Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs and monocytes as a major node in this network. Experimental Design: Monocyte co-cultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow monocytes. Orthotopic, syngeneic colon carcinoma models using co-transplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Results: Our co-culture studies identify IL-6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that co-operate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, co-transplanted CAFs elevated IL-6 and GM-CSF levels, TAM infiltration and metastasis. These pathological effects were dramatically reversed by joint IL-6 and GM-CSF blockade. A positive correlation between GM-CSF and IL-6 expression and disease course was observed by meta-analyses of the clinical data. Conclusions: Our studies indicate a significant reappraisal of the role of IL-6 and GM-CSF in metastasis and implicate CAFs as the 'henchmen' for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL-6 is a promising new approach for inhibiting metastasis.
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