Barrett's esophagus (BE) is a metaplastic lesion of the distal esophagus that develops as a consequence of chronic gastroesophageal reflux disease (GERD). Bile and gastric acid in the refluxate are two of the major factors involved in the pathogenesis of BE. Multiple studies show that BE is associated with increased risk of esophageal adenocarcinoma (EAC). Barrett's esophagus is very common among the veteran population and affects more than 10% of those with GERD-related symptoms. The growth of tumor cells is often driven by cytokines that stimulate cell proliferation and apoptosis resistance. Interleukin 6 (IL-6) is a cytokine that is frequently increased in different cancers. The central hypothesis of this proposal is that repeated exposure of esophageal tissue to bile acids and gastric acid leads to IL-6 upregulation, increased activation of transcription factor STAT3, apoptosis resistance, and cancer development. Our preliminary data indicate that IL-6/STAT3 signaling is elevated as BE progresses from the nondysplastic stage to the dysplastic stage and cancer and that chronic exposure to bile acids and gastric acid leads to increased secretion of IL-6, STAT3 activation and resistance to cell death. This proposal has three specific aims.
Specific Aim #1 will determine if IL-6/STAT3 signaling is elevated during progression to EAC. The expression and activation of different components of IL-6/STAT3 pathways will be evaluated in human biopsies from BE patients with different grades of dysplasia and from EAC patients. The expression of biomarkers will be also evaluated in nondysplastic BE obtained prior to the development of EAC ("progressors") and in those who have not progressed to EAC ("nonprogressors").
Specific Aim # 2 will evaluate the mechanism of bile acid-induced IL-6/STAT3 activation. The hypothesis is that bile acids and gastric acid increase oxidative stress, which leads to NF-kB activation, increased IL-6 production, and STAT3 activation. The effects of bile acids and/or gastric acid on IL-6/STAT3 will be determined in various esophageal cell lines and human biopsies.
Specific Aim #3 will test the hypothesis that alteration of bile acid composition leads to decrease in IL- 6/STAT3 signaling and increased apoptosis.
This specific aim will evaluate whether UDCA can modulate IL- 6/STAT3 signaling and expression of anti-apoptotic proteins in human BE samples from patients treated with UDCA and in esophageal cell lines. A total of 30 patients with BE and low-grade dysplasia are being recruited at SAVAHCS into a UDCA clinical trial that is funded through NCI. Biopsies from these patients'Barrett's mucosa at baseline and at the end of treatment will be compared. The proposed studies using human biopsies and esophageal cell lines have the promise of contributing to the development of novel biomarkers, therapeutic targets, and therapeutic modalities for inhibiting the pathway leading to the development of BE and/or progression of BE to EAC.
Approximately 1-2 million people in the United States have Barrett's esophagus, a lesion of the distal esophagus that is associated with an increased risk of esophageal adenocarcinoma. Barrett's esophagus is particularly common among the veteran population, making it one of the most challenging clinically dilemmas in gastroenterology for the VA Health Care System. In this proposal we will test the hypothesis that exposure to bile acids and gastric acids leads to the alterations in cytokine balance and apoptosis resistance. However, this effect of reflux may be reversed by treatment with ursodeoxycholic acid. We anticipate that the results of these studies will lead to the development of novel biomarkers and new therapeutic targets for inhibiting the pathways leading to the development and/or progression of Barrett's esophagus to esophageal adenocarcinoma.