E-Cadherin and the Esophagus

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Science Translational Medicine  22 Jun 2011:
Vol. 3, Issue 88, pp. 88ec95
DOI: 10.1126/scitranslmed.3002783

What goes down, should not come up. Yet, it is estimated that 20% of adults are affected by gastroesophageal reflux disease (GERD), a common disorder that is identified on the basis of self-reported symptoms that result from excessive reflux of gastric acid and pepsin. When symptoms of GERD are typical (such as heartburn, chronic cough, and hoarseness) and the patient responds to therapy, no diagnostic tests are necessary. However, many patients present with atypical symptoms that require endoscopic evaluation to rule out alternative diagnoses, such as gastric or esophageal cancer.

Toward accurate diagnosis of GERD, Jovov et al. identified an early molecular event in the pathogenesis of this disease: the proteolytic cleavage of E-cadherin, a junctional protein that is important in the barrier function of esophageal epithelium. The esophageal endothelium in GERD patients has increased junctional permeability owing to proteolytic cleavage of E-cadherin, as shown by the presence of its degradation products in biopsy samples and serum of 10 patients with GERD. The authors used a conditional knockout mouse model to show that the loss of E-cadherin expression results in increased esophageal endothelium permeability and histologic features of GERD, such as dilated intercellular space. Jovov and colleagues speculate that cleavage of E-cadherin probably represents a crucial molecular event in the pathogenesis of this disease. Identification of E-cadherin fragments might therefore serve as a diagnostic and treatment biomarker for GERD, if validated in larger, population-based studies.

Although the detailed molecular pathway from acid injury to the esophageal endothelium and the proteolytic cleavage of E-cadherin remains unknown, these findings have far-reaching implications in the clinical approach to gastrointestinal disease. For example, detection of degraded E-cadherin in patient serum might encourage earlier treatment with proton pump inhibitors. In the drug discovery realm, E-cadherin or its protease might now be considered druggable targets for future development. As such, despite the preliminary nature of the results, these findings may stimulate large-scale clinical studies for a common condition.

B. Jovov et al., Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am. J. Gastroenterol. 106, 1039–1047 (2011). [Abstract]

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