In a study, supported by the National Cancer Institute (NCI), researchers at the Columbia University Medical Center (CUMC) have identified where and how esophageal adenocarcinoma (EAC) arises.
The study findings highlight possible targets for new clinical therapies.
According to the research team, EAC is usually triggered by gastroesophageal reflux disease (GERD), in which bile acid and other stomach contents leak backwards from the stomach to the esophagus, the muscular tube that moves food from the mouth to the stomach.
Over time, acid reflux can irritate and inflame the esophagus, leading to Barrett’s esophagus, an asymptomatic precancerous condition in which the tissue lining the esophagus is replaced by tissue similar to the lining of the intestine. A small number of people with Barrett’s esophagus eventually go on to develop EAC.
Using a new genetically engineered mouse model of esophagitis, the CUMC researchers have clarified critical cellular and molecular changes that occur during the development of Barrett’s esophagus and EAC.
In human patients, acid reflux often leads to overexpression of a molecule called interleukin-1 beta, reported study leader Timothy Wang. Thus, Mr Wang and his colleagues created a transgenic mouse in which interleukin-1 beta was overexpressed in the esophagus.
Overexpression of interleukin-1 beta in the mouse esophagus resulted in chronic esophageal inflammation (esophagitis) and expansion of progenitor cells that were sustained by the notch signaling pathway.
Notch is a fundamental signaling system used by neighboring cells to communicate with each other in order to assume their proper developmental role. “When we inhibited notch signaling, that blocked proliferation and survival of the pre-malignant cells, so that's a new possible clinical strategy to use in Barrett's patients at high risk for cancer development,” said Mr Wang.
For decades, investigators thought that the physiological changes associated with Barrett's esophagus originate in the lower esophagus. “However, our study shows that Barrett’s esophagus actually arises in the gastric cardia, a small region between the lower part of the esophagus and the upper, acid-secreting portion of the stomach,” said Mr Wang. “What happens is that the bile acid and inflammatory cytokines activate stem cells at this transition zone, and they begin migrating up toward the esophagus, where they take on this intestinal-like appearance.”
The researchers also demonstrated that these changes occur primarily in columnar-like epithelial cells, rather than in goblet cells, as was previously thought.
“All told, the findings present a new model for the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma,” said Mr Wang.
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