Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway.
OBJECTIVE
Accumulating evidence indicates that prostaglandin E(2) (PGE(2)), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE(2) pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE(2) in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes.


METHODS
We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE(2) level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice.


RESULTS
K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development.


CONCLUSIONS
Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE(2) pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.
Oshima
Hiroko
H
Division of Genetics, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. oshimam@kenroku.kanazawa-u.ac.jp
Matsunaga
Akihiro
A
Fujimura
Takashi
T
Tsukamoto
Tetsuya
T
Taketo
Makoto M
MM
Oshima
Masanobu
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005753:Gastric Mucosa / Q000473:pathology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D053539:Keratin-19 / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000071876:Prostaglandin-E Synthases; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051155:Wnt1 Protein / Q000235:genetics* / Q000378:metabolism*
D053539:Keratin-19; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone