Acid, bile, and CDX: the ABCs of making Barrett's metaplasia.
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.
Department of Medicine, Veterans Affairs North Texas Health Care System and the University of Texas Southwestern Medical School, USA. rhonda.souza@utsouthwestern.edu
Rhonda F
RF
Souza
Kumar
K
Krishnan
Stuart Jon
SJ
Spechler
D000818:Animals; D001471:Barrett Esophagus / Q000150:complications*; D000071616:CDX2 Transcription Factor; D000089742:Doublecortin-Like Kinases; D004938:Esophageal Neoplasms / Q000209:etiology*; D004947:Esophagus / Q000196:embryology; D005764:Gastroesophageal Reflux / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008679:Metaplasia / Q000209:etiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases