Mouse models of gastric tumors: Wnt activation and PGE2 induction.
Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E(2) (PGE(2)) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE(2) pathway in gastric mucosa induces development of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE(2) pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE(2) pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE(2) pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis.
Oshima
Hiroko
H
Division of Genetics, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Japan.
Oshima
Masanobu
M
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051153:Wnt Proteins; D015232:Dinoprostone