Skip to main content
Log in

CXCR4–SDF-1 Signalling, Locomotion, Chemotaxis and Adhesion

  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

Chemokines, small pro-inflammatory chemoattractant cytokines, that bind to specific G-protein-coupled seven-span transmembrane receptors present on plasma membranes of target cells are the major regulators of cell trafficking. In addition some chemokines have been reported to modulate cell survival and growth. Moreover, compelling evidence is accumulating that cancer cells may employ several mechanisms involving chemokine–chemokine receptor axes during their metastasis that also regulate the trafficking of normal cells. Of all the chemokines, stromal-derived factor-1 (SDF-1), an α-chemokine that binds to G-protein-coupled CXCR4, plays an important and unique role in the regulation of stem/progenitor cell trafficking. First, SDF-1 regulates the trafficking of CXCR4+ haemato/lymphopoietic cells, their homing/retention in major haemato/lymphopoietic organs and accumulation of CXCR4+ immune cells in tissues affected by inflammation. Second, CXCR4 plays an essential role in the trafficking of other tissue/organ specific stem/progenitor cells expressing CXCR4 on their surface, e.g., during embryo/organogenesis and tissue/organ regeneration. Third, since CXCR4 is expressed on several tumour cells, these CXCR4 positive tumour cells may metastasize to the organs that secrete/express SDF-1 (e.g., bones, lymph nodes, lung and liver). SDF-1 exerts pleiotropic effects regulating processes essential to tumour metastasis such as locomotion of malignant cells, their chemoattraction and adhesion, as well as plays an important role in tumour vascularization. This implies that new therapeutic strategies aimed at blocking the SDF-1–CXCR4 axis could have important applications in the clinic by modulating the trafficking of haemato/lymphopoietic cells and inhibiting the metastatic behaviour of tumour cells as well. In this review, we focus on a role of the SDF-1–CXCR4 axis in regulating the metastatic behaviour of tumour cells and discuss the molecular mechanisms that are essential to this process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adams GB, Chabner KT, Foxall RB, Weibrecht KW, Rodrigues NP, Dombkowski D, Fallon R, Poznansky MC, Scadden DT (2003) Heterologous cells cooperate to augment stem cell migration, homing, and engraftment. Blood 101: 45–51.

    Google Scholar 

  • Ara T, Nakamura Y, Egawa T, Sugiyama T, Abe K, Kishimoto T, Matsui Y, Nagasawa T (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 USA 100: 5319–5323.

    Google Scholar 

  • Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M, Pleasure SJ (2002) The chemokine SDF-1 regulates migration of dentate granule cells. Development 129: 4249–4260.

    Google Scholar 

  • Baj-Krzyworzeka M, Majka M, Pratico D, Ratajczak J, Vilaire G, Kijowski J, Reca R, Janowska-Wieczorek A, Ratajczak MZ (2002) Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp Hematol 30: 450–459.

    Google Scholar 

  • Barbero S, Bajetto A, Bonavia R, Porcile C, Piccioli P, Pirani P, Ravetti JL, Zona G, Spaziante R, Florio T, Schettini G (2002) Expression of the chemokine receptor CXCR4 and its ligand stromal cells-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro. Ann NY Acad Sci 973: 60–69.

    Google Scholar 

  • Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G (2003) Stromal cell-derived factor 1α stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinase 1/2 and Akt. Cancer Res 63: 1969–1974.

    Google Scholar 

  • Bertolini F, Dell'Agnola C, Mancuso P, Rabascio C, Burlini A, Monestiroli S, Gobbi A, Pruneri G, Martinelli G (2002) CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res 62: 3106–3112.

    Google Scholar 

  • Bonavia R, Bajetto A, Barbero S, Pirani P, Florio T, Schettini G (2003) Chemokines and their receptors in the CNS: Expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation. Toxicol Lett 139: 181–189.

    Google Scholar 

  • Broxmeyer HE, Cooper S, Kohli L, Hangoc G, Lee Y, Mantel C, Clapp DW, Kim CH (2003a) Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo. J Immunol 170: 421–429.

