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Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway
Hiroko Oshima1, Akihiro Matsunaga, Takashi Fujimura
1Division of Genetics, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. oshimam@kenroku.kanazawa-u.ac.jp
Gastroenterology
|October 13, 2006
Summary
Activating both Wnt signaling and prostaglandin E(2) (PGE(2)) pathways in mice promotes gastric tumorigenesis. This study reveals how these pathways interact to drive the development of undifferentiated gastric tumors.
Area of Science:
- Gastroenterology
- Cancer Biology
- Molecular Oncology
Background:
- Prostaglandin E(2) (PGE(2)), a cyclooxygenase 2 (COX-2) product, and the Wnt pathway are implicated in gastric cancer development.
- The precise molecular mechanisms linking Wnt and PGE(2) pathways to gastric tumorigenesis are not fully understood.
Purpose of the Study:
- To investigate the combined roles of Wnt and PGE(2) signaling in gastric cancer.
- To examine the phenotypes of transgenic mice engineered to activate both pathways.
Main Methods:
- Generated K19-Wnt1 transgenic mice to activate Wnt1 in the gastric mucosa.
- Crossed K19-Wnt1 mice with K19-C2mE mice (expressing COX-2 and mPGES-1 for increased PGE(2)) to create compound transgenic mice.
- Analyzed gastric phenotypes in both K19-Wnt1 and K19-Wnt1/C2mE mice.
Main Results:
- K19-Wnt1 mice exhibited suppressed epithelial differentiation and preneoplastic lesions with macrophage accumulation.
- Co-expression of COX-2 and mPGES-1 in K19-Wnt1 mice led to dysplastic gastric tumors by 20 weeks.
- Mucous cell metaplasia was observed in K19-Wnt1/C2mE mice as early as 5 weeks, preceding tumor formation.
Conclusions:
- Wnt signaling maintains gastric progenitor cell undifferentiation.
- Simultaneous activation of Wnt and PGE(2) pathways drives dysplastic gastric tumors via a metaplasia-carcinoma sequence.
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