Trends in Molecular Medicine
ReviewBile acids and colon cancer: Solving the puzzle with nuclear receptors
Section snippets
Colon carcinogenesis and bile acids: overview
Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of cancer deaths worldwide, with over 1.2 million new cases of CRC and 609 000 estimated deaths in 2008, as reported by the International Agency for Research on Cancer [1]. Approximately 20% of all CRC cases occur in inherited patterns, notably familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), whereas the remaining cases of CRC are sporadic [2] (see Glossary).
Colon cancer pathogenesis: from gene to environment
The colon has a flat surface epithelium, composed of colonocytes, enteroendocrine cells and Goblet cells, that invaginate to form crypts (approximately 107 in number) (Figure 2a). Crypt cells divide rapidly and travel to the top of the epithelium, where they differentiate and undergo apoptosis within 48–72 h. At the bottom of the crypts reside between one and ten stem cells, identified by expression of the marker gene Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5) [11], which
Bile acids (BAs) as signaling molecules: relevance to colon cancer pathogenesis
BAs are end products of cholesterol metabolism, synthesized and conjugated in the liver and subsequently excreted via bile into the small intestine where they aid solubilization and absorption of lipids, nutrients and vitamins [6]. Beyond their well-established roles in dietary lipid absorption and cholesterol homeostasis 21, 22, BAs behave as signaling molecules controlling hepatic glucose homeostasis, thermogenesis, energy homeostasis and inflammatory responses, partly through activation of
Bile acid-sensing nuclear receptors
A ‘clade’ of NRs composed of FXR, PXR, VDR and CAR tightly controls the concentrations of BAs through modulation of BA influx, efflux and detoxification. NRs are ligand-activated transcription factors that regulate the cell cycle, mitosis, proliferation and apoptosis 9, 45, and the recent characterization of an intestinal NR signature indicates that the localization pattern of a receptor in normal intestine can predict the modulation of its expression in tumors [10].
FXR transcriptional hypothesis for diet-induced susceptibility to CRC
A large body of evidence suggests a role for FXR in both hepatic and intestinal tumorigenesis. Given the crucial role of FXR in maintaining BA concentrations within a physiological range, thereby preventing BA-induced cytotoxicity, the loss of FXR would be expected to be associated with a protumorigenic phenotype. Accordingly, FXR knockout mice develop hepatocellular carcinoma (HCC) at 12–15 months of age 62, 63. The oncosuppressive role of FXR in intestinal tumorigenesis was first suggested by
Detoxification hypothesis
The earliest observation that inhibition of the detoxifying enzyme system could be associated with an increased risk of CRC upon ingestion of high-fat meals was made by Schneider [67]. As discussed earlier, a finely orchestrated network of metabolizing enzymes is responsible for maintaining sublethal concentrations of toxic nutrients and xenobiotics. Emerging evidence suggests that FXR can elicit tumor-suppressive effects by transcriptional induction of detoxifying enzymes that mediate the
Concluding remarks and future perspectives
CRC incidence and mortality rates are projected to increase in the next two decades [1] and an in-depth investigation of the molecular and cellular mechanisms underlying CRC pathogenesis, along with the development of personalized therapeutic regimens, appear imperative to contain the CRC burden. Multiple CRC features need to be considered when developing both effective screening and pharmacological approaches. CRC is a multifaceted disease that may stem from somatic mutations of the Wnt
Acknowledgments
We are grateful to C. Gardmo for critically reading the manuscript and R. Le Donne for artwork. We apologize to our distinguished colleagues whose work was not cited owing to the format limitations. A.M. is funded by the Italian Association for Cancer Research (AIRC, IG 10416), Italian Ministry of University (FIRB IDEAS RBID08C9N7), Italian Ministry of Health (Young Researchers Grant GR-2008-1143546), European Community's Seventh Framework Program FP7/2007–2013 under Grant Agreement No. 202272
Glossary
- Aneuploidy
- change in chromosome number.
- BAs (bile acids)
- amphipathic molecules synthesized from cholesterol in a reaction mediated by the hepatic enzyme cholesterol-7α-hydroxylase (CYP7A1). Primary BAs, notably chenodeoxycholic acid (CDCA) and cholic acid (CA), originate in the liver whereas secondary BAs, namely deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA), are formed in the large intestine through reactions mediated by enteric bacteria enzymes.
- CIN (chromosomal
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Current address: Institute of Food, Nutrition and Health, ETH Zurich, SLA B38, 8603 Schwerzenbach, Switzerland.