Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice

Masanobu Oshima, Hiroko Oshima, Akihiro Matsunaga, Makoto Mark Taketo
Cancer Research 2005 October 15, 65 (20): 9147-51
We showed recently that Helicobacter infection induces expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in the mouse stomach, and that transgenic mice expressing both cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (K19-C2mE mice) develop hyperplastic gastric tumors with inflammatory histopathology. To investigate possible roles of proinflammatory cytokines and acquired immunity in the gastric hyperplasia of K19-C2mE mice, we introduced knockout mutations for tumor necrosis factor-alpha (TNF-alpha; Tnf), interleukin-1 receptor-alpha chain (Il1r1), and Rag2 genes, respectively. Among the compound mutants, only the Tnf (-/-) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced cell proliferation. In contrast, tumorigenesis remained unaffected in either compound mutants of K19-C2mE containing Il1r1 or Rag2 mutation, indicating that neither interleukin-1beta signaling nor T cell/B cell response was required for the 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, indicating that TNF-alpha-dependent inflammation is responsible for SPEM development. Because gastric metaplasia to the SPEM lineage is considered as a preneoplastic lesion of gastric cancer, it is possible that inhibition of TNF-alpha-dependent inflammation, together with eradication of Helicobacter, can be an effective prevention strategy for gastric cancer.

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