Title:New Advances in the Pathogenesis and Progression of Barrett’s Esophagus
Volume: 14
Issue: 1
Author(s): M. M. Streppel, E. A. Montgomery and A. Maitra
Affiliation:
Keywords:
Barrett’s esophagus, esophageal adenocarcinoma, hedgehog, next generation sequencing, notch,
origin, wnt.
Abstract: Barrett’s esophagus (BE) is a premalignant condition in the esophagus, with a rising incidence rate
among Caucasians, and an established risk factor for the subsequent progression to esophageal
adenocarcinoma (EAC). In contrast to the stratified squamous epithelium that normally lines the distal
esophagus, BE is characterized by columnar epithelium that to some extent resembles the mucosa of the
lower intestinal tract. The mechanism of intestinalization of the esophagus is still uncertain. For many years, it
was postulated that either abnormal differentiation of resident progenitor cells in the esophagus, or
transdifferentiation of mature esophageal keratinocytes provoked by reflux-induced genetic alterations,
resulted in the BE phenotype. However, more recent studies suggest that indigenous progenitor cells at the
gastro-esophageal junction might, under unfavorable conditions such as TP63 loss or an activated
inflammatory response, migrate to the esophagus and initiate columnar cell differentiation. In this review, we
discuss the competing theories of the origins of BE, as well as the role of developmental signaling pathways
such as Notch, Hedgehog, and Wnt/β-catenin signaling that have been implicated in the molecular
pathogenesis of BE and EAC. Additionally, we provide an overview of the mutational landscapes of BE and
EAC, derived from the results of recently published next generation sequencing (NGS) studies. Future
research should elucidate whether NGS on endoscopic mucosal biopsies can help in identifying BE patients at
highest risk for EAC development, and whether some of the prevalent mutations are “actionable”, leading to
improvements in current therapeutic strategies for BE and EAC.
