Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus

Navtej S Buttar; Kenneth K Wang


Nat Clin Pract Gastroenterol Hepatol. 2004;1(2) 

In This Article


Gastrin is an important regulator of gastric acid secretion that has recently been implicated in the regulation of cell survival and differentiation in the gastrointestinal tract, and it may promote carcinogenesis.[21,22,23,24] A large number of patients with Barrett's esophagus are on acid suppressive therapy with either PPIs or H2-receptor antagonists,[5] both of which increase postprandial and fasting serum gastrin levels,[22] which may have a role in promotion of carcinogenesis.[23,24]

The effect of gastrin on survival of Barrett's epithelia may explain how it could promote the development of cancer in Barrett's esophagus. Gastrin can bind to the cholecystokinin (CCK2) receptor, the stimulation of which can induce expression of epidermal growth factor and the trefoil peptide.[23,24] This gastrin-induced signaling can eventually induce COX-2 expression, which seems to be important for carcinogenesis in Barrett's esophagus (discussed above).[24] Indeed, Barrett's mucosa express more CCK2 receptors than normal squamous mucosa[23,24] and it has also been shown that gastrin exposure increases proliferation in an esophageal cancer cell-culture model.[23,24] Further downstream effects of gastrin-related CCK2 receptor stimulation can inactivate proapoptotic factors and therefore potentially promote carcinogenesis.[23,24]

The importance of these observations in the clinical management of patients with Barrett's esophagus remains unclear. Any potentially procarcinogenic effect of increased gastrin levels caused by PPIs could be counterbalanced by the ability of the PPIs to suppress acid-reflux-related procarcinogenic signaling. Clinical evidence that hypergastrinemia (for example in Zollinger Ellison syndrome) promotes carcinogenesis is lacking. The combined use of PPIs along with inhibitors of gastrin-dependent signaling, however, may be a future strategy to prevent the development of esophageal cancer.


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