Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells

• Keisuke Oguma ^[1] ; Hiroko Oshima ^[1] ; Masahiro Aoki ^[2] ; Ryusei Uchio ^[1] ; Kazuhito Naka ^[1] ; Satoshi Nakamura ^[4] ; Atsushi Hirao ^[1] ; Hideyuki Saya ^[3] ; Makoto Mark Taketo ^[2] ; Masanobu Oshima ^[1]
  1. [1] Kanazawa University

     Kanazawa University

     Japón

     
  2. [2] Kyoto University

     Kyoto University

     Kamigyō-ku, Japón

     
  3. [3] Keio University

     Keio University

     Japón

     
  4. [4] Department of Biomedical Research and Development, Link Genomics, Tokyo, Japan

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 27, Nº. 12, 2008, págs. 1671-1681
• Idioma: inglés
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• Resumen

  • 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.