    Google Scholar 

  • Broxmeyer HE, Kohli L, Kim CH, Lee Y, Mentel C, Cooper S, Hangoc G, Shaheen M, Li X, Clapp DW(2003b) Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cell through CXCR4and Gα i proteins and enhances engraft-ment of competitive, repopulating stem cells. J Leukoc Biol 73: 630–638.

    Google Scholar 

  • Cheng ZJ, Zhao J, Sun Y, Hu W, Wu YL, Cen B, Wu GC, Pei G (2000) β-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization and this implicates multiple interaction sites between β-arrestin and CXCR4. J Biol Chem 275: 2479–2485.

    Google Scholar 

  • Chernock RD, Cherla RP, Ganju RK (2001) SHP2 and cbl participate in á-chemokine receptor CXCR4-mediated signaling pathways. Blood 97: 608–615.

    Google Scholar 

  • Christopherson KW 2nd, Hangoc G, Broxmeyer HE (2002) Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34 progenitor cells. J Immunol 169: 7000–7008.

    Google Scholar 

  • Christopherson KW, Cooper S, Broxmeyer HE (2003) Cell surface pepti-dase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor Cells. Blood 101: 4680–4686.

    Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420: 860–867.

    Google Scholar 

  • Crane IJ, Wallace CA, McKillop-Smith S, Forrester JV (2000) CXCR4 receptor expression on human retinal pigment epithelial cells from blood-retina barrier leads to chemokine secretion and migration in response to stromal cell-derived factor 1α. J Immunol 165: 4372–4378.

    Google Scholar 

  • Crazzolara R, Kreczy A, Mann G, Heitger A, Eibl G, Fink FM, Mohle R, Meister B (2001) High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol 115: 545–553.

    Google Scholar 

  • Delgado MB, Clark-Lewis I, Loetscher P, Langen H, Thelen M, Baggiolini M, Wolf M (2001) Rapid inactivation of stromal cell-derived factor-1 by cathepsin G associated with lymphocytes. Eur J Immunol 31: 699–707.

    Google Scholar 

  • Ding Z, Issekutz TB, Downey GP, Waddell TK (2003) l-selectin stimulation enhances functional expression of surface CXCR4 in lymphocytes: Implications for cellular activation during adhesion and migration. Blood 101: 4245–4252.

    Google Scholar 

  • Farzan M, Mirzabekov T, Kolchinsky P, Wyatt R, Cayabyab M, Gerard NP, Gerard C, Sodroski J, Choe H (1999) Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96: 667–676.

    Google Scholar 

  • Fernandis AZ, Cherla RP, Ganju RK (2003) Differential regulation of CXCR4-mediated T-cell chemotaxis and mitogen-activated protein kinase activation by the membrane tyrosine phosphatase, CD45. J Biol Chem 278: 9536–9543.

    Google Scholar 

  • Floridi F, Trettel F, Di Bartolomeo S, Ciotti MT, Limatola C (2003) Signalling pathways involved in the chemotactic activity of CXCL12 in cultured rat cerebellar neurons and CHP100 neuroepithelioma cells. J Neuroimmunol 135: 38–46.

    Google Scholar 

  • Fox JA, Ung K, Tanlimco SG, Jirik FR (2002) Disruption of a single Pten allele augments the chemotactic response of B lymphocytes to stromal cell-derived factor-1. J Immunol 169: 49–54.

    Google Scholar 

  • Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13: 555–562.

    Google Scholar 

  • Ganju RK, Brubaker SA, Meyer J, Dutt P, Yang Y, Qin S, Newman W, Groopman JE (1998) The á-chemokine stromal cell-derived factor-1α binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem 273: 23169–23175.

    Google Scholar 

  • Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, Ben-Baruch A (2001) A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the develop-ment of bone marrow metastasis in neuroblastoma. J Immunol 167: 4747–4757.

    Google Scholar 

  • Gewirtz AM, Sokol DL, Ratajczak MZ (1998) Nucleic acid therapeutics: State of the art and future prospects. Blood 92: 712–736.

