Chemokine Receptor Signaling and the Hallmarks of Cancer

The chemokines are a family of chemotactic cytokines that mediate their activity by acting on seven-transmembrane-spanning G protein-coupled receptors. Both the ability of the chemokines and their receptors to form homo- and heterodimers and the promiscuity of the chemokine-chemokine receptor interaction endow this protein family with enormous signaling plasticity and complexity that are not fully understood at present. Chemokines were initially identified as essential regulators of homeostatic and inflammatory trafficking of innate and adaptive leucocytes from lymphoid organs to tissues. Chemokines also mediate the host response to cancer. Nevertheless, chemokine function in this response is not limited to regulating leucocyte infiltration into the tumor microenvironment. It is now known that chemokines and their receptors influence most-if not all-hallmark processes of cancer; they act on both neoplastic and untransformed cells in the tumor microenvironment, including fibroblasts, endothelial cells (blood and lymphatic), bone marrow-derived stem cells, and, obviously, infiltrating leucocytes. This review begins with an overview of chemokine and chemokine receptor structure, to better define how chemokines affect the proliferation, survival, stemness, and metastatic potential of neoplastic cells. We also examine the main mechanisms by which chemokines regulate tumor angiogenesis and immune cell infiltration, emphasizing the pro- and antitumorigenic activity of this protein superfamily in these interrelated processes.