Barrett?s esophagus (BE) is a precursor to esophageal adenocarcinoma, a cancer with increasing incidence and a five-year survival less than 17%. BE and esophageal adenocarcinoma arise in the setting of abnormal esophageal repair. Our prior work has shown that patients with esophageal injury or BE display acinar ductal metaplasia within esophageal submucosal glands (ESMGs). Furthermore, using a pig model, we have found that ESMGs respond to injury with proliferation and a shift to a ductal phenotype with expression of BE markers. However, the factors that contribute to development of this metaplasia are unknown. Our preliminary data suggest that metaplasia in ESMGs may be elicited by elevated gastrin exposure as we have identified: 1) increased expression of the gastrin receptor in the ESMGs and 2) ESMG proliferation in response to gastrin in vitro. These findings are clinically relevant since proton pump inhibitors (PPIs), which are commonly used for acid suppression and currently recommended for BE, raise serum gastrin levels. Elevated gastrin levels are associated with increased risk of metaplasia, dysplasia and cancer in the stomach, colon and pancreas. The objective of this proposal is to determine the effects of PPIs and elevated gastrin on esophageal proliferation and metaplasia in ESMGs, the highly specialized submucosal structures that contain esophageal progenitors and respond to esophageal injury. To accomplish this objective, we will use our novel in vitro and in vivo porcine models of ESMGs and esophageal repair, and our large cohort of human esophagectomy samples. Our central hypothesis is that gastrin promotes proliferation, and metaplasia within ESMGS via the gastrin receptor (CCKBR). We will test the hypothesis that gastrin signaling drives esophageal proliferation and acinar ductal metaplasia through the gastrin receptor by pursuing three specific aims: 1) Quantify effects of the gastrin receptor (CCKBR) activation and inhibition on ESMG proliferation and differentiation using in vitro and in vivo porcine models. 2) Determine the downstream mechanisms between gastrin exposure and acinar ductal metaplasia. 3) Validate gastrin receptor and signaling targets in human ESMGs and develop ex vivo platforms to test therapies for acinar ductal metaplasia and BE prevention. Through the proposed aims, we will establish pre-clinical models to determine the pathological effects of gastrin on ESMG proliferation and induction of acinar ductal metaplasia. This will be accomplished by characterizing injury-induced changes in gastrin receptor expression and down-stream signaling effects of gastrin levels found with PPI use. The proposed aims will address the current debate regarding safety of PPIs and elevated gastrin levels in esophageal metaplasia and dysplasia and these studies could lead to rapid translation of our findings.
As a treatment for esophageal reflux disease and Barrett?s esophagus, proton pump inhibitors (PPIs) are quite common and these drugs are often continued for many years. Recent reports have emphasized potential for harm associated with PPI use; one consequence of long-term PPI use is elevated serum gastrin levels. Our proposed research will investigate the role of gastrin in esophageal repair and metaplasia using novel porcine models that include esophageal submucosal glands and develop new human platforms for preclinical studies.
