Gastroenterology

Gastroenterology

Volume 124, Issue 7, June 2003, Pages 1879-1890
Gastroenterology

Basic-alimentary tract
Host and microbial constituents influence helicobacter pylori-induced cancer in a murine model of hypergastrinemia☆

https://doi.org/10.1016/S0016-5085(03)00406-2Get rights and content

Abstract

Background & Aims:

Helicobacter pylori cag+ strains and high-expression host interleukin 1β (IL-1β) polymorphisms augment the risk for intestinal-type gastric adenocarcinoma, a malignancy that predominates in males. We examined the effects of an H. pylori cancer-associated determinant (cagE), IL-1β, and host gender in a transgenic hypergastrinemic (INS-GAS) murine model of gastric carcinogenesis.

Methods:

Male and female INS-GAS mice infected with wild-type H. pylori, an H. pylori cagE− mutant, or H. felis were killed 2–24 weeks postchallenge. Gastric injury was scored from 0 to 4, and mucosal IL-1β levels were quantified by ELISA.

Results:

Male INS-GAS mice infected with H. pylori uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks. Mucosal IL-1β concentrations increased 12 weeks following Helicobacter challenge, but levels then decreased by 24 weeks. Inactivation of cagE delayed the progression to carcinoma, but neoplasia ultimately developed in all males infected with the H. pylori mutant. In contrast, none of the H. pylori-infected female mice developed cancer, and injury scores, but not IL-1β levels, were significantly higher in males compared with females.

Conclusions:

H. pylori infection induces gastric adenocarcinoma in an experimental mouse model of disease. Cancer is restricted to males and loss of cagE temporally retards but does not abrogate pathologic progression. Mucosal levels of IL-1β increase prior to the development of gastric cancer but are not related to gender. The INS-GAS model is effective for investigating discrete host-microbial interactions that culminate in gastric cancer within the context of biologic conditions induced by H. pylori.

Section snippets

Animals, bacteria, and experimental infections

Ninety-two (22 female, 70 male) specific pathogen-free INS-GAS mice generated on an FVB/N background were used in this study.29 For time-course studies examining injury, a minimum of 4 male mice/time point were infected with broth alone, H. pylori wild-type or mutant strains, or H. felis. For long-term studies to evaluate the effect of gender on cancer development, 22 female and 26 male mice were similarly infected. All experiments were approved by the MIT Animal Care Committee. H. felis was

H. pylori colonization efficiency and localization

Success of H. pylori challenge was defined as histologic and/or culture/quantitative PCR positivity. All mice challenged with H. pylori strain B128 or the cagE− mutant were successfully infected. Using Warthin-Starry staining (Figure 1A) coupled with an independent H. pylori stain (Figure 1B), small clusters of argyrophilic spiral bacteria were identified along the gastric surface and within pits and glands. To specifically distinguish H. pylori from transmigrating bacteria, genus-specific

Discussion

Recent investigations into mechanisms that underlie H. pylori-induced gastric cancer have emphasized that disease risk involves specific and choreographed interactions between pathogen and host, which, in turn, are dependent upon H. pylori strain and host genotypes. For example, Figueiredo et al. demonstrated that a synergistic effect on gastric cancer risk is present when virulence determinants of infecting H. pylori isolates, such as vacA s1 and m1 alleles and cagA, were examined in

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    ☆

    Supported in part by National Institutes of Health grants DK 58587 (to R.M.P.), AI 37750 and RR 07036 (to J.G.F.), and CA 93405 (to T.C.W.); by the F. D. H. N. Fiterman Foundation Award; and by the Medical Research Service of the Department of Veterans Affairs.

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    Copyright © 2003 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.