Moreover intestinal chronic inflammation is a promoting fact
Moreover, intestinal chronic inflammation is a promoting factor in the development of CRC in patients affected by inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. We have previously shown that pharmacological FXR activation via its ligand obeticolic protease inhibitor counteracts inflammation and preserve the intestinal barrier function in two chemically-induced murine colitis models by reducing inflammatory infiltrate, goblet cell loss and intestinal permeability, and decreases cytokine secretion in lamina propria derived monocytes in IBD patients (Gadaleta et al., 2011a). On the other hand, intestinal inflammation strongly reduces FXR activation (Gadaleta et al., 2011b). Therefore, FXR not only inhibits inflammation, but is also targeted by the inflammatory response itself. This could result in a vicious cycle where reduced FXR activity results in less repression of inflammation, contributing to development of chronic intestinal inflammation (Gadaleta et al., 2011b), and potentially to the onset of inflammation-induced CRC. In fact, increased TNFα production and mucosal infiltration of activating neutrophils and macrophages can play a critical role in promoting the Wnt signalling pathway and increasing tumors susceptibility of Apc+/−FXR−/− mice (Modica et al., 2008). Last but not least, it has been also demonstrated that CDX2 expression could be induced by BAs in oesophageal keratinocytes in Barrets' epithelium (Kazumori et al., 2006), therefore it is tempting to speculate that BAs stimulate their own detoxification by inducing CDX2 which in turn could induce FXR expression (Modica et al., 2014).
Conclusions Given the crucial role of FXR in maintaining BA concentrations within a physiological range, thereby preventing BA-induced cytotoxicity, it is not surprising that the loss of FXR is associated with a pro-tumorigenic phenotype. However, it is also important to mention that in response to high and toxic BA levels FXR is not the lonely player, but is part of a complex nuclear receptor clade including also the Vitamin D receptor (VDR), master regulator of vitamin D metabolism, and the xenobiotic pregnane X receptor (PXR) and constitutive androstane receptor (CAR), both regulating the induction of the lipid-metabolizing phase I and phase II enzymes (Degirolamo et al., 2011, Kliewer et al., 1998, Schmidt and Mangelsdorf, 2008, Xie et al., 2000). All together they cooperate to activate a transcriptional network coordinating BA influx, efflux and detoxification that has been found to be progressively downregulated from normal to dysplastic enterocytes in rodents and human models of CRC (Modica et al., 2010). Physiologically, this enteric NR team provides intestinal preservation from BA cytotoxicity promoting detoxifying and apoptotic machineries. In CRC pathogenesis, when the first genetic mutation occurs and neoplastic transformations arise, the expression of these NRs is reduced, making cells more sensitive to the detrimental effect of BA-toxicity. In this scenario, these NR driven protective mechanisms would not be effective to counteract the deleterious effects of a long-term inappropriate Western diet engagement and its associated high level of toxic BAs in the organism, delineating a phenotype in which this diet would boost the speed of CRC onset and development. To date, no clinically described single nucleotide polymorphism (SNPs) explaining FXR expression reduction associated with CRC exists. Similarly, different SNPs have been detected for both PXR and CAR, but the association of these genetic variations with specific human disease phenotypes is yet to be established (Moore et al., 2006). On the contrary, RAS activating mutations, common in colon cancer, have been associated with lower VDR mRNA and protein levels in colon epithelial cells (DeSmet and Fleet, 2017). However, the mechanism underlying the RAS-mediated suppression of VDR expression have not been described yet.