Differential Regulation of Gastric Tumor Growth by Cytokines That Signal Exclusively Through the Coreceptor gp130

Background & Aims: 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 ∼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.

Abbreviations used in this paper:  ECM, extracellular matrix , ERK, extracellular signal–regulated kinase , GAPDH, glyceraldehyde-3-phosphate dehydrogenase , IL, interleukin , MMP, matrix metalloproteinase , NK, natural killer , PCR, polymerase chain reaction , PMN, polymorphonuclear , pYSTAT3, phosphorylated STAT3 , TIMP, tissue inhibitor of matrix metalloproteinase