Abstract
Prostaglandin E2 (PGE2) and Wnt signaling are two indispensable pathways for gastrointestinal tumorigenesis. As a downstream product of cyclooxygenase 2 (COX-2), PGE2 plays a key role in gastric tumorigenesis. The Wnt pathway also plays a causal role in gastric carcinogenesis. However, crosstalk or cooperation of these pathways for tumorigenesis remains poorly understood yet. To investigate their roles in gastric cancer development, we have generated two transgenic lines that activate either of two pathways in the gastric epithelial cells. First, we constructed K19-C2mE mice that expressed COX-2 and mPGES-1 simultaneously using the keratin 19 (K19) promoter. K19-C2mE mice showed increased PGE2 level in the gastric mucosa that caused mucous cell metaplasia and hyperplasia. We next constructed K19-Wnt1 transgenic mice expressing Wntl in the gastric mucosa driven by K19 promoter. K19- Wnt1 mice had a significant suppression of epithelial differentiation, and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. However, K19-Wnt1 mice did not develop gastric tumors. We then crossed K19-Wnt1 mice with K19-C2mE to obtain K19-Wnt1/C2mE compound transgenic mice. Importantly, simultaneous activation of PGE2 and Wnt pathways converted the preneoplastic lesions in the K19-Wntl mice into malignant gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the compound K19-Wnt1/ C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. These results indicate that cooperation of Wnt and PGE2 pathways causes malignant gastric tumor development through the metaplasia-carcinoma sequence. Accordingly, K19- Wnt1/ C2mE mouse model is a useful tool to study the genetic mechanism of gastric carcinogenesis through activation of the Wnt and PGE2 pathways.
