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).
- "Entrez Gene: CXCL12 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1)".
- De La Luz Sierra M, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R, Zhang HH, Fales H, Tosato G (April 2004). "Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity". Blood 103 (7): 2452–9. doi:10.1182/blood-2003-08-2857. PMID 14525775.
- Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (September 1996). "A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)". J. Exp. Med. 184 (3): 1101–9. doi:10.1084/jem.184.3.1101. PMC 2192798. PMID 9064327.
- Ara T, Nakamura Y, Egawa T, Sugiyama T, Abe K, Kishimoto T, Matsui Y, Nagasawa T (April 2003). "Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1)". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5319–23. doi:10.1073/pnas.0730719100. PMC 154343. PMID 12684531.
- Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS (August 2003). "Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy". Lancet 362 (9385): 697–703. doi:10.1016/S0140-6736(03)14232-8. PMID 12957092.
- Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (August 1998). "Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice". Proc. Natl. Acad. Sci. U.S.A. 95 (16): 9448–53. doi:10.1073/pnas.95.16.9448. PMC 21358. PMID 9689100.
- Zheng H, Fu G, Dai T, Huang H (September 2007). "Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway". J. Cardiovasc. Pharmacol. 50 (3): 274–80. doi:10.1097/FJC.0b013e318093ec8f. PMID 17878755.
- Kryczek I, Wei S, Keller E, Liu R, Zou W (March 2007). "Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis". Am. J. Physiol., Cell Physiol. 292 (3): C987–95. doi:10.1152/ajpcell.00406.2006. PMID 16943240.
- Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A (March 2001). "Involvement of chemokine receptors in breast cancer metastasis". Nature 410 (6824): 50–6. doi:10.1038/35065016. PMID 11242036.
- Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U (September 2009). "CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival". Eur. J. Cancer 45 (14): 2579–87. doi:10.1016/j.ejca.2009.06.026. PMID 19646861.
- Wendt MK, Cooper AN, Dwinell MB (February 2008). "Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells". Oncogene 27 (10): 1461–71. doi:10.1038/sj.onc.1210751. PMID 17724466.
- Welford, AF; Biziato, D; Coffelt, SB; Nucera, S; Fisher, M; Pucci, F; Di Serio, C; Naldini, L et al. (2011). "TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice.". The Journal of Clinical Investigation 121 (5): 1969–73. doi:10.1172/JCI44562. PMC 3083764. PMID 21490397
- , Cancer Research UK blog.
- Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B. (August 1996). "The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.". Nature 382 (6594): 833–5. doi:10.1038/382833a0. PMID 8752281.
- Bleul et al. (1996). "The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry". Nature 382 (6594): 829–833. doi:10.1038/382829a0. PMID 8752280.
- Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F (October 2005). "The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes". J. Biol. Chem. 280 (42): 35760–6. doi:10.1074/jbc.M508234200. PMID 16107333.
- Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (September 2006). "A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development". J. Exp. Med. 203 (9): 2201–13. doi:10.1084/jem.20052144. PMC 2118398. PMID 16940167.
- Cruz-Orengo, L.; Holman, D. W.; Dorsey, D.; Zhou, L.; Zhang, P.; Wright, M.; McCandless, E. E.; Patel, J. R. et al. (2011). "CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity". Journal of Experimental Medicine 208 (2): 327–339. doi:10.1084/jem.20102010. PMC 3039853. PMID 21300915.
- Shirozu M, Nakano T, Inazawa J, et al. (August 1995). "Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene". Genomics 28 (3): 495–500. doi:10.1006/geno.1995.1180. PMID 7490086.
- Deloukas P, Earthrowl ME, Grafham DV, et al. (May 2004). "The DNA sequence and comparative analysis of human chromosome 10". Nature 429 (6990): 375–81. doi:10.1038/nature02462. PMID 15164054.
Further reading 
- Kucia M, Reca R, Miekus K, et al. (2005). "Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis". Stem Cells 23 (7): 879–94. doi:10.1634/stemcells.2004-0342. PMID 15888687.
- Kryczek I, Wei S, Keller E, et al. (2007). "Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis". Am. J. Physiol., Cell Physiol. 292 (3): C987–95. doi:10.1152/ajpcell.00406.2006. PMID 16943240.
- Stellos K, Gawaz M (2007). "Platelets and stromal cell-derived factor-1 in progenitor cell recruitment". Semin. Thromb. Hemost. 33 (2): 159–64. doi:10.1055/s-2007-969029. PMID 17340464.
- Arya M, Ahmed H, Silhi N, et al. (2007). "Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration". Tumour Biol. 28 (3): 123–31. doi:10.1159/000102979. PMID 17510563.