Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130
AuthorHowlett, M; Judd, LM; Jenkins, B; La Gruta, NL; Grail, D; Ernst, M; Giraud, AS
PublisherW B SAUNDERS CO-ELSEVIER INC
University of Melbourne Author/sJudd, Louise; La Gruta, Nicole; Ernst, Matthias; Giraud, Andrew; JENKINS, BRENDAN; HOWLETT, MEEGAN
AffiliationMedicine - Royal Melbourne And Western Hospitals
Document TypeJournal Article
CitationsHowlett, M., Judd, L. M., Jenkins, B., La Gruta, N. L., Grail, D., Ernst, M. & Giraud, A. S. (2005). Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130. GASTROENTEROLOGY, 129 (3), pp.1005-1018. https://doi.org/10.1053/j.gastro.2005.06.068.
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C1 - Journal Articles Refereed
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 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.
KeywordsGastroenterology and Hepatology; Oncology and Carcinogenesis; Cancer and Related Disorders; Digestive System Disorders
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