    Google Scholar 

  • Haribabu B, Richardson RM, Fisher I, Sozzani S, Peiper SC, Horuk R, Ali H (1997) Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem 272: 28726–28731.

    Google Scholar 

  • Hatch H, Zheng D, Jorgensen ML, Petersen BE (2002) SDF-1α /CXCR4: A mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells4: 339–351.

    Google Scholar 

  • Hecht I, Cahalon L, Hershkoviz R, Lahat A, Franitza S, Lider O (2003) Heterologous desensitization of T cell functions by CCR5 and CXCR4 ligands: Inhibition of cellular signaling, adhesion and chemotaxis. Int Immunol 15: 29–38.

    Google Scholar 

  • Helbig G, Christopherson II KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H (2003) NF-ê B promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278: 21631–21638.

    Google Scholar 

  • Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, Klotman ME, Diaz GA (2003) Mutation in the chemokine receptor. gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genetics 34: 70–74.

    Google Scholar 

  • Hidalgo A, Sanz-Rodriguez F, Rodriguez-Fernandez JL, Albella B, Blaya C, Wright N, Cabanas C, Prosper F, Gutierrez-Ramos JC, Teixido J (2001) Chemokine stromal cell-derived factor-1alpha modu-lates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells. Exp Hematol 29: 345–355.

    Google Scholar 

  • Homey B, Muller A, Zlotnik A (2002) Chemokines: Agents for the immunotherapy or cancer. Nat Rev 2: 175–184.

    Google Scholar 

  • Honczarenko M, Le Y, Glodek AM, Majka M, Campbell JJ, Ratajczak MZ, Silberstein LE (2002) CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor. Blood 100: 2321–2329.

    Google Scholar 

  • Horuk R (2001) Chemokine receptors. Cytokine Growth Factor Rev 12: 313–335.

    Google Scholar 

  • Hwang JH, Hwang JH, Chung HK, Kim DW, Hwang ES, Suh JM, Kim H, You KH, Kwon OY, Ro HK, Jo DY, Shong M (2003) CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. J Clin Endocrinol Metab 88: 408–416.

    Google Scholar 

  • Jankowski K, Kucia M, Wysoczynski M, Janowska-Wieczorek A, Ratajczak MZ(2003) Both hepatocyte growth/scatter factor (HGF/SF) and stromal derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF/SF enhances their resistance to radio-chemotherapy. Exp Hematol 31(Suppl): 201.

    Google Scholar 

  • Janowska-Wieczorek A, Marquez LA, Dobrowsky A, Ratajczak MZ, Cabuhat ML (2000) Differential MMP and TIMP production by human marrow and peripheral blood CD34 cells in response to chemokines. Exp Hematol 28: 1274–1285.

    Google Scholar 

  • Janowska-Wieczorek A, Majka M, Kijowski J, Baj-Krzyworzeka M, Reca R, Turner AR, Ratajczak J, Emerson SG, Kowalska MA, Ratajczak MZ (2001) Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment. Blood 98: 3143–3149.

    Google Scholar 

  • Kijima T, Maulik G, Ma PC, Tibaldi EV, Turner RE, Rollins B, Sattler M, Johnson BE, Salgia R (2002) Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 62: 6304–6311.

    Google Scholar 

  • Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2001) The SDF-1–CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 19: 453–466.

    Google Scholar 

  • Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M(2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand recep-tor system in pancreatic cancer: A possible role for tumor progression. Clin Cancer Res 6: 3530–3535.

    Google Scholar 

  • Kremer KN, Humphreys TD, Kumar A, Qian NX, Hedin KE (2003) Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extra-cellular signal-regulated protein kinase by the stromal cell-derived factor-1alpha/CXCL12 chemokine. J Immunol 171: 360–367.

    Google Scholar 

  • Kowalska MA, Ratajczak J, Hoxie J, Brass LF, Gewirtz A, Poncz M, Ratajczak MZ (1999) Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: Determination of response to stromal-derived factor-1 by megakaryo-cytes and platelets.. Br J Haematol 104: 220–229.

