Chronic gastroesophageal acid reflux and its sequela, Barrett's esophagus (BE), are strong risk factors for esophageal adenocarcinoma, a tumor whose frequency has increased six-fold over the past 30 years. The molecular events that underlie both the development of BE and its neoplastic progression remain unclear. The elucidation of the molecular mechanisms of carcinogenesis in the colon has resulted in important clinical advances in the diagnosis, prevention and treatment of colorectal cancer. If there are to be similar advances in the management of patients with BE, we must first understand the molecular pathways underlying metaplasia and neoplasia in the esophagus. My laboratory has found that acid exposure activates the mitogen activated protein kinase (MAPK) pathways in esophageal cells in patterns that appear to differ among mucosal types as well as within mucosal types among patients with different esophageal diseases. For example, we have shown that acid activates ERK MAPK in the esophageal squamous mucosa of patients who have gastroesophageal reflux disease (GERD) without BE, but not in those who have BE. Using Barrett's cancer cells, we have linked acid-induced MAPK activation with pro-proliferative effects. However, the results of studies on cancer cells, which have diverse and poorly characterized genetic alterations, may not be applicable to benign cells. Recently, we have used telomerase technology to generate immortal, but benign, metaplastic Barrett's and esophageal squamous cell lines from patients with and without BE. We propose to use these cell lines to explore the molecular pathways activated by acid reflux that lead to the development and neoplastic progression of BE. Our preliminary data show that acid activates MAPK in metaplastic Barrett's cells in a pattern similar to that seen in BE in vivo, but different from that seen in Barrett's cancer cells. Unlike the pro- proliferative effects of acid on those cancer cells, we have found that acid exposure has anti-proliferative effects in our benign Barrett's cells. We hypothesize that the effects of acid on proliferation and apoptosis in esophageal cells depend on the pattern of MAPK activation induced by acid and on how the activated MAPK proteins affect the G1-S cell cycle checkpoint.
The aims of this study are to delineate the effects of those activated MAPK proteins on the G1-S cell cycle checkpoint in normal esophageal squamous and metaplastic Barrett's cells in vivo and in vitro, and to disrupt the key mediators of the G1-S cell cycle checkpoint to determine the effects of these disruptions on acid-mediated proliferation and apoptosis in vitro. The relevance to public health is the identification of specific molecular markers that can be used to select a subset of our many patients with GERD who might benefit from aggressive acid suppressive therapy to prevent the development of BE as well as to select a subgroup of patients with BE who would benefit most from interventions to prevent esophageal adenocarcinoma. The relevance to public health is the identification of specific molecular markers that can be used to select a subset of our many patients with gastroesophageal reflux disease who might benefit from aggressive acid suppressive therapy to prevent the development of Barrett's esophagus as well as to select a subgroup of patients with Barrett's esophagus who would benefit most from interventions to prevent esophageal adenocarcinoma.
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