Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130.
OBJECTIVE
We have shown that mice with a mutation in gp130 (gp130(757F/F)), the signal transducing receptor for interleukin (IL)-6 family cytokines, have chronic gastric inflammation and develop distal stomach tumors associated with deregulated phosphorylated STAT3 expression. This model recapitulates many characteristics of intestinal-type gastric cancer in humans.


METHODS
To evaluate the role of IL-6 and IL-11 as ligands regulating tumor growth and submucosal invasion, we compared tumor characteristics of gp130(757F/F) mice with gp130(757F/F) mice lacking IL-6 or mature T and B cells.


RESULTS
As a result of the gp130(757F/F) mutation, expression of IL-6 and IL-11 was greatly up-regulated concomitant with activation of STAT3 and development of tumors. However, the lack of IL-6 or T and B cells did not impact on tumor growth. While IL-6 did not regulate tumor growth or tumor vascularization, gp130(757F/F)/IL-6(-/-) mice showed approximately 10-20-fold more submucosal tumor invasion, reduced mononuclear inflammatory cell infiltrate, and greater IL-11 and matrix metalloproteinase (MMP)-13 and MMP-9 synthesis than gp130(757F/F) mice. Expression of MMP-13 was largely restricted to tumor-associated stroma, but MMP-9 was also expressed in polymorphonuclear cells and a subset of epithelial cells. In addition, treatment with recombinant IL-11 stimulated expression of MMP-13 and MMP-9 in stomachs of wild-type mice.


CONCLUSIONS
Increased submucosal invasion in gp130(757F/F)/IL-6(-/-) mice could not be explained by increased vascularization or reduced immunosurveillance but was most likely facilitated by augmented metalloproteinase activity driven by elevated IL-11 levels.
Howlett
Meegan
M
Department of Medicine, University of Melbourne at Western Hospital, Footscray, Australia.
Judd
Louise M
LM
Jenkins
Brendan
B
La Gruta
Nicole L
NL
Grail
Dianne
D
Ernst
Matthias
M
Giraud
Andrew S
AS
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D001483:Base Sequence; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D005753:Gastric Mucosa / Q000276:immunology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017403:In Situ Hybridization; D017370:Interleukin-11 / Q000235:genetics / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics
D015703:Antigens, CD; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D017370:Interleukin-11; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130