Matsunaga Akihiro

Oshima Hiroko

Oshima Masanobu

Taketo Makoto Mark

Kanazawa University Repository for Academic Resources

―  ― 70Host inflammatory responses and gastrointestinal tumorigenesis  H. Oshima, A. Matsunaga*, M.M. Taketo* and M. Oshima (*Department of Pharmacology, Kyoto University Graduate School of Medicine)   Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid biosynthesis, plays a key role in gastrointestinal carcinogenesis.  Among various prostanoids, prostaglandin E2 (PGE2) appears to be most responsible for cancer development.  It has been shown that Helicobacter pylori infection induces expression of COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the gastric mucosa, resulting in increased level of PGE2 in the stomach.  To investigate the role of PGE2 in gastric tumorigenesis, we constructed transgenic mice (K19-C2mE) expressing COX-2 and mPGES-1 in the gastric mucosa.  The transgenic mice developed hyperplastic gastric tumors associated with inflammatory responses.  To further investigate the roles of PGE2-dependent host inflammatory and immune responses in gastric tumorigenesis, we introduced knockout mutations for tumor necrosis factor (TNF)-α, interleukin (IL)-1 receptor α chain and Rag 2 genes, respectively, into K19-C2mE mice.  Among the compound mutants, only TNF-α (−/−) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced epithelial cell proliferation (Figure).  Importantly, spasmolytic polypeptide-expressing metaplasia (SPEM) in the K19-C2mE stomach was also suppressed in the TNF-α (−/−) K19-C2mE mice.  Gastric metaplasia to the SPEM lineage has been considered as a preneoplastic lesion of gastric cancer.  These results indicate that TNF-α-dependent inflammation caused by increased PGE2 is responsible for development of hyperplastic tumors and SPEM (Figure).  Therefore, it is possible that inhibition of TNF-α-dependent inflammation together with eradication of Helicobacter is an effective prevention strategy for gastric cancer.        H. pylori infection gastric stem cell  progenitor cells  Terminal differentiation SPEM cells  TNF-α-associated COX-2/mPGES-1  inflammation  

Host inflammatory responses and gastrointestinal tumorigenesis

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Host inflammatory responses and gastrointestinal tumorigenesis

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