2354

Epidemiologically, Helicobacter pylori infection is closely linked to gastric cancer. Helicobacter infection induces expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in the gastric mucosa, resulting in increased level of prostaglandin E2 in the stomach. We showed recently that transgenic mice expressing both COX-2 and mPGES-1 (K19-C2mE mice) develop hyperplastic gastric tumors associated with inflammatory responses through macrophage accumulation and activation. To investigate possible roles of inflammatory cytokines and host immune reaction in gastric tumorigenesis, we introduced knockout mutations for tumor necrosis factor (TNF)-α (Tnf), interleukin (IL)-1 receptor α chain (Il1r1) and Rag 2 (Rag2) genes, respectively, into K19-C2mE mice. Among the compound mutants, Tnf (-/-) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced epithelial cell proliferation. On the other hand, tumorigenesis remained unaffected in either compound mutants of K19-C2mE with Il1r1 or Rag2 mutation, indicating that neither IL-1β signaling nor T cell/B cell response was required for development of hyperplastic tumors. Importantly, spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) in the K19-C2mE stomach was also suppressed in the Tnf (-/-) K19-C2mE mice. Gastric metaplasia to the SPEM lineage has been considered as a preneoplastic lesion of gastric cancer. Moreover, epithelial cell differentiation and migration was suppressed in the K19-C2mE stomach, which could be reversed by treatment with neutralizing anti-TNF-α antibody. These results indicate that TNF-α-dependent inflammation is responsible for development of SPEM and suppression of epithelial differentiation. Therefore, it is possible that inhibition of TNF-α-dependent inflammation together with eradication of Helicobacter is an effective prevention strategy for gastric cancer. Oshima H. et al. EMBO J, 23: 1669, 2004 Oshima M. et al. Cancer Res, 65: 9147, 2005

[Proc Amer Assoc Cancer Res, Volume 47, 2006]