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

Keisuke Oguma, Hiroko Oshima, Masahiro Aoki, Ryusei Uchio, Kazuhito Naka, Satoshi Nakamura, Atsushi Hirao, Hideyuki Saya, Makoto Mark Taketo, Masanobu Oshima

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215 Citations (Scopus)

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 Apc Δ716 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.

Original languageEnglish
Pages (from-to)1671-1681
Number of pages11
JournalEMBO Journal
Volume27
Issue number12
DOIs
Publication statusPublished - 2008 Jun 18

Keywords

  • Gastric cancer
  • Inflammation
  • Macrophage
  • Tumour necrosis factor-α
  • Wnt

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Oguma, K., Oshima, H., Aoki, M., Uchio, R., Naka, K., Nakamura, S., Hirao, A., Saya, H., Taketo, M. M., & Oshima, M. (2008). Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells. EMBO Journal, 27(12), 1671-1681. https://doi.org/10.1038/emboj.2008.105