Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3

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)-1 beta from macrophages, which induced phosphorylation of GSK3 beta, stabilized beta-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-1 beta-specific antibodies, or silencing of IL-1 beta in THP1 macrophages, showed that IL-1 beta 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-1 beta and thus for the activation of beta-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-1 beta in macrophages, and therefore-in a vitamin D receptor-dependent manner-inhibited 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. Oncogene (2009) 28, 3892-3902; doi:10.1038/onc.2009.247; published online 24 August 2009