Stromal cell-derived factor 1

The stromal cell-derived factor 1 (SDF-1) also known as C-X-C motif chemokine 12 (CXCL12) is a is_associated_with::chemokine is_associated_with::protein that in humans is encoded by the CXCL12 is_associated_with::gene.

Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the is_associated_with::chemokine family, members of which activate is_associated_with::leukocytes and are often induced by proinflammatory stimuli such as is_associated_with::lipopolysaccharide, TNF, or IL1. The chemokines are characterized by the presence of 4 conserved is_associated_with::cysteines that form 2 is_associated_with::disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, the cysteine residues are adjacent to each other. In the CXC subfamily, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group.

Structure
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 is_associated_with::cysteines, which form two is_associated_with::disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening is_associated_with::amino acid.

Chemotaxis
CXCL12 is strongly is_associated_with::chemotactic for is_associated_with::lymphocytes. During embryogenesis it directs the migration of hematopoietic cells from foetal is_associated_with::liver to is_associated_with::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 is_associated_with::macrophages to breast tumours in mice in response to the experimental anti-cancer drug is_associated_with::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 is_associated_with::CXCR4, the receptor for CXCL12, with is_associated_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.

CXCL12 is expressed in the area of inflammatory bone destruction. It is chemotactic for is_associated_with::mesenchymal stem cells and mediates their suppressive effect on osteoclastogenesis.

Other
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 is_associated_with::brain, is_associated_with::thymus, is_associated_with::heart, is_associated_with::lung, is_associated_with::liver, is_associated_with::kidney, is_associated_with::spleen and is_associated_with::bone marrow).

Receptor
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.

Gene
The gene for CXCL12 is located on human is_associated_with::chromosome 10. In human and mouse both CXCL12 and CXCR4 show high identity of sequence: 99% and 90%, respectively.