Abstract

The majority of deaths caused by cancer are due to metastasis. This fact indicates that metastatic tumours are resistant to available therapies. Tumors consist not only of malignant cells but also a wide-range of non-mutated normal cells including those of the immune system.  Among these immune cells, macrophages are particularly abundant in a wide range of tumors. Our studies focussing on breast cancer have indicated that macrophages promote tumor progression to malignancy in mouse models.  Recently we have identified a sub-population of metastasis-associated macrophages (MAM) that help metastatic tumour cells seed at distant sites and prosper. Lineage tracking indicates that MAMs derive from the Ly6Chi population of circulating monocytes that are recruited by tumour cell produced chemokine CCL2 at the metastatic site. CCL2 signals via CCR2 in the monocytes to upregulate expression of CCL3 that in turn binds to CCR1 in an autocrine manner. This signaling pathway results in the retention of the monocytes and their differentiation into MAMs that then deliver a survival signal to the tumour cells. Differentiation of the monocytes to MAMs involves several intermediate steps whereby these cells also attain immunosuppressive phenotypes against activated T cells. Inhibition of any of these steps of MAM recruitment or differentiation using genetic or inhibitor approaches reduces metastasis in these mouse models. Such data suggest that therapeutics directed against the pro-tumoral functions of these myeloid cells might become part of a strategy that will improve survival of patients with metastatic disease.