Insights Into the Pathophysiology of Esophageal Adenocarcinoma

Abstract

Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett's esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett's esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett's esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals.

Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium

“…Furthermore, since the glandular stomach disappears completely in these mice, the pit surface seems to be indispensable for maintaining the normal structure of 46 H Kinoshita et al the gastric epithelium. The finding that glandular epithelium was gradually replaced with squamous epithelium, which seemed to expand from the lesser curvature side of the squamocolumnar junction, supports the 'competition' model for establishing the boundary of squamous and glandular epithelium [41]. In fact, there have been several reports of squamous metaplasia in the gastric cardia in the setting of chronic injury to glandular epithelium [42][43][44][45], which might be modeled by our Tff1-Cre;Cdh1 flox/flox mice.…”

Helicobacter pylori infection, chronic atrophic gastritis and risk of stomach and esophagus cancer: Results from the prospective population‐based ESTHER cohort study

“…The following mechanism of an inverse association between H. pylori infection and occurrence of esophageal ACs has been postulated: chronic inflammation with concomitant atrophy and loss of parietal cells may result in a reduction of acidity and as a consequence, in less reflux esophagitis, Barett's esophagus and development of ACs . It has further been hypothesized, that translocation of gastric bacteria due to reflux might affect immune homeostasis by shifting the balance to tumor‐promoting immune responses . However, an association between the absence of H. pylori and increased gastroesophageal reflux remains questionable .…”

“…20,50 It has further been hypothesized, that translocation of gastric bacteria due to reflux might affect immune homeostasis by shifting the balance to tumor-promoting immune responses. 51 However, an association between the absence of H. pylori and increased gastroesophageal reflux remains questionable. 52 It is further unclear, whether H. pylori may be directly interacting with host epithelial cells and/or affecting the microbial composition in the esophagus.…”

Comprehensive molecular profiling of the B7 family in gastrointestinal cancer

“…Patients with Barrett’s oesophagus and reflux history have significantly higher level of B7‐H5/H7 mRNA expression. Reflux disease may lead to dysplasia, which has been regarded as an important factor in forming Barrett’ oesophagus and damaging the distal oesophagus (Figure ). Barrett’s oesophagus is a critical risk factor in oesophageal cancer .…”