Influence of acid reflux on stromal epithelial interaction in Barrett?s esophagus

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DESCRIPTION (provided by applicant): Barrett's esophagus (BE) is an important risk factor for esophageal adenocarcinoma. Duodenogastric reflux leads to chronic inflammation and the development of BE in a subset of patients1, 2. Chronic inflammation may activate fibroblasts which can promote carcinogenesis in the gastrointestinal tract by secreting growth factors 4. Myofibroblast derived growth factors are known to promote proliferation of epithelial neoplasms 5-7. Although acid and bile promote proliferation of Barrett's epithelium, control of reflux decreases proliferation and promotes differentiation 8 and control of acid reflux is associated with lower risk of dysplasia in BE 9, the precise mechanisms, the degree of reflux control needed and the influence of acid reflux on BE stroma is unknown. Based on these concepts, it is our hypothesis that gastroduodenal reflux results in stromal fibroblast activation which promotes oncogenesis via growth factor secretion. The first aim of this proposal will be to compare stromal activation in patients with known BE without dysplasia, who have controlled and persistent acid reflux. Patients with BE without dysplasia will undergo endoscopy with biopsies and a 24 hour pH study on treatment with proton pump inhibitors (PPIs). Patients will then be divided into Group A (GER): with acid reflux (characterized by either presence of esophagitis (as determined by the Los Angeles classification) 10 on endoscopy, and/or a positive pH study defined by standard criteria 11 and Group B (NGER): with controlled acid reflux (negative endoscopy and pH study on treatment). We will compare the presence of myofibroblasts and expression of COX-2, assessed by immunohistochemistry between the 2 groups. We will also assess the influence of acid and bile on esophageal fibroblast proliferation and apoptosis in vitro. The second aim of this application will be to assess and compare the presence of stromal derived growth factors (EGF, HGF) and their receptors (EGFR, HER2 for EGF and c-Met for HGF) in BE biopsies of subjects with persistent and controlled acid reflux using immunohistochemistry and quantitative PCR. In addition we will also assess stromal epithelial interaction in BE using co-culture models and attempt to block this interaction by using inhibitors of stromal derived growth factors. The goal of our research program is to identify and ultimately study with clinical trials novel chemopreventive agents in Barrett's esophagus. This translational proposal aims to identify novel targets for chemoprevention by studying the mechanisms of and the influence of acid reflux on stromal-epithelial interaction in Barrett's esophagus. Successful completion of this study will help further define the role of acid reflux control in modulating stromal activation and carcinogenesis in BE. Preliminary data gathered from these experiments would allow us to further investigate mechanisms of stromal epithelial interaction in BE as well as identify evidence based molecular targets for the chemoprevention of neoplasia in BE and launch clinical trials for chemopreventive agents. Project Narrative The purpose of this study is to determine the association between acid reflux and cell changes in Barrett's esophagus.