Stromal cell-derived factor 1
|Chemokine (C-X-C motif) ligand 12|
PDB rendering based on 1a15.
|RNA expression pattern|
Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the intercrine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. The intercrines are characterized by the presence of 4 conserved cysteines that form 2 disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, which includes beta chemokine, the cysteine residues are adjacent to each other. In the CXC subfamily, which includes alpha chemokine, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group.
SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid.
CXCL12 is strongly chemotactic for lymphocytes. During embryogenesis it directs the migration of hematopoietic cells from foetal liver to bone marrow and the formation of large blood vessels. Mice that were knocked-out for CXCL12 gene were lethal before the birth or within just 1 hour of life.
In adulthood, CXCL12 plays an important role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism. It is this function of CXCL12 that makes it a very important factor in carcinogenesis and the neovascularisation linked to tumour progression. CXCL12 also has a role in tumor metastasis where cancer cells that express the receptor CXCR4 are attracted to metastasis target tissues that release the ligand, CXCL12. In breast cancer, however, increased expression of CXCL12 determines a reduced risk of distant metastasis.
In 2011, CXCL12 was shown to be responsible for recruiting macrophages to breast tumours in mice in response to the experimental anti-cancer drug combretastatin A-4 phosphate, which damages tumour blood vessels. This macrophage recruitment is believed to stimulate tumour blood vessel growth, counteracting the effects of the drug.
Blocking CXCR4, the receptor for CXCL12, with Plerixafor (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, it is presumed by preventing macrophages from being recruited to tumours.
By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains. CXCL12 was shown to be expressed in many tissues in mice (including brain, thymus, heart, lung, liver, kidney, spleen and bone marrow).
The receptor for this chemokine is CXCR4, which was previously called LESTR or fusin. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently it was suggested that CXCL12 may also bind the CXCR7 receptor. The CXCR4 receptor is a G-Protein Coupled Receptor that can be bound by man-made proteins such as Granuloycte-Colony Stimulating Factors (G-CSFs). G-CSFs bind CXCR4 to prevent SDF-1 binding, which results in the inhibition of the pathway. Neutrophils in the bone marrow, for example, are bound by G-CSFs and are released into the bloodstream to help fight diseases or infections following chemotherapy treatment. Drugs like Neupogen (a therapeutic G-CSF) dislodge neutrophils in the bone marrow to help fight diseases resulting from neutropenia (often caused by chemotherapy treatments).
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