SCF and IL-33 regulate mouse mast cell pro-inflammatory functions during tumor progression

Background: Mast cells (MC) are innate immune cells that derive from bone marrow pluripotent cells and mature under the influence of the stem cell factor (SCF). They are mainly known for their involvement in Ig-E mediated allergic reactions and also observed in tumor microenvironment. However, MC-derived mediators can either exert pro-tumorigenic functions, causing progression and spread of the tumor, or anti-tumorigenic functions, limiting tumor growth. Purpose: The aim of this study is to evaluate the role and phenotypes of MC in CRC development, identifying the molecular pathways able to modulate MC functions during tumor progression. Results: We used a conventional colitis-induced CRC mouse model (AOM/DSS) and observed by flow cytometry that the frequency of c-kit/FceRIa double positive MCs increases in colon of DSS-induced colitis mice, respect to control mice and in the tumor of AOM/DSS mice compared to unaffected surrounding tissue. We have then evaluated MC functionality by assessing the presence of cytokines by flow cytometry and RNA-SCOPE and found that tumor-infiltrating MCs showed a much higher production of both IL-6 and TNF-a compared to unaffected tissue. Moreover, we observed higher levels of SCF and IL-33 on tumor lesions compared with unaffected colon tissue. By employing primary cultures of peritoneum-derived MCs we observed that SCF can act synergistically to induce the production of TNFa and IL-6 through the phosphorylation of key signaling molecules and transcription factors. Conclusion: Overall, our data suggest that MCs are activated in the tumor microenvironment by the combined action of SCF and IL-33 and contribute to initial transformation by releasing proinflammatory cytokines.