Chemokines are a superfamily of small secreted peptides. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells. The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. The chemokine family currently includes some 45 human ligands and 19 receptors, although this list may grow as more chemokine/receptor like candidate genes exist in the human genome. Each chemokine contains 65 ~ 120 amino acids, with molecular weight of 8 ~ 10 kD.
Chemokine receptors belong to G-protein-coupled receptors. However, cells can only respond to a chemokine in a given organ or tissue if the cell possesses a receptor that specifically recognizes the chemokine that is present in the local environment. In this way, each chemokine-chemokine receptor combination may direct a different inflammatory response and this response can be tailored by the body based on the type of injury, irritation, or other threat. Different chemokines are made in different tissues at different times and different chemokine receptors are expressed on the surface of different types of inflammatory cells. Chemokines and other chemoattractants direct inflammatory responses by serving to precisely coordinate the movement of cells of the immune system. Inappropriate activity of the chemokine network is at the core of numerous autoimmune and inflammatory conditions. For example, in Crohn’s disease, dysregulation of either the chemokine CCL25 or the chemokine receptor to which it binds, CCR9, is thought to selectively attract inflammatory T cells to, and subsequently attack, tissues in the digestive tract.
Originally studied because of their role in inflammation, chemokines and their receptors are now known to play a crucial part in directing the movement of mononuclear cells throughout the body, engendering the adaptive immune response and contributing to the pathogenesis of a variety of diseases. Many chemokine/receptor pairs are expressed in tumours, not only by cancer cells but also by cells of the tumour microenvironment, including cells of the stroma (endothelial cells, fibroblasts) and leukocytes, thus contributing to the cross-talk between the tumour and its microenvironment to control tumour growth and progression. The interaction of chemokines, their receptors, growth factors, inflammatory with cancer cells forms a complex network at the tumour site, responsible for the overall progression or rejection of the tumour. In the malignancy context, chemokines play diverse effects, most of them deriving from their ability to induce cell migration. The ability of chemokines to enhance the motility of leukocytes, endothelial cells, and/or tumour cells is a key factor in determining the cancer establishment and progression. Depending on their specific expression pattern on target cells, on tumour type and on tumour microenvironment factors, several chemokines support malignancy, while others can at times inhibit this process. On the basis of these evidences, the characterization of the different chemokine networks in various types of cancer cells may foster better knowledge for understanding the immune-related mechanisms of cancer development and application in cancer immunotherapy.
Chemokines have potential as therapeutic agents in several ways. One can use modified antagonists of the proteins themselves or of their N-termini; use monoclonal antibodies directed either to a specific chemokine or to its receptor; and use small molecules that inhibit their receptors. Current knowledge of chemokine biology should propel the field toward a better understanding of the contribution that chemokine dysregulation makes to chronic inflammation, excess or impaired angiogenesis, and, equally important but more challenging, their role in pathological wound healing. Available information in preclinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies.
Chemokines are derived from their ability to induce directed chemotaxis in nearby responsive cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Different chemokines are made in different tissues at different times and different chemokine receptors are expressed on the surface of different types of inflammatory cells. Inappropriate activity of the chemokine network is at the core of numerous autoimmune and inflammatory conditions.
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