Gastroenterology

Gastroenterology

Volume 126, Issue 1, January 2004, Pages 196-207
Gastroenterology

Basic-alimentary tract
Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130

https://doi.org/10.1053/j.gastro.2003.10.066Get rights and content

Abstract

Background & Aims: We have developed a mouse model of gastric cancer that resembles human intestinal-type adenocarcinoma. The aim of this study was to determine the identity and temporal changes in mediators of IL-6 signaling regulating tumor development. Methods: gp130757F/F Mice that lack the SHP2-binding site on the IL-6 family receptor gp130 and have increased STAT 3 activity and wild-type littermates were used. Cohorts were assessed by quantitative histology and immunohistochemistry for gastric cell phenotype and proliferation markers from 4 to 40 weeks of tumor development. Northern blotting and in situ hybridization were used to quantify expression of the tumor suppressor TFF1 and the mitogens gastrin and Reg I. Expression of epidermal growth factor receptor (EGFr) and its ligands was measured by RT-PCR analysis. Age-matched differences in gene expression profiles were tested by ANOVA. Results: Hyperplastic antral tumors with inflammation and ulceration were evident in gp130757F/F mice at 4 weeks of age and reached maximum size by 20 weeks. Tumor progression was marked by gastritis, atrophy, intestinal metaplasia, dysplasia, and submucosal invasion after 30 weeks. Both TFF1 and gastrin expression were progressively inhibited during tumorigenesis, whereas Reg I was stimulated. The EGFr and its ligands transforming growth factor (TGF)-α and heparin-binding EGF had increased expression corresponding to maximal tumor growth. Conclusions: gp130757F/F Mice rapidly develop distal stomach tumors, with loss of SHP2/Erk/AP-1 transcriptional regulation exemplified by decreased TFF1 expression and increased STAT1/3 regulated genes such as Reg I. Tumor development occurs in a hypogastrinemic environment. Balanced IL-6 signaling is required for maintaining gastric homeostasis.

Section snippets

Mice

gp130757F/F mice were developed as previously described.7 Briefly, a “knock-in” mutation was generated such that amino acid substitutions Y757F and V760A were introduced into the gp130 gene. All mice were kept on a 129 Sv-J/C57BL/6 mixed background, and control age-matched mice were littermates. Mice were housed in a standard animal facility that has been shown to be free of H. pylori infection. All animal experiments were performed with the approval of the Melbourne Health Directorate Animal

Age-dependent development of gastric adenomas in gp130757F/F mice

Lesions in the stomachs of gp130757F/F mice develop with 100% penetrance in a predictable, age-dependent manner. By 6 weeks of age, discrete adenomas were macroscopically evident, usually just proximal to the pylorus, and this was often accompanied by focal gastric ulceration coincident with the adenoma itself (Figure 1B). In older animals, adenomas had increased in number, become significantly larger, and more heavily vascularized and were no longer restricted to the antrum but were also

Discussion

The gp130757F/F mouse was originally developed to genetically dissect the contribution of the SHP-2/Erk pathway in mediating intracellular signals elicited by IL-6 family cytokines. An unexpected finding was the rapid and fully penetrant development of distal stomach tumors, resulting from the loss of gp130-dependent SHP-2/Erk/AP-1 signaling. This is accompanied by exaggerated STAT3 activation because of disruption of negative reciprocal regulation of the 2 pathways.7 In this study, we have

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Supported by grants from the National Health and Medical Research Council of Australia.

1

L.M.J. and B.M.A. contributed equally to this work.

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