Cancer and Metastasis Reviews

, Volume 29, Issue 4, pp 709–722 | Cite as

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

  • Xueqing Sun
  • Guangcun Cheng
  • Mingang Hao
  • Jianghua Zheng
  • Xiaoming Zhou
  • Jian Zhang
  • Russell S. Taichman
  • Kenneth J. Pienta
  • Jianhua Wang


Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.


Chemokines CXCL12 / CXCR4 / CXCR7 chemokine axis Cancer progression 



We apologize to the many authors whose excellent work we could not cite owing to space limitation. Research in the authors’ laboratory is supported by the National Natural funding of China (30973012,81071747), National key program (973) for Basic Research of China (NO2010CB504300), Shanghai Education Committee Key Discipline and Specialties Foundation Project Number J50208, and Shanghai Pujiang Program (10PJ1406400). Taichman and Pienta are supported by the National Cancer Institute (CA93900).


  1. 1.
    Vindrieux, D., Escobar, P., & Lazennec, G. (2009). Emerging roles of chemokines in prostate cancer. Endocrine-Related Cancer, 16(3), 663–673.PubMedCrossRefGoogle Scholar
  2. 2.
    Ransohoff, R. M. (2009). Chemokines and chemokine receptors: Standing at the crossroads of immunobiology and neurobiology. Immunity, 31(5), 711–721.PubMedCrossRefGoogle Scholar
  3. 3.
    Bieche, I., Chavey, C., Andrieu, C., Busson, M., Vacher, S., Le Corre, L., et al. (2007). Cxc chemokines located in the 4q21 region are up-regulated in breast cancer. Endocrine-Related Cancer, 14(4), 1039–1052.PubMedCrossRefGoogle Scholar
  4. 4.
    New, D. C., & Wong, Y. H. (2003). Cc chemokine receptor-coupled signalling pathways. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai), 35(9), 779–788.Google Scholar
  5. 5.
    Rot, A., & von Andrian, U. H. (2004). Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells. Annual Review of Immunology, 22, 891–928.PubMedCrossRefGoogle Scholar
  6. 6.
    Lazennec, G., & Richmond, A. (2010). Chemokines and chemokine receptors: New insights into cancer-related inflammation. Trends Mol Med, 16(3), 133–144.PubMedCrossRefGoogle Scholar
  7. 7.
    Keeley, E. C., Mehrad, B., & Strieter, R. M. (2010). Cxc chemokines in cancer angiogenesis and metastases. Adv Cancer Res, 106, 91–111.PubMedCrossRefGoogle Scholar
  8. 8.
    Kruizinga, R. C., Bestebroer, J., Berghuis, P., de Haas, C. J., Links, T. P., de Vries, E. G., et al. (2009). Role of chemokines and their receptors in cancer. Current Pharmaceutical Design, 15(29), 3396–3416.PubMedCrossRefGoogle Scholar
  9. 9.
    Allinen, M., Beroukhim, R., Cai, L., Brennan, C., Lahti-Domenici, J., Huang, H., et al. (2004). Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell, 6(1), 17–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Hartmann, T. N., Burger, M., & Burger, J. A. (2004). The role of adhesion molecules and chemokine receptor cxcr4 (cd184) in small cell lung cancer. Journal of Biological Regulators and Homeostatic Agents, 18(2), 126–130.PubMedGoogle Scholar
  11. 11.
    Secchiero, P., Celeghini, C., Cutroneo, G., Di Baldassarre, A., Rana, R., & Zauli, G. (2000). Differential effects of stromal derived factor-1 alpha (sdf-1 alpha) on early and late stages of human megakaryocytic development. The Anatomical Record, 260(2), 141–147.PubMedCrossRefGoogle Scholar
  12. 12.
