Hyperplastic gastric tumor of K19-C2mE transgenic mouse

Cyclooxygenase-2 (COX-2), the 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. To investigate the role of PGE2 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 PGE2 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 PGE2 production, suggesting that the COX-2/mPGES-1 pathway contributes to the Helicobacter associated gastric tumorigenesis. Keywords: disease state analysis We used DNA Chip Consortium Mouse Microarray v2.0 (oligonucleotide microarray) to examine the gene expression profile in the hyperplastic gastric tumors of K19-C2mE transgenic mice. Each DNA chip contains 65-mer oligonuleotide probes for 21,997 mouse transcripts. We examined expression profile in the hyperplastic gastric tumors of the K19-C2mE transgenic mice compared with normal glandular stomach of the littermate wild-type mice by analyses of three individual arrays from both groups.