title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto and Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsunaga
authors.forename: Makoto Mark
authors.initials: MM
authors.lastname: Taketo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016481:Helicobacter Infections / Q000150:complications; D006965:Hyperplasia; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011230:Precancerous Conditions / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology*; D000071876:Prostaglandin-E Synthases; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C451060:spasmolytic polypeptide; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases