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In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.
Mutations in the ATP4A proton pump prevent gastric acidification and explain the chronic autoimmune gastritis scenario that conducts the gastric neuroendocrine tumor (gNET) formation. Here, we wanted to investigate the co-occurrence cytomegalovirus (CMV) infection and intestinal inflammation that presented all members of a family affected with gNET and carrying an ATP4A mutation. Intestinal inflammation persisted after CMV eradication and anemia treatment. The inflammation was compatible with a ileitis/Crohn's disease and was originated by the same autoimmune mechanism described in the tumorigenesis of gNETS. The same secondary disease but no the CMV infection was observed in all members affected with gNET and carrying the ATP4A mutation. Our results suggest that the ATP4A malfunction not only explained gNETs but also the co-occurring disease and opportunistic infections, which allowed to link autoimmune pathologies and gNETs in a unique mechanism. Our results open a new window to better understand not only gastric neoplasms formation but the co-occurring autoimmune disorders and the inflammatory mechanism that compose a premalignant scenario for other tumor formation. Our findings are important since contribute to describe the genetic landscape of the Inflammatory Bowel/Crohn's disease and alert clinicians to monitor patients with gastric neoplasms mediated by achlorhydria mechanisms for concomitant secondary pathologies.
By 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 ATP4a(R703C) 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.
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