Clinical issue

Barrett’s esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma in 0.5% of these patients each year. Cancer of the esophagus is almost invariably lethal, and its incidence has increased dramatically in recent years. BE is believed to be caused by chronic reflux from the acidic contents of the stomach and bile, which converts the squamous epithelium lining the esophagus into columnar epithelium resembling that of the lower intestine. Subsequent mutations then lead to adenocarcinoma. Currently, there is no cure for BE once it is established. Patients are routinely monitored by endoscopy, while the reflux is treated to prevent progression to more advanced disease. Eventually, endoscopic surgical intervention may be necessary to remove affected tissue. Basic research into esophageal adenocarcinoma has focused on determining the molecular events required for the initial squamous-columnar transition, the genes required for progression, and possible methods of inhibiting or reversing the pre-cancerous and cancerous changes. It is possible that, as the mutated columnar epithelium is similar to colonic epithelium, the Notch pathway, which is a signaling cascade that is central to both normal and neoplastic colonic development, may be involved.

Results

The authors previously found that the Notch pathway controls the vigorous cell division in the lining of the normal gut. Here, they show using biopsy samples that the Notch pathway is not active in the normal squamous lining of the esophagus but that it is highly active in the areas of the esophagus that have changed into columnar Barrett’s epithelium. To determine whether inhibition of the Notch pathway could revert or destroy Barrett’s epithelium, dibenzazepine (DBZ), a known inhibitor of the Notch pathway, was used to treat rats with surgically induced Barrett’s epithelium. As shown previously in normal colonic epithelium, Notch inhibition converted the proliferative Barrett’s cells into arrested terminally differentiated goblet cells, whereas the normal squamous epithelium was unaffected. In some cases, the Barrett’s epithelium was entirely exfoliated, leaving bare submucosal tissue.

Implications and future directions

These data imply that local application of Notch inhibitors may present a simple therapeutic strategy for BE. However, further studies are required to optimise a method of delivery and, importantly, to determine the nature of any epithelial regrowth following treatment.