Barrett’s esophagus (BE) is a common premalignant lesion of the esophagus that arises as a consequence of chronic duodenogastroesophageal reflux (DGER). This condition predisposes patients to esophageal adenocarcinoma. We have shown previously that the secretion and expression of interleukin-6 (IL-6) is increased in epithelial cells of BE at the protein and mRNA levels compared to duodenum or squamous epithelium. In addition, we found that the proteins that are associated with IL-6 signaling - phosphorylated signal transducer and activator of transcription 3 (STAT-3) and the antiapoptotic proteins Bcl-xL and Mcl-1 - are also over-expressed in the same tissues. In this study, we evaluated whether STAT-3 is constitutively activated in BE and whether this activation correlates with the degree of dysplasia. In addition, expression of Bcl-xL, an antiapoptotic protein regulated by IL-6/STAT3, was evaluated. Biopsies of 67 patients with different levels of dysplasia - non-dysplastic BE, low grade dysplasia, high grade dysplasia, and esophageal adenocarcinoma - were evaluated for expression of phosphorylated STAT-3 and Bcl-xL using immunohistochemical staining. Results: Intense staining of phosphorylated STAT-3 was detected in the nucleus and cytoplasm of epithelial cells in BE biopsies with low-grade and high-grade dysplasia. In contrast, no or mild staining was detected in the majority patients with stable non-dysplastic disease for several years without ever displaying dysplasia. However, two patients out of seven with non-dysplastic BE for more than 4 years had intense staining for phosphorylated STAT-3. These patients will be closely followed for the development of dysplasia and adenocarcinoma. In adenocarcinoma tissue, staining of activated STAT-3 was concentrated in the nucleus; however, the intensity of staining was lower than in the patients with low grade or high grade dysplasia. In one patient, who developed cancer serial biopsies over 6 years were available. Interestingly, activated STAT-3 was consistently positive throughout his course, prior to development of dysplasia and cancer. Bcl-xL follows the same pattern of expression: the highest expression levels were observed in low grade dysplasia tissue, while less intense staining was detected in non-dysplastic tissues and adenocarcinoma. These data, taken together, suggest that constitutive activation of STAT-3 in BE may contribute to malignant progression and that staining for activated STAT-3 may be a useful biomarker for patients at greater risk for developing cancer.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]