Proton Pump Inhibitor and H2-Receptor Antagonist Therapy Accelerates Gastric Carcinoid Development in a Menin & Somatostatin Gene Knockout Mouse Model
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Carcinoid tumors are slow growing neuroendocrine tumors (NETs) commonly developing in the gastrointestinal tract, pancreas, and lungs. Mice with inactivated Men1 (Villin-Cre x Men1FL/FL) and somatostatin (SOM-/-) gene loci have been found to generate enterchromaffin-like cell (ECL) hyperplasia and gastric carcinoids at 23 months. However, it remained unclear if gastric carcinoid development could be accelerated by environmental conditions such as therapy with acid suppressing proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs). VC:Men1FL/FL; SOM-/- mice were treated with the PPI omeprazole and the H2RA ranitidine, necropsied and analyzed. PPI and H2RA therapy was anticipated to generate favorable conditions for the development of gastric carcinoids, including the induction of severe atrophic gastritis and hypergastrinemia. Subsequently, we expected to observe ECL hyperplasia and gastric carcinoids at 3-4 months rather than at 2 years. After 3 months of acid suppression, gastric carcinoid tumors were not observed in our VC:Men1FL/FL; SOM-/- mice. However, while gastric histology and gastric acidity remained unchanged, signs for the early stages of ECL proliferation and hyperplasia were observed. Expression for chromogranin A, the gastrin peptide, and G cells increased. Furthermore, there was a significant decrease in the expression of the cyclin dependent kinase inhibitor p27Kip1. These changes in expression patterns are known signs for gastric carcinoid formation. In conclusion, the study showed that VC:Men1FL/FL; SOM-/- mice can induce NET formation and that acid suppression through PPI/H2RA therapy can accelerate their development within an extended timeframe (4-5 months).