Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells; a crosstalk interrupted by vitamin D(3)

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 IL-1β from macrophages, which induced phosphorylation of GSK3β, stabilized β-catenin, enhanced 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, revealed that IL-1β was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of STAT1 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 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 cross-talk between tumor epithelial cells and the tumor microenvironment.