    Google Scholar 

  • Kowalska MA, Ratajczak MZ, Majka M, Jin J, Kunapuli S, Brass L, Poncz M(2000) Stromal cell-derived factor-1 and macrophage-derived chemokine: 2 chemokines that activates platelets. Blood 96: 50–57.

    Google Scholar 

  • Kucia M, Ratajczak J, Reca R, Janowska-Wieczorek A, Ratajczak MZ (2004) Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. Blood Cells Mol. Dis. 32: 52–57.

    Google Scholar 

  • Lapidot T, Kollet O (2002) The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2mnull mice. Leukemia 16: 1992–2003.

    Google Scholar 

  • Lataillade JJ, Clay D, Bourin P, Herodin F, Dupuy C, Jasmin C, Le Bousse-Kerdiles MC (2002) Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G0/G1 transition in CD34+ cells: Evidence for an autocrine/paracrine Mechanism. Blood 99: 1117–1129.

    Google Scholar 

  • Lazarini F, Tham TN, Casanova P, Arenzana-Seisdedos F, Dubois-Dalcq M (2003) Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia 42: 139–148.

    Google Scholar 

  • Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, Ratajczak MZ (2002) CXCR4–SDF-1 signaling is active in rhabdo-myosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 100: 2597–2606.

    Google Scholar 

  • Liotta LA (2001) An attractive force in metastasis. Nature 410: 24–25.

    Google Scholar 

  • Lukacs NW, Berlin A, Schols D, Skerlj RT, Bridger GJ (2002) AMD3100,a CXCR4antagonist, attenuates allergic lung inflammation and airway hyperreactivity. Am J Pathol 160: 1353–1360.

    Google Scholar 

  • Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis and derailed cerebellar neuron migration in CXCR4-and SDF-1-deficient mice. Proc Natl Acad Sci USA 95: 9448–9453.

    Google Scholar 

  • Ma Q, Jones D, Springer TA (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10: 463–471.

    Google Scholar 

  • Mackay CR (2001) Chemokines: Immunology's high impact factors. Nat Immunol 2: 95–101.

    Google Scholar 

  • Majka M, Janowska-Wieczorek A, Ratajczak J, Kowalska A, Vilaire G, Pan ZK, Honczarenko M, Marquez LA, Poncz M, Ratajczak MZ (2000a) Stromal-derived factor1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. Blood 96: 4142–4151.

    Google Scholar 

  • Majka M, Ratajczak J, Kowalska MA, Ratajczak MZ (2000b) Binding of stromal derived factor-1alpha (SDF-1alpha) to CXCR4 chemokine receptor in normal human megakaryoblasts but not in platelets induces phosphorylation of mitogen-activated protein kinase p42/44 (MAPK), ELK-1 transcription factor and serine/threonine kinase AKT. Eur J Haematol 64: 164–172.

    Google Scholar 

  • Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA, Gewirtz AM, Emerson SG, Ratajczak MZ (2001) Numerous growth factors, cytokines, and chemokines are secreted by human CD34( +) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 97: 3075–3085.

    Google Scholar 

  • Majka M, Ratajczak J, Villaire G, Kubiczek K, Marquez LA, Janowska-Wieczorek A, Ratajczak MZ (2002) Thrombopoietin but not cytokines binding to gp130 protein-coupled receptors activates MAPKp42/44, AKTand STAT proteins in normal human CD34 cells, megakaryocytes and platelets. Exp Hematol 30: 751–760.

    Google Scholar 

  • Mantes S, Lacalle RA, Gomez-Mouton C, del Real G, Mira E, Martinez-AC (2001) Membrane raft microdomains in chemokine receptor function. Immunology 13: 147–157.

    Google Scholar 

  • Marquez-Curtis LA, Dobrowsky A, Montano J, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A (2001) Matrix metallo-proteinase and tissue inhibitors of metalloproteinase secretion by haematopoietic and stromal precursors and their production in normal and leukaemic long-term marrow cultures. Br J Haematol 115: 595–604.

