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Am J Physiol Gastrointest Liver Physiol 295: G211-G218, 2008. First published June 12, 2008; doi:10.1152/ajpgi.90250.2008
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REVIEW

Acid, Bile, and CDX: the ABCs of making Barrett's metaplasia

Rhonda F. Souza,1,2 Kumar Krishnan,1 and Stuart Jon Spechler1

1Department of Medicine, Veterans Affairs North Texas Health Care System and the University of Texas Southwestern Medical School and 2Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Submitted 24 March 2008 ; accepted in final form 8 June 2008

ABSTRACT

Barrett's esophagus, a squamous-to-columnar cell metaplasia that develops as a result of chronic gastroesophageal reflux disease (GERD), is a risk factor for esophageal adenocarcinoma. The molecular events underlying the pathogenesis of Barrett's metaplasia are poorly understood, but recent studies suggest that interactions among developmental signaling pathways, morphogenetic factors, and Caudal homeobox (Cdx) genes play key roles. Strong expression of Cdx genes normally is found in the intestine but not in the esophagus and stomach. When mice are genetically engineered so that their gastric cells express Cdx, the stomach develops a metaplastic, intestinal-type epithelium similar to that of Barrett's esophagus. Exposure to acid and bile has been shown to activate the Cdx promoter in certain esophageal cell lines, and Cdx expression has been found in inflamed esophageal squamous epithelium and in the specialized intestinal metaplasia of Barrett's esophagus. Barrett's metaplasia must be sustained by stem cells, which might be identified by putative, intestinal stem cell markers like leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and doublecortin and CaM kinase-like-1 (DCAMKL-1). Emerging concepts in tumor biology suggest that Barrett's cancers may develop from growth-promoting mutations in metaplastic stem cells or their progenitor cell progeny. This report reviews the roles of developmental signaling pathways and the Cdx genes in the development of normal gut epithelia and the potential mechanisms whereby GERD may induce the esophageal expression of Cdx genes and other morphogenetic factors that mediate the development of Barrett's metaplasia. The role of stem cells in the development of metaplasia and in carcinogenesis and the potential for therapies directed at those stem cells also is addressed.

molecular; Barrett's esophagus; gastroesophageal reflux; stem cell


Address for reprint requests and other correspondence: R. Souza, Div. of Gastroenterology (111B1), Dallas VA Medical Ctr., 4500 S. Lancaster Rd., Dallas, TX 75216 (e-mail: rhonda.souza{at}utsouthwestern.edu)






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