Hypergastrinemia increases gastric epithelial susceptibility to apoptosis.
Plasma concentrations of the hormone gastrin are elevated by Helicobacter pylori infection and by gastric atrophy. It has previously been proposed that gastrin acts as a cofactor during gastric carcinogenesis and hypergastrinemic transgenic INS-GAS mice are prone to developing gastric adenocarcinoma, particularly following H. pylori infection. We hypothesised that the increased risk of carcinogenesis in these animals may partly result from altered susceptibility of gastric epithelial cells to undergo apoptosis. Gastric corpus apoptosis was significantly increased 48 h after 12Gy gamma-radiation in mice rendered hypergastrinemic by transgenic (INS-GAS) or pharmacological (omeprazole treatment of FVB/N mice) methods and in both cases the effects were inhibited by the CCK-2 receptor antagonist YM022. However, no alteration in susceptibility to gamma-radiation-induced gastric epithelial apoptosis was observed in mice overexpressing progastrin or glycine-extended gastrin. Apoptosis was also significantly increased in gastric corpus biopsies obtained from H. pylori-infected humans with moderate degrees of hypergastrinemia. We conclude that hypergastrinemia specifically renders cells within the gastric corpus epithelium more susceptible to induction of apoptosis by radiation or H. pylori. Altered susceptibility to apoptosis may therefore be one factor predisposing to gastric carcinogenesis in INS-GAS mice and similar mechanisms may also be involved in humans.
Przemeck
S M C
SM
Division of Gastroenterology, School of Clinical Sciences, University of Liverpool, UK.
Varro
A
A
Berry
D
D
Steele
I
I
Wang
T C
TC
Dockray
G J
GJ
Pritchard
D M
DM
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D017209:Apoptosis; D001569:Benzodiazepines / Q000494:pharmacology; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005720:Gamma Rays; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D005755:Gastrins / Q000097:blood*; D016480:Helicobacter pylori; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009853:Omeprazole / Q000494:pharmacology; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors; D013274:Stomach Neoplasms / Q000209:etiology*
D000897:Anti-Ulcer Agents; D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D001569:Benzodiazepines; C087260:YM 022; D009853:Omeprazole