Barrett's Esophagus

Molecular Basis

Barrett's esophagus usually develops in the context of chronic gastroesophageal reflux. Presumably, the repeated exposure to acid and bile in the refluxate induces tissue injury in the lower esophagus, and the intestinal metaplasia that forms during the healing process likely reflects an adaptive response in which the damaged mucosa is replaced with a more acid- and bile-resistant epithelium. The prevailing view is that acid and bile in the refluxate, either directly or indirectly, induces genetic and/or epigenetic changes that lead to the onset of Barrett's esophagus and its progression to cancer.

Genetic Abnormalities

Multiple genetic changes are detectable in Barrett's esophagus. Whole-genome studies have demonstrated that the majority of Barrett's esophagus samples show some level of chromosomal instability, as characterized by copy number gains, copy number losses, and the loss of heterozygosity (LOH).^[62–64] These changes increase in frequency and size as the condition progresses, with single nucleotide polymorphism (SNP) array analyses suggesting that genomic abnormalities increase from involving less than 2% of the genome in early-stage Barrett's metaplasia to over 30% in late-stage Barrett's esophagus.^[63] The most frequent change seen is loss of the short arm of chromosome 9, including 9p21.3 (CDKN2A/p16). Other common abnormalities in early-stage Barrett's esophagus include copy loss on 3p across the FHIT gene locus (3p59.8–60.6) and 16q, across the WWOX locus (16q77.3).^[63] A variety of somatic genetic alterations usually associated with cancer, including the loss of p53, adenomatous polyposis coli (APC), and Rb (retinoblastoma protein), and the overexpression of cyclin D1, Bcl2, and SRC kinase, are also readily detectable in Barrett's metaplasia tissue.^[65] However, there is little evidence that these events have a direct role in the development of Barrett's esophagus itself, and it is likely that many are actually early events in the progression of Barrett's metaplasia to dysplasia and EAC.

Similarly, gene array studies have reported many genes that are differentially expressed between Barrett's esophagus and normal esophageal mucosa^[66,67] but the problem is in distinguishing between those changes that simply reflect the phenotypic differences between squamous and columnar cells and those that are actually responsible for driving the transdifferentiation process.

Cdx

Intuitively, the mechanism(s) directly driving transdifferentiation is/are likely to involve important transcriptional regulators, such as the homeobox genes, a family of DNA-binding proteins that play a crucial role in tissue patterning and cell fate determination. Cdx1 and Cdx2 are intestinal-specific transcription factors that are thought to direct the development and differentiation of the columnar epithelium in the intestine,^[68,69] and there is increasing evidence to suggest they might have a role in the development of Barrett's esophagus. Although neither is expressed in the normal esophagus or stomach, both are highly expressed in regions of intestinal metaplasia in these tissues.^[70–73] Strikingly, the transgenic expression of Cdx1 or Cdx2 in the stomach leads to the development of intestinal metaplasia in mice,^[74–76] while the loss of Cdx2 in intestinal tissue leads to the formation of stratified squamous epithelium similar to that found in the esophagus.^[77] Furthermore, chronic exposure to acid induces the expression of Cdx2 in normal mouse esophageal cells.^[60] While these data strongly support Cdx1 and Cdx2 as likely candidate genes involved in the development of Barrett's esophagus, attempts to demonstrate this have not been successful, suggesting that these genes alone are insufficient to drive the generation of a columnar phenotype in the esophagus (Dr Daniel Croagh & Associate Professor Wayne Phillips, unpublished data).

Hedgehog Signaling

The hedgehog (Hh) signaling pathway is critical for normal gut development, and thus represents another potential candidate as a molecular mediator of Barrett's esophagus. Hh signaling is crucial to the development of columnar epithelium in the gastrointestinal tract, including the early esophagus.^[78,79] Hh signaling is extinguished during the transition of the esophageal epithelium from the primitive columnar cells that characterize the embryonic esophagus to the stratified squamous lining of the adult organ.^[78] However, recent studies have shown that while the normal squamous epithelium of the esophagus does not express the Hh ligands Sonic hedgehog and Indian hedgehog, both are markedly upregulated in Barrett's esophagus^[80] and in acid-treated esophageal squamous epithelial cells.^[80,81] Consistent with the activation of Hh signaling in Barrett's esophagus, the Hh target genes Ptch1 and Bmp4 were found to be expressed in the stromal compartment associated with Barrett's esophagus, but not in the stroma underlying normal squamous epithelium.^[80] Furthermore, BMP4 (bone morphogenic protein 4) was shown to induce the expression of SOX9, a transcription factor known to upregulate the expression of DMBT1 (Deleted in Malignant Brain Tumors 1), a gene linked to the induction of columnar epithelial differentiation, thus providing a potential mechanism by which Hh signaling could mediate the development of intestinal metaplasia in the esophagus.

J Gastroenterol Hepatol. 2011;26(4):639-648. © 2011 Blackwell Publishing

Cite this: Barrett's Esophagus - Medscape - Apr 01, 2011.