Chemokines: key players in cancer progression and metastasis

Abstract

Instructed cell migration is a fundamental component of various biological systems and is critical to the pathogenesis of many diseases including cancer. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. However, functional mechanisms of chemokine are not well implicit, which is crucial for designing new therapeutics to control tumor growth and metastasis. Multiple functions and mode of actions have been advocated for chemokines and their receptors in the progression of primary and secondary tumors. In this review, we have discussed current advances in understanding the role of the chemokines and their corresponding receptor in tumor progression and metastasis.

Figure 1

The chemokine system: Chemokines, their receptors, and predominant receptor repertoires in different leukocyte populations are listed. The selected ligands are identified with one old acronym and the new nomenclature, the first part of the name identifies the family and L stands for “ligand,” followed by a progressive number. Chemokine acronyms are as follows: BCA, B-cell activating chemokine; BRAK, breast and kidney chemokine; CTACK, cutaneous T-cell–attracting chemokine; ELC, Epstein-Barr virus–induced receptor ligand chemokine; ENA-78, epithelial cell–derived neutrophil-activating factor (78 amino acids); GCP, granulocyte chemo attractant protein; GRO, growth-related oncogene; HCC, hemofiltrate CC chemokine; IP, interferon-inducible protein; I-TAC, interferon-inducible T-cell A chemo attractant; MCP, monocyte chemo attractant protein; MDC, macrophage-derived chemokine; Mig, monokine induced by γ interferon; MIP, macrophage inflammatory protein; MPIF, myeloid progenitor inhibitory factor; NAP, neutrophil-activating protein; PARC, pulmonary and activation-regulated chemokine; RANTES, regulated upon activation normal T cell–expressed and secreted; SCM, single C motif; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine; TARC, thymus and activation-related chemokine; TECK, thymus-expressed chemokine. Ba, basophils; CC, chemokine with the first 2 cysteines in adjacent positions; Eo, eosinophils; iDC, immature dendritic cells; MC, mast cells; mDCs, mature dendritic cells; Mo, monocytes; Mø, macrophages; NK, natural killer cells; PMN, neutrophils; T act, activated T cells; T naive, naive T cells; T muc, mucosal-homing T cells; Treg, regulatory T cells; T skin, skin-homing T cells.

Figure 2

Summary of major signal transduction pathways downstream of chemokine receptors. This simplified figure depicts signaling molecules activated following chemokine receptor activation. The binding of chemokines to their respective receptors results in the activation of three main downstream signaling pathways to various cellular responses. The classical G-protein pathway activates various downstream systems including PLC, PI3K, FAK and MAPK, leading to cell adhesion, polarization and chemotaxis. Inactivating Giα using PTX can be inhibite this pathway. The activation of the JAK/STAT pathway being initiated following the tyrosine phosphorylation of activated chemokine receptors has been documented. The signaling pathways initiated by phosphorylation at serine/threonine residues on the COOH-terminus region involve the activities of GRKs and β-arrestins. This pathway is responsible for internalization and recycling/degradation of the activated receptors. Arrows indicate “activated downstream”. Question marks indicate unclear downstream signaling pathways. FAK focal adhesion kinase, PLC phospholipase C, PI3K phosphatidylinositol 3-kinase, MAPK mitogen-activated protein kinase, PTX pertussis toxin, JAK/STAT Janus kinase/Signal transducer and activator of transcription, GRKs G-protein-coupled receptor kinases.