Macrophage-derived IL-1Β stimulates Wnt signaling and growth of colon cancer cells: A crosstalk interrupted by vitamin D"3

P. Kaler, L. Augenlicht, L. Klampfer

Research output: Contribution to journalArticle

159 Scopus citations

Abstract

Tumor-associated macrophages mediate the link between inflammation and cancer progression. Here, we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of interleukin (IL)-1Β from macrophages, which induced phosphorylation of GSK3Β, stabilized Β-catenin, enhanced T-cell factor (TCF)-dependent gene activation and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti-IL-1Β-specific antibodies, or silencing of IL-1Β in THP1 macrophages, showed that IL-1Β was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)1 in THP1 macrophages was essential for the induction of IL-1Β and thus for the activation of Β-catenin signaling in tumor cells. Vitamin D"3, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1Β in macrophages, and thereforein a vitamin D receptor-dependent mannerinhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D"3 exerts its chemopreventive activity by interrupting a crosstalk between tumor epithelial cells and the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)3892-3902
Number of pages11
JournalOncogene
Volume28
Issue number44
DOIs
StatePublished - Nov 2009

Keywords

  • Colon cancer
  • IL-1
  • Macrophages
  • STAT1
  • Vitamin D

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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