Review
Bile acids and colon cancer: Solving the puzzle with nuclear receptors

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Colorectal cancer is the third most common malignancy worldwide and is often linked to obesity, a sedentary lifestyle, carbohydrate- and fat-rich diets and elevated fecal excretion of secondary bile acids. Accumulation of toxic bile acids triggers oxidative damage, mitochondrial dysfunction and tumor progression. Nuclear receptors are transcription factors crucially involved in the regulation of bile acid metabolism and detoxification, and their activation may confer protection from bile acid tumor-promoting activity. In this review, we explore the tangled relationships among bile acids, nuclear receptors and the intestinal epithelium, with particular emphasis on the role of the farnesoid X receptor in colorectal cancer prevention and on novel nuclear receptor-based approaches to expand the portfolio of chemotherapeutic agents.

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

References (79)

  • K. Cheng et al.

    Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors

    Biochem. Pharmacol.

    (2005)
  • S. Jean-Louis

    Deoxycholic acid induces intracellular signaling through membrane perturbations

    J. Biol. Chem.

    (2006)
  • J.D. Amaral

    Bile acids: regulation of apoptosis by ursodeoxycholic acid

    J. Lipid Res.

    (2009)
  • B.W. Katona

    Characterization of enantiomeric bile acid-induced apoptosis in colon cancer cell lines

    J. Biol. Chem.

    (2009)
  • H. Wang

    Endogenous bile acids are ligands for the nuclear receptor FXR/BAR

    Mol. Cell

    (1999)
  • C.J. Sinal

    Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis

    Cell

    (2000)
  • T. Kok

    Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein

    J. Biol. Chem.

    (2003)
  • R.M. Gadaleta

    Bile acids and their nuclear receptor FXR: relevance for hepatobiliary and gastrointestinal disease

    Biochim. Biophys. Acta

    (2010)
  • T. Inagaki

    Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

    Cell Metab.

    (2005)
  • P.A. Dawson

    The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter

    J. Biol. Chem.

    (2005)
  • C. Stedman

    Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice

    J. Biol. Chem.

    (2004)
  • S.A. Kliewer

    An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

    Cell

    (1998)
  • H. Schneider

    A factor in the increased risk of colorectal cancer due to ingestion of animal fat is inhibition of colon epithelial cell glutathione S-transferase, an enzyme that detoxifies mutagens

    Med. Hypotheses

    (1992)
  • D.R. Schmidt

    AKR1B7 is induced by the farnesoid X receptor and metabolizes bile acids

    J. Biol. Chem.

    (2011)
  • T. Maruyama

    Identification of membrane-type receptor for bile acids (M-BAR)

    Biochem. Biophys. Res. Commun.

    (2002)
  • H. Yasuda

    Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells

    Biochem. Biophys. Res. Commun.

    (2007)
  • J.R. Pearson

    Diet, fecal water, and colon cancer – development of a biomarker

    Nutr. Rev.

    (2009)
  • A. Berg

    Nutrition, development, and population growth

    Popul. Bull.

    (1973)
  • A. Chao

    Meat consumption and risk of colorectal cancer

    JAMA

    (2005)
  • H. Kirkegaard

    Association of adherence to lifestyle recommendations and risk of colorectal cancer: a prospective Danish cohort study

    BMJ

    (2010)
  • A. Bajor

    Bile acids: short and long term effects in the intestine

    Scand. J. Gastroenterol.

    (2010)
  • S.E. McGarr

    Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature

    J. Clin. Gastroenterol.

    (2005)
  • Bernstein, C. et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch. Toxicol. (in...
  • D.R. Schmidt et al.

    Nuclear receptors of the enteric tract: guarding the frontier

    Nutr. Rev.

    (2008)
  • S. Modica

    The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors

    Gastroenterology

    (2010)
  • N. Barker

    Identification of stem cells in small intestine and colon by marker gene Lgr5

    Nature

    (2007)
  • J. Schneikert et al.

    The canonical Wnt signalling pathway and its APC partner in colon cancer development

    Gut

    (2007)
  • I. D’Errico et al.

    Nuclear receptors, intestinal architecture and colon cancer: an intriguing link

    Cell. Mol. Life Sci.

    (2008)
  • A.R. Clarke

    Wnt signalling in the mouse intestine

    Oncogene

    (2006)
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    Current address: Institute of Food, Nutrition and Health, ETH Zurich, SLA B38, 8603 Schwerzenbach, Switzerland.

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