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 journalArticle

200 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

Fingerprint

Catenins
Macrophages
Tumors
Stomach
Tumor Necrosis Factor-alpha
Cells
Neoplasms
Carcinogenesis
Glycogen Synthase Kinase 3
Chemical activation
Phosphorylation
Macrophage Activation
Helicobacter Infections
Conditioned Culture Medium
Gastric Mucosa
Infiltration
Stomach Neoplasms
Mucous Membrane
Stabilization

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Medicine(all)

Cite this

Oguma, K., Oshima, H., Aoki, M., Uchio, R., Naka, K., Nakamura, S., ... 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

Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells. / Oguma, Keisuke; Oshima, Hiroko; Aoki, Masahiro; Uchio, Ryusei; Naka, Kazuhito; Nakamura, Satoshi; Hirao, Atsushi; Saya, Hideyuki; Taketo, Makoto Mark; Oshima, Masanobu.

In: EMBO Journal, Vol. 27, No. 12, 18.06.2008, p. 1671-1681.

Research output: Contribution to journalArticle

Oguma, K, Oshima, H, Aoki, M, Uchio, R, Naka, K, Nakamura, S, Hirao, A, Saya, H, Taketo, MM & Oshima, M 2008, 'Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells', EMBO Journal, vol. 27, no. 12, pp. 1671-1681. https://doi.org/10.1038/emboj.2008.105
Oguma, Keisuke ; Oshima, Hiroko ; Aoki, Masahiro ; Uchio, Ryusei ; Naka, Kazuhito ; Nakamura, Satoshi ; Hirao, Atsushi ; Saya, Hideyuki ; Taketo, Makoto Mark ; Oshima, Masanobu. / Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells. In: EMBO Journal. 2008 ; Vol. 27, No. 12. pp. 1671-1681.
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