Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130
| Autor: | Diane Grail, Arthur Shulkes, Louise M. Judd, Jill Moverley, Andrew S. Giraud, Barbara M. Alderman, Brendan J. Jenkins, Matthias Ernst, Meegan Howlett, Chris Dow |
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| Rok vydání: | 2004 |
| Předmět: |
Adenoma
medicine.medical_specialty Down-Regulation Muscle Proteins Mice Transgenic Nerve Tissue Proteins In situ hybridization medicine.disease_cause Mice Antigens CD Stomach Neoplasms Internal medicine Gastrins Lithostathine Cytokine Receptor gp130 medicine Animals Epidermal growth factor receptor education Gastrin education.field_of_study Binding Sites Membrane Glycoproteins Hepatology biology Calcium-Binding Proteins Mucins Gastroenterology Trefoil factor 2 Cancer medicine.disease Endocrinology Gastric Mucosa Tumor progression Mutation Cancer research biology.protein Trefoil Factor-1 Trefoil Factor-2 Peptides Carcinogenesis Transforming growth factor |
| Zdroj: | Gastroenterology. 126:196-207 |
| ISSN: | 0016-5085 |
| Popis: | 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: gp130 757F/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 gp130 757F/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: gp130 757F/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. |
| Databáze: | OpenAIRE |
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