    Google Scholar 

  • Martinez MA, Gutierrez A, Armand-Ugon M, Blanco J, Parera M, Gomez J, Clotet B, Este JA (2002) Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. AIDS 16: 2385–2390.

    Google Scholar 

  • Moepps B, Braun M, Knopfle K, Dillinger K, Knochel W, Gierschik P (2000) Characterization of a Xenopus laevis CXC chemokine receptor 4: Implications for hematopoietic cell development in the vertebrate embryo. Eur J Immunol 30: 2924–2934.

    Google Scholar 

  • Mohle R, Green D, Moore MA, Nachman RL, Rafii S (1997) Constitu-tive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94: 663–668.

    Google Scholar 

  • Muller A, Homey B, Soto H, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegul E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer Metastasis. Nature 410: 50–56.

    Google Scholar 

  • Murphy PM (2001) Chemokines and the molecular basis of cancer metastasis. N Engl J Med 345: 833–835.

    Google Scholar 

  • Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635–638.

    Google Scholar 

  • Neuhaus T, Stier S, Totzke G, Gruenewald E, Fronhoffs S, Sachinidis A, Vetter H, Ko YD (2003) Stromal cells-derived factor 1 alpha (SDF-1 alpha) induces gene-expression of early growth response-1 (Egr-1) and VEGF in human arterial endothelial cells and enhances VEGF induced cell proliferation. Cell Prolif 36: 75–86.

    Google Scholar 

  • Nguyen DH, Taub D (2002) CXCR4 function requires membrane cholesterol: Implication for HIVinfection. J Immunol 168: 4121–4126.

    Google Scholar 

  • Oh SB, Endoh T, Simen AA, Ren D, Miller RJ (2002) Regulation of calcium currents by chemokines and their receptors. J Neuroimmunol 123: 66–75.

    Google Scholar 

  • Owen SM, Rudolph D, Schols D, Fujii N, Yamamoto N, Lal RB (2002) Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds. J Med Virol 68: 147–155.

    Google Scholar 

  • Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S, Grabovsky V, Slav MM, Nagler A, Lider O, Alon R, Zipori D, Lapidot T (2000) The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: Role in transendothelial/stromal migration and engraftment of NOD.SCID mice. Blood 95: 3289–3296.

    Google Scholar 

  • Pituch-Noworolska A, Majka M, Janowska-Wieczorek A, Baj-Krzyworzeka M, Urbanowicz B, Malec E, Ratajczak MZ (2003) Circulating CXCR4-positive stem/progenitor cells compete for SDF-1 positive niches in bone marrow, muscle and neural tissues: An alternative hypothesis to stem cell plasticity. Folia Histochemica et Cytobiologica 41: 13–21.

    Google Scholar 

  • Proost P, Struyf S, Scholls D, Durinx C, Wuyts A, Lenaerts JP, De Clercq E, De Meester I, Van Damme J (1998) Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1 alpha. FEBS Lett 432: 73–76.

    Google Scholar 

  • Ratajczak J, Majka M, Kijowski J, Baj M, Pan ZK, Marquez LA, Janowska-Wieczorek A, Ratajczak MZ (2001) Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythro-poietic factors in normal human early erythroid cells. Br J Haematol 115: 195–204.

    Google Scholar 

  • Ratajczak MZ, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S, Janowska-Wieczorek A (2003) Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibro-blasts is associated with the presence of both muscle progenitors in bone marrowand hematopoietic stem/progenitor cells in muscles. Stem Cells 21: 363–371.

    Google Scholar 

  • Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J (2004) Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells “hide out” in the bone marrow. Leukemia 18: 29–40.

    Google Scholar 

  • Reca R, Mastellos D, Majka M, Marquez L, Ratajczak J, Franchini S, Glodek A, Honczarenko M, Spruce LA, Janowska-Wieczorek A, Lambris JD, Ratajczak MZ (2003) Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells and C3a enhances their homing-related responses to SDF-1. Blood 101: 3784–3793.

    Google Scholar 

  • Reiss K, Mentlein R, Sievers J, Hartmann D (2002) Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactin factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 115: 295–305.

