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Hyperplastic gastric tumors induced by activated macrophages in COX‐2/mPGES‐1 transgenic mice
Author(s) -
Oshima Hiroko,
Oshima Masanobu,
Inaba Kayo,
Taketo Makoto M
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600170
Subject(s) - biology , metaplasia , proinflammatory cytokine , genetically modified mouse , carcinogenesis , hyperplasia , prostaglandin e2 , prostaglandin e , transgene , gastric mucosa , helicobacter pylori , prostaglandin , cancer research , stomach , inflammation , medicine , immunology , endocrinology , cancer , biochemistry , genetics , gene
Cyclooxygenase‐2 (COX‐2), the rate‐limiting enzyme for prostanoid biosynthesis, plays a key role in gastrointestinal carcinogenesis. Among various prostanoids, prostaglandin E 2 (PGE 2 ) appears to be most responsible for cancer development. To investigate the role of PGE 2 in gastric tumorigenesis, we constructed transgenic mice simultaneously expressing COX‐2 and microsomal prostaglandin E synthase (mPGES)‐1 in the gastric epithelial cells. The transgenic mice developed metaplasia, hyperplasia and tumorous growths in the glandular stomach with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics treatment did not affect the macrophage accumulation. Notably, treatment of the transgenic mice with lipopolysaccharides induced proinflammatory cytokines through Toll‐like receptor 4 in the gastric epithelial cells. These results indicate that an increased level of PGE 2 enhances macrophage infiltration, and that they are activated through epithelial cells by the gastric flora, resulting in gastric metaplasia and tumorous growth. Furthermore, Helicobacter infection upregulated epithelial PGE 2 production, suggesting that the COX‐2/mPGES‐1 pathway contributes to the Helicobacter ‐associated gastric tumorigenesis.