    Wright, L. M., Maloney, W., Yu, X., Kindle, L., Collin-Osdoby, P., & Osdoby, P. (2005). Stromal cell-derived factor-1 binding to its chemokine receptor cxcr4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts. Bone, 36(5), 840–853.PubMedCrossRefGoogle Scholar
  13. 13.
    Gillette, J. M., Larochelle, A., Dunbar, C. E., & Lippincott-Schwartz, J. (2009). Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche. Nature Cell Biology, 11(3), 303–311.PubMedCrossRefGoogle Scholar
  14. 14.
    Hayakawa, J., Migita, M., Ueda, T., Fukazawa, R., Adachi, K., Ooue, Y., et al. (2009). Dextran sulfate and stromal cell derived factor-1 promote cxcr4 expression and improve bone marrow homing efficiency of infused hematopoietic stem cells. Journal of Nippon Medical School, 76(4), 198–208.PubMedCrossRefGoogle Scholar
  15. 15.
    Kyriakou, C., Rabin, N., Pizzey, A., Nathwani, A., & Yong, K. (2008). Factors that influence short-term homing of human bone marrow-derived mesenchymal stem cells in a xenogeneic animal model. Haematologica, 93(10), 1457–1465.PubMedCrossRefGoogle Scholar
  16. 16.
    Tashiro, K., Tada, H., Heilker, R., Shirozu, M., Nakano, T., & Honjo, T. (1993). Signal sequence trap: A cloning strategy for secreted proteins and type i membrane proteins. Science, 261(5121), 600–603.PubMedCrossRefGoogle Scholar
  17. 17.
    Dettin, M., Pasquato, A., Scarinci, C., Zanchetta, M., De Rossi, A., & Di Bello, C. (2004). Anti-hiv activity and conformational studies of peptides derived from the c-terminal sequence of sdf-1. Journal of Medicinal Chemistry, 47(12), 3058–3064.PubMedCrossRefGoogle Scholar
  18. 18.
    Janowski, M. (2009). Functional diversity of sdf-1 splicing variants. Cell Adhesion & Migration, 3(3), 243–249.CrossRefGoogle Scholar
  19. 19.
    Kucia, M., Wojakowski, W., Reca, R., Machalinski, B., Gozdzik, J., Majka, M., et al. (2006). The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an sdf-1-, hgf-, and life-dependent manner. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 54(2), 121–135.CrossRefGoogle Scholar
  20. 20.
    Yu, L., Cecil, J., Peng, S. B., Schrementi, J., Kovacevic, S., Paul, D., et al. (2006). Identification and expression of novel isoforms of human stromal cell-derived factor 1. Gene, 374, 174–179.PubMedCrossRefGoogle Scholar
  21. 21.
    Neiva, K., Sun, Y. X., & Taichman, R. S. (2005). The role of osteoblasts in regulating hematopoietic stem cell activity and tumor metastasis. Brazilian Journal of Medical and Biological Research, 38(10), 1449–1454.PubMedCrossRefGoogle Scholar
  22. 22.
    Jung, Y., Wang, J., Schneider, A., Sun, Y. X., Koh-Paige, A. J., Osman, N. I., et al. (2006). Regulation of sdf-1 (cxcl12) production by osteoblasts; a possible mechanism for stem cell homing. Bone, 38(4), 497–508.PubMedCrossRefGoogle Scholar
  23. 23.
    Taichman, R. S., Cooper, C., Keller, E. T., Pienta, K. J., Taichman, N. S., & McCauley, L. K. (2002). Use of the stromal cell-derived factor-1/cxcr4 pathway in prostate cancer metastasis to bone. Cancer Research, 62(6), 1832–1837.PubMedGoogle Scholar
  24. 24.
    Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., et al. (1999). Dependence of human stem cell engraftment and repopulation of nod/scid mice on cxcr4. Science, 283(5403), 845–848.PubMedCrossRefGoogle Scholar
  25. 25.
