Abstract 1705: CCK2R marks a gastrin-responsive stem cell that gives rise to Barrett's esophagus

Abstract

Abstract The incidence of esophageal adenocarcinoma (EAC) has markedly increased in the United States over the last few decades. Barrett's esophagus (BE) is the most significant known risk factor for this malignancy. Barrett's metaplasia, a condition of esophagus characterized by a columnar-cell metaplasia that replaces the native squamous-cell epithelium is considered to be a complication of gastroesophageal reflux disease (GERD), another risk factor for EAC. The paradigm is that BE arises from an adaptation to the harsh intra-esophageal environment of chronic GERD, and predisposes to EAC. Other established risk factors for EAC include obesity, smoking, poor diet. Moreover, while BE patients often undergo periodic endoscopic examinations, screening for dysplasia has not been shown to decrease mortality and remains controversial. Thus, a better understanding of the risk factors for BE progression is needed. The precise role of CCK2R in the gastric cardia and Barrett's esophagus has not been defined. CCK2R is upregulated in the esophagus in human BE and EAC, and real-time PCR of BE tissues indicated that the level of expression was 2x higher than that in esophageal tissues from normal control patients. CCK2R is upregulated in the gastric cardia of mice with Barrett's metaplasia, and this effect is enhanced with administration of bile acids, a key component of the refluxate. In this study we used the L2-IL-1β model to determine whether CCK2R-expressing cells can give rise to BE, and whether inhibition of CCK2R could ameliorate the BE phenotype in our mouse model. In order to understand the role of CCK2R-expressing cells in normal cardia, we performed lineage tracing studies in CCK2R-CreERT mice. We generated CCK2R-CreERT/TdTomato mice and induced them with tamoxifen at 6 weeks of age. Single Tomato-red positive cells became visible at the base of the cardia at 24 hours after induction. By days 2, 3, and 5 these Tomato-red cells expanded and moved upward in the cardia gland in contiguous fashion until almost all the cells in the gland were labeled. Tomato-red cells persisted for as long as one year in the cardia. Thus, CCK2R labels a progenitor cell in the normal gastric cardia whose progeny populate the gland and persist for at least one year, suggesting the ability to self-renew and consistent with a cardia stem cell. Since CCK2R marks a proliferating progenitor cell in the cardia, we verified whether CCK2R also has functional importance in BE progression. We hypothesized that overexpression of gastrin, the ligand for CCK2R, could accelerate BE in L2-IL-1β mice. INS-GAS mice, which overexpress amidated gastrin under the transcriptional control of the insulin promoter, were crossed with L2-IL-1β mice. L2-IL-1β/INS-GAS mice treated with bile acids had significantly increased areas of BE involvement compared to L2-IL-1β or INS-GAS controls. No areas of BE were seen in wild type or INS-GAS mice treated with bile acids until the age of 12 months. Citation Format: Aleksandra M. Urbanska, Yoomi Lee, Yoku Hayakawa, Julian A. Abrams, Michael Quante, Timothy C. Wang. CCK2R marks a gastrin-responsive stem cell that gives rise to Barrett's esophagus. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1705.