Chemokines and chemokine receptors
Introduction
Cancer is a collection of diseases characterized by abnormal and uncontrolled cellular growth caused primarily by genetic mutations. Based on their role in cancer progression, driver genes can be classified into two main categories: oncogenes and tumor suppressor genes. Oncogene addiction refers to the phenomenon that certain tumours depend on one or more activated oncogenes, also known as driver oncogenes, to maintain their malignant biological phenotype.
Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.
Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and C. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, includes CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13. This classification is not strict, for example, CCL20 can act also as pro-inflammatory chemokine. Others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. These chemokines are formed under pathological conditions (on pro-inflammatory stimuli, such as IL-1, TNF-alpha, LPS, or viruses) and actively participate in the inflammatory response attracting immune cells to the site of inflammation, such as CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10.
Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production
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