    Google Scholar 

  • Riviere C, Subara F, Cohen-Solal K, Cordette-Lagarde V, Letestu R, Auclair C, Vainchenker W, Louache F (1999) Phenotypic and functional evidence for the expression of CXCR4 receptor during megakaryocytopoiesis Blood 93: 1511–1523.

    Google Scholar 

  • Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I, van Muijen GNP, Sanchez-Mateos P, Teixido J (2001) Expression of functional chemokine receptor CXCR3 and CXCR4 on human melanoma cells. J Biol Chem 276: 45098–45105.

    Google Scholar 

  • Roland J, Murphy BJ, Ahr B, Robert-Hebmann V, Delauzun V, Nye KE, Devaux C, Biard-Piechaczyk M (2003) Role of intracellular domains of CXCR4 in SDF-1-mediated signaling. Blood 101: 399–406.

    Google Scholar 

  • Rosu-Myles M, Gallacher L, Murdoch B, Hess DA, Keeney M, Kelvin D, Dale L, Ferguson SS, Wu D, Fellows F, Bhatia M (2000) The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. Proc Natl Acad Sci USA 19: 14626–14631.

    Google Scholar 

  • Sanchez X, Cousins-Hodges B, Aguilar T, Gosselink P, Lu Z, Navarro J (1997) Activation of HIV-1 coreceptor (CXCR4) mediates myelo-suppression. J Biol Chem 272: 27529–27531.

    Google Scholar 

  • Sanchez X, Suetomi K, Cousins-Hodges B, Horton JK, Navarro J (1998) CXCchemokines suppress proliferation of myeloid progenitor cells by activation of the CXC chemokine receptor 2. J Immunol 160: 906–910.

    Google Scholar 

  • Sandberg AA, Stone JF, Czarnecki L, Cohen JD (2001) Hematologic masquerade of rhabdomyosarcoma. Am J Hematol 68: 51–57.

    Google Scholar 

  • Sbaa-Ketata E, Courel MN, Delpech B, Vannier JP (2002) Hyaluronan-derived oligosaccharides enhance SDF-1-dependent chemotactic effect on peripheral blood hematopoietic CD34 cells. Stem Cells 20: 585–587.

    Google Scholar 

  • Schen W, Bendall LJ, Gottlieb DJ, Bradstock KF (2001) The chemokine receptor CXCR4 enhances integrin-mediated in vitro adhesion and facilitates engraftment of leukemic precursor-B cells in the bone marrow Exp Hematol 29: 1439–1447.

    Google Scholar 

  • Schier AF (2003) Chemokine signaling: Rules of attraction. Curr Biol 13: R192–R194.

    Google Scholar 

  • Schrader AJ, Lechner O, Templin M, Dittmar KEJ, Machtens S, Mengel M, Probst-Kepper M, Franzke A, Wollensak T, Gatzlaff P, Atzpodien J, Buer J, Lauber J (2002) CXCR4?CXCL12 expression and signaling in kidney cancer. Brit J Cancer 86: 1250–1256.

    Google Scholar 

  • Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Hollt V, Schulz S (2002) A dual role for SDF-1/CXCR4 chemokine receptor system in adult brain: Isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cere-bral leukocyte recruitment after focal ischemia. J Neurosci 22: 5865–5878.

    Google Scholar 

  • Su S, Mukaida N, Wang J, Zang Y, Takami A, Nakao S, Matsushima K (1997) Inhibition of immature erythroid progenitor cell proliferation by macrophage inflammatory protein-1a by interacting mainly with a C-C chemokine receptor, CCR1. Blood 90: 605–611.

    Google Scholar 

  • Sun Y, Cheng Z, Ma L, Pei G (2002) β-arrestin 2 is critically involved in CXCR4-mediated chemotaxis and this is mediated by its enhancement of p38 MAPK activation. J Biol Chem 277: 49212–49219.

    Google Scholar 

  • Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, Taichman RS (2003) Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (Pca) in vivo. J Cell Biochem 89: 462–473.

    Google Scholar 

  • Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK (2002) Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res 62: 1832–1837.

