Molecular Mechanisms of Barrett’s Esophagus

Abstract

Barrett’s esophagus (BE) is defined as metaplastic conversion of esophageal squamous epithelium to intestinalized columnar epithelium. As a premalignant lesion of esophageal adenocarcinoma (EAC), it develops as a result of chronic gastroesophageal reflux disease (GERD). Many studies have been conducted to undertand the molecular mechanism of this disease. This review summarizes recent results of involving squamous transcription factors, intestinal transcription factors, signaling pathways, stromal factors, microRNAs, and other factors in the development of BE. A conceptual framework is proposed to guide future studies. We expect elucidation of the molecular mechanism of BE will help us develop proper management of GERD, BE, and EAC.

Transgenic Overexpression of cdx1b Induces Metaplastic Changes of Gene Expression in Zebrafish Esophageal Squamous Epithelium

“…29 As CDX1B TRANSGENIC ZEBRAFISHa crucial transcription factor for endoderm formation, Sox17 regulates endodermal gene expression such as Gata5 and Gata6, 34 which are known to be differentially expressed in human BE. 9 By examining expression of these genes with microarray and in situ hybridization, we aimed at determining how cdx1b may cause metaplastic changes in the squamous epithelium of cdx1b transgenic zebrafish. Indeed, the overexpression of Agr2, Nkx2.2a, Fabp2, Slc15a1, Cdh17, and Sox17 in the squamous epithelial cells of cdx1b transgenic zebrafish was observed.…”

“…''NE'' indicated that this gene is known to be expressed in the normal human esophagus more than Barrett's esophagus. 9,16 ''Cdx2'' indicated regulation of this gene by mammalian Cdx2, ''Cdx1'' by mammalian Cdx1, and ''cdx1b'' by zebrafish cdx1b, respectively. b Genes expressed in normal mammalian esophagus.…”

“…7,8 Gene expression profiling of human BE suggested that multiple genetic pathways and transcription factors, especially Cdx2, might play a critical role in the development of BE. 9 Stable transfection of Cdx2 in esophageal squamous epithelial cells caused metaplastic changes in both morphology and gene expression. 10 In vivo, stomach-specific Cdx2 transgenic overexpression induced IM in the mouse stomach within weeks after birth.…”

Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia

“…A number of signaling pathways and transcription factors have been implicated in the pathogenesis of Barrett's metaplasia, based on their roles in the normal gastrointestinal tract (9). Conceivably, squamous epithelium might be induced to assume a columnar Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype.…”

A surprise cell of origin for Barrett’s esophagus

“…The first mechanism is direct conversation of differentiated cells, a process called transdifferentiation. 10 The second mechanism is the development from stem or progenitor cells. This work strongly supports a stem/ progenitor cell model and argues against the need for transdifferentiation.…”