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

Research output: Contribution to journalArticlepeer-review

254 Citations (Scopus)


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
Issue number12
Publication statusPublished - 2008 Jun 18
Externally publishedYes


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

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology


Dive into the research topics of 'Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells'. Together they form a unique fingerprint.

Cite this