This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oshima, M. Articles by Taketo, M. M. Search for Related Content PubMed PubMed Citation Articles by Oshima, M. Articles by Taketo, M. M.

Hyperplastic Gastric Tumors with Spasmolytic Polypeptide–Expressing Metaplasia Caused by Tumor Necrosis Factor-–Dependent Inflammation in Cyclooxygenase-2/Microsomal Prostaglandin E Synthase-1 Transgenic Mice

¹ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto and ² Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

Requests for reprints: Makoto Mark Taketo, Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé, Sakyo, Kyoto 606-8501, Japan. Phone: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp.

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- (TNF-; Tnf), interleukin-1 receptor- 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-1ß 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-–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-–dependent inflammation, together with eradication of Helicobacter, can be an effective prevention strategy for gastric cancer.

This article has been cited by other articles:

				X. Guo, H. Oshima, T. Kitmura, M. M. Taketo, and M. Oshima Stromal Fibroblasts Activated by Tumor Cells Promote Angiogenesis in Mouse Gastric Cancer J. Biol. Chem., July 11, 2008; 283(28): 19864 - 19871. [Abstract] [Full Text] [PDF]

				B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target Pharmacol. Rev., September 1, 2007; 59(3): 207 - 224. [Abstract] [Full Text] [PDF]

				T. Tsukamoto, T. Mizoshita, and M. Tatematsu Animal Models of Stomach Carcinogenesis Toxicol Pathol, August 1, 2007; 35(5): 636 - 648. [Abstract] [Full Text] [PDF]

				J. R. Goldenring and S. Nomura Differentiation of the Gastric Mucosa III. Animal models of oxyntic atrophy and metaplasia. Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G999 - G1004. [Abstract] [Full Text] [PDF]