1. Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells.
- Author
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Oguma, Keisuke, Oshima, Hiroko, Aoki, Masahiro, Uchio, Ryusei, Naka, Kazuhito, Nakamura, Satoshi, Hirao, Atsushi, Saya, Hideyuki, Taketo, Makoto Mark, and Oshima, Masanobu
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CARCINOGENESIS , *GASTROINTESTINAL tumors , *MACROPHAGES , *CANCER cells , *TUMOR necrosis factors , *GASTROINTESTINAL mucosa , *GASTRIC mucosa - Abstract
The activation of Wnt/β-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/β-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β-catenin activity in gastric tumorigenesis. We found β-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in ApcΔ716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-α. Furthermore, treatment with TNF-α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β-catenin accumulation. These results suggest that macrophage-derived TNF-α promotes Wnt/β-catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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