Do Transcription Factors Hold the Key to Understanding the Development of Barrett’s Esophagus?

Abstract

Barrett’s esophagus is a complex metaplasia which can occur as a pure gastric or intestinal histopathological phenotype but more commonly occurs as a mosaic comprising gastric and intestinal forms. Intestinal metaplasia is typified by the presence of goblet cells seen on light microscopy. Some studies indicate that the chances of identifying goblet cells are related to the length of Barrett’s, location of the biopsies (more goblet cells in proximal esophagus), number of biopsies, patient age and gender, being more common in men [1]. Most interest has focussed on those patients with an endoscopically visible columnar lined epithelium containing intestinal metaplasia since this is the form most clearly associated with malignancy with an annual progression rate estimated to be in the region of 0.3–0.4% per annum [2, 3]. However, recent studies comparing goblet and non-goblet containing metaplastic epithelium have shown that both types demonstrate the same frequency of DNA content abnormalities [4, 5], suggesting that the gastric form is not entirely benign. The molecular and cell biological process by which Barrett’s esophagus arises is poorly understood. The emerging theories include trans-differentiation from a mature esophageal keratinocyte or altered differentiation of an esophageal or submucosal stem cell [6]. More recently it has been suggested that Barrett’s may occur from expansion of an embryological remnant [7]. Whichever theory is correct, all appear to depend on the activation of transcription factors to alter the cell fate. To date most effort has focussed on the homeobox genes Cdx1 and 2 which, in contrast to the dramatic effect observed when ectopically expressed in the murine stomach [8], fail to induce intes