Deciphering the cellular crosstalk that induces pro-metastatic TAMs in the tumor microenvironment

Abstract

This research makes a thematic description of the components belonging to the tumor microenvironment (such as “Cancer- associated fibroblasts (CAFs)” and “M2 type macrophages”, both of which reside in proximity to the cancer cells). This research focuses on the molecular crosstalk between CAFs and M2 macrophages, which occurs through the secretion of soluble factors, such as interleukin 6 (IL-6) and garnulaocyte-macrophage colony stimulating factor (GM-CSF). It was observed that cancer cells activated CAFs, which in turn produce M2-like macrophage-differentiating factors in vitro. We have validated this discovery in the orthotopic-syngeneic model of mouse colon cancer, by using co-injection of cancer cells with mouse-derived CAFs. In addition, antibody blockade of IL-6 and GM-CSF cooperatively reduced tumor growth and metastasis in this model. This research results enhances our understanding of the key signaling factors between cancer cells, fibroblasts and immune cells to promote metastasis. Moreover, it has the potential to contribute to the development of new anticancer drugs that control the microenvironment surrounding developing tumors. Furthermore, the activation of CAFs in our orthotopic syngeneic colon carcinoma model was investigated. It was observed that that CAF activation is also decreased by anti-IL6 and anti-GM-CSF treatment. Expression of a well-known CAF activation marker (α-smooth muscle actin (α-SMA)) was tested, and was found to have decreased expression in colon tumor tissue after dual blockade. Additionally, we bserved that TGF-β treatment activates normal fibroblasts into the CAF phenotype in vitro, whereas IL10 (a major cytokine of the M2-like TAMs secretome) had no significant effect. TGF-β expression could also be induced in bone marrow-derived monocytes by treatment with IL6 and/or GM-CSF. These additional data suggest that blockade strategies targeting TAM activation by CAF (such as dual treatment of anti-IL6 and anti-GM-CSF) or the reciprocal CAF activation by TAMs (via TGF-β secretion) can stimulate this positive feedback loop within the tumor ecological niche. These findings that IL6 and GM-CSF induce TGF-β expression in differentiating monocytes can be of great significance, because TGF-β-mediated programming of the stroma initiates metastasis in colorectal cancer.