Abstract
ABSTRACTBy whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4aR703C mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.
Highlights
Type I gastric neuroendocrine tumors are multifocal cellular lesions, usually benign in behavior and associated with hypochlorhydria and hypergastrinemia (Zhang et al, 2011; Vannella et al, 2012)
A knockin mouse line carrying the p.R702C mutation in the Atp4a gene in homozygosis, normal at birth, developed most of the clinical features and the premalignant condition previously described in human individuals who are homozygous for the same mutation (Calvete et al, 2015)
The mice did not develop gastric NETs; premalignant pathology and cellular dysplasia, similar to those observed in the non-tumor affected areas of the stomachs of human individuals, were found
Summary
Type I gastric neuroendocrine tumors (gNETs, known as gastric carcinoids) are multifocal cellular lesions, usually benign in behavior and associated with hypochlorhydria and hypergastrinemia (Zhang et al, 2011; Vannella et al, 2012). Gastrin is secreted by the G cells located in the antrum of the stomach ( pyloric glands), and stimulates acid secretion by the gastric oxyntic glands, which are located in the corpus region of the stomach. These glands are mainly composed of chief (or zymogenic) cells, enterochromaffin-like cells (ECL cells) and parietal cells (PCs). Gastric acid secretion is achieved through proton pumps (encoded by the ATP4a gene) located in PCs. Gastric acid is needed for the conversion of pepsinogen to pepsin (activated form), and facilitates iron absorption in the duodenum (Schubert, 2015). PCs in humans produce intrinsic factor (IF), which is necessary for the absorption of vitamin B12
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