Abstract
ObjectiveThe incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice.DesignL2-IL-1β mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug.ResultsHypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia.ConclusionsOur data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.
Highlights
The incidence of esophageal adenocarcinoma (EAC) has risen 6-fold in the U.S since the 1970s [1, 2]
Hypergastrinemia can result from Proton Pump Inhibitors (PPI) use, and the effects of hypergastrinemia in human Barrett’s esophagus (BE) should be studied further
In the gastric corpus of the proximal stomach, the receptor mediates acid secretion as well as growth and differentiation of the epithelium. [13,14,15] Cholecystokinin 2 receptor (CCK2R) is upregulated in the mucosa during ulcer healing, and inhibition impairs mucosal regeneration. [16, 17] While CCK2R might in theory mark a shortlived progenitor cell that expands during healing, we have recently shown that CCK2R marks a +4 gastric antrum progenitor, which is Lgr5neg or low and lineage traces entire antral glands [18]
Summary
The incidence of esophageal adenocarcinoma (EAC) has risen 6-fold in the U.S since the 1970s [1, 2]. Major risk factors for EAC include male gender, obesity, and a history of gastroesophageal reflux disease (GERD), but Barrett’s esophagus (BE) increases the risk of EAC by 11-fold [3,4,5]. In BE, present in up to 1.6% of unselected populations, the normal squamous epithelium of the lower esophagus is replaced by columnar epithelium. The risk of EAC in patients with nondysplastic BE is quite low (0.12% annually) [6]. Screening for dysplasia in BE patients has not been shown to decrease mortality [7, 8]. A better understanding is needed of the factors involved in neoplastic progression of BE
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