Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer

Background & Aims: Hypergastrinemia occurs frequently in association with a cid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined. Methods: The effects of hypergastrinemia, and possible synergy with Helicobacter fel is infection, were investigated in insulin-gastrin (INS-GAS) transgenic mic e. Results: INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but late r progressed to decreased parietal cell number and hypochlorhydria, Develop ment of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth fa ctor or. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia , dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >2 0 months old. Helicobacter felis infection of INS-GAS mice led to accelerat ed (less than or equal to 8 mo) development of intramucosal carcinoma (85%) , with submucosal invasion (54%) and intravascular invasion (46%; P less th an or equal to 0.05). Conclusions: These findings support the unexpected co nclusion that chronic hypergastrinemia in mice can synergize with Helicobac ter infection and contribute to eventual parietal cell loss and progression to gastric cancer.