Chronic Helicobacter pylori infection may result in gastric cancer in hypergastrinemic mice but not in gastrin-deficient mice

C-M Zhao PhD^a,d, X Wang MD PhD^b, L Friis-Hansen MD PhD^c, HL Waldum MD PhD^d, J Halgunset MD^d, T Wadström MD PhD^b, D Chen MD PhD^a,d

^aCancer Research Unit, Cancer Clinic, St. Olavs Hospital, Trondheim, Norway, ^bDepartment of Immunology, University of Lund, Lund, Sweden, ^cDepartment of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark, ^dDepartment of Cancer Research and Molecular Medicine and Laboratory Medicine, Norwegian University of Science and Technology, Trondheim, Norway

Background/Aim: Clinically, it is well established that Helicobacter pylori (H.p.) infection leads to gastric cancer or duodenal ulcer, but the mechanism by which single strain of H. p. may cause the two distinct clinical outcomes is still poorly understood. Recent study in transgenic mice that are hypergastrinemic revealed spontaneous gastric cancer over a period of 1–2 years and accelerated development of the cancer (within 7 months) by H.p. infection. The present study in gastrin-deficient (gene knock-out)(gastrin-/-) vs. wild-type (gastrin+/+) mice was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells in the stomach to chronic H. p. infection. Methods: Gastrin+/+ and gastrin-/- mice were infected with H. p. (CagA positive type I and vacuolating toxin-producing) for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to -subunit of H+/K+-ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. Results: In infected gastrin+/+ mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20-30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin-/- mice had lower the acid output than uninfected gastrin+/+ mice, there was a higher acid output (~3-times) in infected gastrin-/- mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin-/- mice. Hence, chronic H. p. infection resulted in impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but led to vagally induced hypersecretion in gastrin-deficient mice. Conclusions: Taken together, we suggest that apparently disparate effects of H. p. on stomach may be related to genetically determined differences in the host gastrin-secreting capacity. The gastrin turns out as a candidate host factor to influence an individual’s risk of acquiring H. p. infection, as well as to determine the direction taken by the pathological process. This may allow discriminating between those more likely to get gastric cancer and those prone to develop duodenal ulcer. We would suggest that measurement of the circulating gastrin levels might permit the identification of individuals at risk of developing gastric diseases with H. p. infection.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 897 (Precursor lesions).