and malignancy (Anakk et al., 2011, De Gottardi et al., 2004, Degirolamo et al., 2011, Fu et al., 2016b, Maran et al., 2009, Modica et al., 2008, Selmin et al., 2016). Consistent with this, loss of FXR promotes the development of intestinal tumors in the APCmin/+ mouse model of CRC (Maran et al., 2009). Although links between BAs, FXR, and CRC have been suggested, the underlying mechanisms remain unclear. Here, we establish that FXR controls Lgr5+ intestinal stem cell proliferation. In CRC, we show that dietary and genetic risk factors converge to drive FXR-dependent Lgr5+ CSC proliferation and disease progression. Conversely, activation of FXR in the intestine reduces disease severity to markedly increase survival.
    Results
    Discussion The two-step model of CRC proposes that loss of tumor suppressor function provides a survival advantage and facilitates clonal expansion. Here, we identify FXR as a critical regulator of intestinal stem cell proliferation. While not considered a tumor suppressor, we show that disruption of FXR activity in intestinal stem cells is integral to disease progression (Figure 7H).