Gastroenterology

Gastroenterology

Volume 118, Issue 1, January 2000, Pages 36-47
Gastroenterology

Alimentary Tract
Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer,☆☆

https://doi.org/10.1016/S0016-5085(00)70412-4Get rights and content

Abstract

Background & Aims: Hypergastrinemia occurs frequently in association with acid 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 felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice. Results: INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor α. 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 >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (≤8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P ≤ 0.05). Conclusions: These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

GASTROENTEROLOGY 2000;118:36-47

Section snippets

Animals

The insulin-gastrin (INS-GAS) transgenic mice have been described previously12, 13 and are free of specific pathogens. Animals were housed in a microisolator, solid-bottomed polycarbonate cages, fed a commercially prepared pelleted diet, and given water ad libitum. For time-course studies involving ECL and parietal cell numbers, serum gastrin levels, and maximal acid secretion, a minimum of 4 mice were used for each time point. For long-term studies, 8 INS-GAS mice and 18 wild-type FVB/N mice

Hypergastrinemic (INS-GAS) mice show initial increases followed by sustained decreases in acid secretion and parietal cell number

To investigate long-term effects of hypergastrinemia on the gastric mucosa, we studied INS-GAS transgenic mice, which have a chimeric transgene in which the human gastrin gene is transcribed from the rat insulin I promoter.12 These mice express human heptadecapeptide gastrin (G-17) in the pancreatic β cells, which is then secreted into the circulation. We analyzed the effects of increased gastrin secretion over time in these mice and found that the changes could be divided into 2 distinct

Discussion

This study shows that transgenic mice with moderate hypergastrinemia have increased parietal cell numbers and acid secretion up to about 4 months of age. Thereafter, parietal cell numbers and acid secretion decrease gradually and there is increased expression of TGF-α family growth factors and a progression toward gastric cancer. These processes are exacerbated by the presence of Helicobacter infection. The phenotype in hypergastrinemic transgenic mice is distinct from that in rats with

References (46)

  • S Tsutsui et al.

    Induction of heparin binding epidermal growth factor–like growth factor and amphiregulin mRNAs by gastrin in the rat stomach

    Biochem Biophys Res Commun

    (1997)
  • T Watanabe et al.

    Helicobacter pylori infection induces gastric cancer in Mongolian gerbils

    Gastroenterology

    (1998)
  • Y Miyazaki et al.

    Gastrin induces heparin-binding epidermal growth factor–like growth factor in rat gastric epithelial cells transfected with gastrin receptor

    Gastroenterology

    (1999)
  • EM El-Omar et al.

    Helicobacter pylori infection and chronic gastric acid hyposecretion

    Gastroenterology

    (1997)
  • A Varro et al.

    Processing of the gastrin precursor. Modulation of phosphorylated, sulfated, and amidated products

    J Biol Chem

    (1990)
  • T Azuma et al.

    Effects of bombesin on the release of glycine–extended progastrin (gastrin G) in rat antral tissue culture

    Gastroenterology

    (1987)
  • VD Huebner et al.

    Purification and structural characterization of progastrin-derived peptides from a human gastrinoma

    J Biol Chem

    (1991)
  • R Hakanson et al.

    Trophic effects of gastrin

    Scand J Gastroenterol

    (1991)
  • RA Komorowski et al.

    Hyperplastic gastropathy. Clinicopathologic correlation

    Am J Surg Pathol

    (1991)
  • HF Helander et al.

    Stereologic investigations of human gastric mucosa. II. Oxyntic mucosa from patients with Zollinger–Ellison syndrome

    Scand J Gastroenterol

    (1992)
  • EC Klinkenberg-Knol et al.

    Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety

    Ann Intern Med

    (1994)
  • G Mulholland et al.

    Helicobacter pylori related hypergastrinemia is the result of selective increase in gastrin 17

    Gut

    (1993)
  • TC Wang et al.

    Pancreatic gastrin stimulates islet differentiation of TGF-alpha–induced ductular precursor cells

    J Clin Invest

    (1993)
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      Citation Excerpt :

      Transgenic mouse models were introduced to allow researchers in the gastric cancer field more precise control over the tumor initiating events. The INS-GAS transgenic mice were designed to excessively express the gastric hormone, gastrin, under control of the insulin promoter [189,190]. These mice develop gastric atrophy, dysplasia, and gastric cancer [167].

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    Address requests for reprints to: Timothy C. Wang, M.D., Massachusetts General Hospital, Gastrointestinal Unit, GRJ 724, 32 Fruit Street, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617) 726-3673.

    ☆☆

    Supported by National Institutes of Health (NIH) grant RO1 CA67529 (to T.C.W. and J.G.F.), by a Veterans Administration Merit Review and NIH grants (to J.R.G.), and by Swedish MRC 32X-13108 (to D.C.).

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