Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice.

Kristin Matre Aasarød,Arne Kristian Sandvik,Patricia Mjønes,Unni Syversen,Astrid Kamilla Stunes,Arnar Flatberg,Ingunn Bakke,Reidar Fossmark,Helge Lyder Waldum

doi:10.3390/ijms21030927

Abstract

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Highlights

Proton pump inhibitors (PPIs) are widely used in the management of acid-related gastrointestinal diseases such as peptic ulcers and gastro-esophageal reflux
We have examined the effects of the gastrin receptor antagonist NTZ on the oxyntic mucosa of anacidic and hypergastrinemic H+/K+ATPase beta subunit KO mice with particular focus on NE cell hyperplasia and Spasmolytic polypeptide-expression metaplasia (SPEM)
The expression of tryptophan hydroxylase, which is expressed in eiacdnebd. ythNeTeZnitnerKocOhrmomicea.ffin (EC) cells, was not affected by NTZ in agreement with previous studies showing that EC cells are not stimulated by gastrin [27]

Summary

Introduction

Proton pump inhibitors (PPIs) are widely used in the management of acid-related gastrointestinal diseases such as peptic ulcers and gastro-esophageal reflux. The increase in PPI use has been well described in many countries in recent decades [1,2]. An increased risk of gastric neuroendocrine (NE) tumors developing from enterochromaffin-like (ECL) cells and carcinomas has been predicted since the 1980s, and more recently several epidemiological studies have found that patients using PPIs have an increased risk of gastric cancer [5,6,7]. In response to gastric luminal contents and hypoacidity, gastrin is released from antral G cells and stimulates function and proliferation of ECL cells where the gastrin receptor is located [10]. Gastrin release is regulated by gastrin-releasing peptide (GRP) and GRP receptor (GRP-R) expression in the gastrointestinal tract has been located to the antrum [11]. The GRP-R is expressed in a range of tissues outside the gastrointestinal tract [12] as well as in various types of cancer [13,14]

Methods

Results

Conclusion