Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130.
OBJECTIVE
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)-alpha 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.
Judd
Louise M
LM
Department of Medicine, University of Melbourne, Melbourne, Australia.
Alderman
Barbara M
BM
Howlett
Meegan
M
Shulkes
Arthur
A
Dow
Chris
C
Moverley
Jill
J
Grail
Diane
D
Jenkins
Brendan J
BJ
Ernst
Matthias
M
Giraud
Andrew S
AS
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D050822:Cytokine Receptor gp130; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000473:pathology; D005755:Gastrins / Q000097:blood; D051847:Lithostathine; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins; D009124:Muscle Proteins; D009154:Mutation; D009419:Nerve Tissue Proteins; D010455:Peptides / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2
D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D005755:Gastrins; C494200:Il6st protein, mouse; D051847:Lithostathine; D008562:Membrane Glycoproteins; D009077:Mucins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C497615:Reg1 protein, mouse; C481546:TFF2 protein, mouse; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D050822:Cytokine Receptor gp130