Genetic Alteration and Host Reaction in Gastrointestinal Tumorigenesis

Abstract

Accumulating evidence indicates that host reaction including inflammatory responses is a critical component of tumor development. To investigate the role of microenvironment for gastrointestinal tumor development, we have constructed series of genetically engineered mouse models, such as Apc^Δ716 mice, COX-2 gene knockout mice, and COX-2/m PGES-1 transgenic mice. Although homozygous Apc^Δ716 mice were embryonically lethal, heterozygotes developed benign polyps in entire intestinal tract caused by loss of the wild-type Apc gene. Accordingly, activation of Wnt signaling triggered by disruption of Apc gene is a direct cause for intestinal polyp development. We next constructed compound mutants of the Apc^Δ716 with COX-2 knockout mice. COX-2 is a key enzyme for prostaglandin biosynthesis and induced in the stromal cells of variety of tumor tissues including Apc^Δ716 polyps. Homozygous disruption of COX-2 genes in the Apc^Δ716 mice reduced the number of polyps dramatically by 80% compared with COX-2 wild-type mice. Moreover, treatment of Apc^Δ716 mice with a COX-2 selective inhibitor, rofecoxib, also suppressed intestinal polyposis. These results, taken together, indicate that induction of COX-2 in the stromal cells is responsible for tumor cell proliferation (promotion), whereas Wnt activation in the epithelial cells is required for transformation (initiation) . To further investigate the role of COX-2 pathway in the microenvironment, we constructed transgenic mice (K19-C2mE mice) expressing both COX-2 and mPGES-1 simultaneously. The K19-C2mE mice developed hyperplastic tumors in the glandular stomach with submucosal inflammatory responses. Antibiotic treatment suppressed inflammatory cell infiltration and mucosal hyperplasia, suggesting that host responses caused by bacterial infection is responsible for epithelial hyperplasia. Importantly, mucosal macrophages were still found after treatment with antibiotics, indicating that macrophage recruitment was the primary effect of increased level of PGE₂. Furthermore, mucosal macrophages in the K19-C2mE mice were activated by bacterial infection, producing large amount of proinflammatory cytokines such as TNF-α. It is possible that these cytokines as downstream of COX-2 pathway contribute to enhanced proliferation of the epithelial cells in the tumor promotion stage.