    Google Scholar 

  • Thelen M (2001) Dancing to the tune of chemokine Nat Immunol 2: 129–134.

    Google Scholar 

  • Tilton B, Ho L, Oberlin E, Loetscher P, Baleux F, Clark-Lewis I, Thelen M (2000) Signal transduction by CXC chemokine receptor 4: Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extra-cellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med 192: 313–324.

    Google Scholar 

  • Valenzuela-Fernandez A, Planchenault T, Baleux F, Staropoli I, Le-Barillec K, Leduc D, Delaunay T, Lazarini F, Virelizier JL, Chignard M, Pidard D, Arenzana-Seisdedos F (2002) Leukocyte elas-tase negatively regulates stromal cell-derived factor-1 (SDF-1)/CXCR4.Role binding and functional by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem 277: 15677–15689.

    Google Scholar 

  • Vila-Coro AJ, Rodriguez-Frade JM, De Ana AM, Moreno-Ortiz MC, Martinez-AC, Mellado M (1999) The chemokine SDF-1α triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 13: 1699–1710.

    Google Scholar 

  • Vlahakis SR, Villasis-Keever A, Gomez T, Vanegas M, Vlahakis N, Paya CV (2002) G protein-coupled chemokine receptors induced both survival and apoptotic signaling pathways. J Immunol 169: 5546–5554.

    Google Scholar 

  • Wright N, Lain de Lera T, Garcia-Moruja C, Lillo R, Garcia-Sanchez F, Caruz A, Teixido J (2003) Transforming growth factor-â 1 down-regulates expression of chemokine stromal cell-derived factor-1: Functional consequences in cell migration and adhesion. Blood 102: 1978–1984.

    Google Scholar 

  • de Wynter EA, Durig J, Cross MA, Heyworth CM, Testa NG (1998) Differential response of CD34+ cells isolated from cord blood and bone marrow to MIP-1α and the expression of MIP-1a receptors on these immature cells. Stem Cells 16: 349–356.

    Google Scholar 

  • Wysoczynski M, Reca R, Kucia M, Ross G, Ratajczak J, Janowska-Wieczorek A, Ratajczak MZ (2003) Mobilized peripheral blood stem/progenitor cells are primed by several inflammatory molecules for their chemotactic responses to SDF-1: A molecular explanation as to why mobilized peripheral blood cells engraft faster than bone marrow cells after transplantation. Exp Hematol 31(Suppl): 153.

    Google Scholar 

  • Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Boch-Marce M, Masuda H, Losorodo DW, Isner JM, Asahara T (2003) Stromal cell derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107: 1322–1328.

    Google Scholar 

  • Zeelenberg IS, Ruuls-Van Stalle L, Roos E (2001) Retention of CXCR4in the endoplasmic reticulum blocks dissemination of a T cell hybridoma. J Clin Invest 108: 269–277.

    Google Scholar 

  • Zhang W, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, Manfredi JP, Fujii N, Broach JR, Peiper SC (2002) Apoint mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40–4C are weak partial agonists. J Biol Chem 277: 24515–24521.

    Google Scholar 

  • Zhang XF, Wang JF, Matczak E, Proper JA, Groopman JE (2001) Janus kinase 2 is involved in stromal cell-derived factor-1 alpha-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. Blood 97: 3342–3348.

    Google Scholar 

  • Zou Y, Kottmann AH, Kuroda M, Taniuchi I, Littman DR(1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595–599.

    Google Scholar 

  • Zhou Y, Larsen PH, Hao C, Yong VW (2002) CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem 277: 49481–49487.

    Google Scholar 

  • Zlotnik A, Yoshie O (2000) Chemokines: A new classification system and their role in immunity. Immunity 12: 121–127.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kucia, M., Jankowski, K., Reca, R. et al. CXCR4–SDF-1 Signalling, Locomotion, Chemotaxis and Adhesion. Histochem J 35, 233–245 (2004). https://doi.org/10.1023/B:HIJO.0000032355.66152.b8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:HIJO.0000032355.66152.b8

Keywords

Navigation