The chemokine system and cancer

Friday, 10/02/2012  |   Chemokines  |  no comments

Frances R Balkwill. The Journal of Pathology. Special Issue: The Cell Biology of Disease. Volume 226, Issue 2, pages 148–157, January 2012. DOI: 10.1002/path.3029 Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body. Cancer cells acquire the ability to subvert the chemokine system, such that these molecules and their receptors become important regulators of cell movement into and out of the tumour microenvironment and major players in cancer biology. Chemokines and their receptors are involved in all stages of cancer development, influencing the cellular composition of the tumour microenvironment, malignant cell survival and metastatic spread. From their earliest stages, cancers harness this intricate and tightly regulated network to generate a corrupt version of a system that, in healthy vertebrates, is necessary for embryonic development, tissue homeostasis and successful immune responses. A greater understanding of the chemokine system in malignancy can not only give us important new insights into cancer biology but also suggest new treatment approaches. If drugs that target the chemokine system show success in chronic inflammatory disease over the next few years, we have enough preclinical data to warrant trialling them in cancers. Figure 1. The chemokine wheel. This cartoon shows major constituents of the chemokine systems, the G-protein-coupled cell-surface receptors and the chemokine ligands. The ‘inflammatory’ chemokines are inducible and involved in all aspects of the immune response. The ‘homeostatic’ chemokines are involved in development and normal physiology. Atypical chemokine receptors are generally ‘silent’ and act as negative regulators of the systems, ‘decoys’ that reduce chemokine levels.

Viral chemokines and receptors allow the pathogens to modulate immune responses to infection. Inflammatory, homeostatic and atypical chemokine receptors are all found in the tumour microenvironment. Another chemokine receptor, CXCR7, which also binds to CXCL12 and CXCL11, is shown in the homeostatic group, but there is some evidence that it is an atypical chemokine receptor Chemokines (chemo-attractant cytokines) are a group of small proteins that act together with their cell surface receptors, in development, normal physiology and immune responses, to direct cells to specific locations throughout the body 1 , 2 . Gradients of extracellular matrix-bound or soluble chemokines control leukocyte migration and positioning within tissues and direct their patterns of recirculation by inducing extra- or intravasation. They may also control movement of other cell types, such as adult stem cells and endothelial cells. The chemokine system evolved with the vertebrates and there are nearly 50 human genes that encode chemokine ligands, with more than 20 corresponding human chemokine receptor genes, the latter being seven-transmembrane G-protein-coupled receptors, GPCRs. Chemokines are divided into four different groups, CXC, CC, CX3C or C, depending on the position of the conserved cysteine residue, and receptor nomenclature essentially follows that of the chemokines, ie CC chemokines bind to CC chemokine receptors, CXC ligands bind to CXC receptors

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