Abstract
BackgroundWe recently reported that colon tumor cells stimulate macrophages to release IL-1β, which in turn inactivates GSK3β and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Principal FindingsHere we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1β by neutralizing IL-1β antibody, or silencing of IL-1β in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1β was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Δψ) and activation of caspases were prevented by macrophages or by recombinant IL-1β. Pharmacological inhibition of IL-1β release from macrophages by vitamin D3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1β failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIκB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1β stabilized Snail in tumor cells in an NF-κB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1β, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.SignificanceWe have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1β, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D3 halts this amplifying loop by interfering with the release of IL-1β from macrophages. Accordingly, vitamin D3 sensitizes tumor cells to TRAIL-induced apoptosis, suggesting that the therapeutic efficacy of TRAIL could be augmented by this readily available chemopreventive agent.
Highlights
Inflammation contributes to tumor progression by establishing conditions that support tumor cell growth and survival and increase their metastatic potential
We demonstrated that macrophages induce several prosurvival signaling pathways in colon cancer cells, including NF-kB, AKT and Wnt signaling [7,8], suggesting that the presence of macrophages could affect the response of tumor cells to therapeutic agents
Two types of tumor microenvironment mediated drug resistance (TMMDR) have been described: resistance that is mediated by soluble factors produced by the cells in the tumor microenvironment and resistance that develops as a result of the adhesion of tumor cells to stromal fibroblasts or to components of the extracellular matrix [18]
Summary
Inflammation contributes to tumor progression by establishing conditions that support tumor cell growth and survival and increase their metastatic potential. Chronic inflammation has been shown to predispose to development of a variety of tumors, a striking example being inflammatory bowel disease, which is associated with elevated risk of colon cancer [1]. It appears that colon cancers that do not develop as a complication of inflammatory bowel disease are driven by inflammation, because it has been shown that regular use of NSAIDs lowers the mortality from sporadic colon cancer and results in regression of adenomas in FAP patients, who inherit a mutation in the Apc gene [2]. We recently reported that colon tumor cells stimulate macrophages to release IL-1b, which in turn inactivates GSK3b and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells
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