    Ponomaryov, T., Peled, A., Petit, I., Taichman, R. S., Habler, L., Sandbank, J., et al. (2000). Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. Journal of Clinical Investigation, 106(11), 1331–1339.PubMedCrossRefGoogle Scholar
  26. 26.
    Petit, I., Szyper-Kravitz, M., Nagler, A., Lahav, M., Peled, A., Habler, L., et al. (2002). G-csf induces stem cell mobilization by decreasing bone marrow sdf-1 and up-regulating cxcr4. Nature Immunology, 3(7), 687–694.PubMedCrossRefGoogle Scholar
  27. 27.
    Ceradini, D. J., Kulkarni, A. R., Callaghan, M. J., Tepper, O. M., Bastidas, N., Kleinman, M. E., et al. (2004). Progenitor cell trafficking is regulated by hypoxic gradients through hif-1 induction of sdf-1. Natural Medicines, 10(8), 858–864.CrossRefGoogle Scholar
  28. 28.
    Caruz, A., Samsom, M., Alonso, J. M., Alcami, J., Baleux, F., Virelizier, J. L., et al. (1998). Genomic organization and promoter characterization of human cxcr4 gene. FEBS Letters, 426(2), 271–278.PubMedCrossRefGoogle Scholar
  29. 29.
    Gupta, S. K., & Pillarisetti, K. (1999). Cutting edge: Cxcr4-lo: Molecular cloning and functional expression of a novel human cxcr4 splice variant. Journal of Immunology, 163(5), 2368–2372.Google Scholar
  30. 30.
    Wegner, S. A., Ehrenberg, P. K., Chang, G., Dayhoff, D. E., Sleeker, A. L., & Michael, N. L. (1998). Genomic organization and functional characterization of the chemokine receptor cxcr4, a major entry co-receptor for human immunodeficiency virus type 1. The Journal of Biological Chemistry, 273(8), 4754–4760.PubMedCrossRefGoogle Scholar
  31. 31.
    Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I., & Littman, D. R. (1998). Function of the chemokine receptor cxcr4 in haematopoiesis and in cerebellar development. Nature, 393(6685), 595–599.PubMedCrossRefGoogle Scholar
  32. 32.
    Feil, C., & Augustin, H. G. (1998). Endothelial cells differentially express functional cxc-chemokine receptor-4 (cxcr-4/fusin) under the control of autocrine activity and exogenous cytokines. Biochemical and Biophysical Research Communications, 247(1), 38–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Lazarini, F., Casanova, P., Tham, T. N., De Clercq, E., Arenzana-Seisdedos, F., Baleux, F., et al. (2000). Differential signalling of the chemokine receptor cxcr4 by stromal cell-derived factor 1 and the hiv glycoprotein in rat neurons and astrocytes. The European Journal of Neuroscience, 12(1), 117–125.PubMedCrossRefGoogle Scholar
  34. 34.
    Aiuti, A., Tavian, M., Cipponi, A., Ficara, F., Zappone, E., Hoxie, J., et al. (1999). Expression of cxcr4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors. European Journal of Immunology, 29(6), 1823–1831.PubMedCrossRefGoogle Scholar
  35. 35.
    Aiuti, A., Webb, I. J., Bleul, C., Springer, T., & Gutierrez-Ramos, J. C. (1997). The chemokine sdf-1 is a chemoattractant for human cd34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of cd34+ progenitors to peripheral blood. The Journal of Experimental Medicine, 185(1), 111–120.PubMedCrossRefGoogle Scholar
  36. 36.
    Doitsidou, M., Reichman-Fried, M., Stebler, J., Koprunner, M., Dorries, J., Meyer, D., et al. (2002). Guidance of primordial germ cell migration by the chemokine sdf-1. Cell, 111(5), 647–659.PubMedCrossRefGoogle Scholar
  37. 37.
    Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S., Kitamura, Y., et al. (1996). Defects of b-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the cxc chemokine pbsf/sdf-1. Nature, 382(6592), 635–638.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee, R. L., Westendorf, J., & Gold, M. R. (2007). Differential role of reactive oxygen species in the activation of mitogen-activated protein kinases and akt by key receptors on b-lymphocytes: Cd40, the b cell antigen receptor, and cxcr4. Journal of Cell Communication and Signaling, 1(1), 33–43.PubMedCrossRefGoogle Scholar
  39. 39.
    Lu, D. Y., Tang, C. H., Yeh, W. L., Wong, K. L., Lin, C. P., Chen, Y. H., et al. (2009). Sdf-1alpha up-regulates interleukin-6 through cxcr4, pi3k/akt, erk, and nf-kappab-dependent pathway in microglia. European Journal of Pharmacology, 613(1–3), 146–154.PubMedCrossRefGoogle Scholar
  40. 40.
    Princen, K., Hatse, S., Vermeire, K., De Clercq, E., & Schols, D. (2003). Evaluation of sdf-1/cxcr4-induced ca2+ signaling by fluorometric imaging plate reader (flipr) and flow cytometry. Cytometry. Part A, 51(1), 35–45.CrossRefGoogle Scholar
  41. 41.
    Roland, J., Murphy, B. J., Ahr, B., Robert-Hebmann, V., Delauzun, V., Nye, K. E., et al. (2003). Role of the intracellular domains of cxcr4 in sdf-1-mediated signaling. Blood, 101(2), 399–406.PubMedCrossRefGoogle Scholar
  42. 42.
    Balkwill, F. (2004). Cancer and the chemokine network. Nature Reviews. Cancer, 4(7), 540–550.PubMedCrossRefGoogle Scholar
  43. 43.
    Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Scotton, C. J., Wilson, J. L., Milliken, D., Stamp, G., & Balkwill, F. R. (2001). Epithelial cancer cell migration: A role for chemokine receptors? Cancer Research, 61(13), 4961–4965.PubMedGoogle Scholar
  45. 45.
    Zagzag, D., Lukyanov, Y., Lan, L., Ali, M. A., Esencay, M., Mendez, O., et al. (2006). Hypoxia-inducible factor 1 and vegf upregulate cxcr4 in glioblastoma: Implications for angiogenesis and glioma cell invasion. Laboratory Investigation, 86(12), 1221–1232.PubMedCrossRefGoogle Scholar
  46. 46.
    Burns, J. M., Summers, B. C., Wang, Y., Melikian, A., Berahovich, R., Miao, Z., et al. (2006). A novel chemokine receptor for sdf-1 and i-tac involved in cell survival, cell adhesion, and tumor development. The Journal of Experimental Medicine, 203(9), 2201–2213.PubMedCrossRefGoogle Scholar
  47. 47.
    Balabanian, K., Lagane, B., Infantino, S., Chow, K. Y., Harriague, J., Moepps, B., et al. (2005). The chemokine sdf-1/cxcl12 binds to and signals through the orphan receptor rdc1 in t lymphocytes. The Journal of Biological Chemistry, 280(42), 35760–35766.PubMedCrossRefGoogle Scholar
  48. 48.
    Libert, F., Parmentier, M., Lefort, A., Dumont, J. E., & Vassart, G. (1990). Complete nucleotide sequence of a putative G protein coupled receptor: Rdc1. Nucleic Acids Research, 18(7), 1917.PubMedCrossRefGoogle Scholar
  49. 49.
    Jones, S. W., Brockbank, S. M., Mobbs, M. L., Le Good, N. J., Soma-Haddrick, S., Heuze, A. J., et al. (2006). The orphan G-protein coupled receptor rdc1: Evidence for a role in chondrocyte hypertrophy and articular cartilage matrix turnover. Osteoarthritis and Cartilage, 14(6), 597–608.PubMedCrossRefGoogle Scholar
  50. 50.
    Raggo, C., Ruhl, R., McAllister, S., Koon, H., Dezube, B. J., Fruh, K., et al. (2005). Novel cellular genes essential for transformation of endothelial cells by kaposi's sarcoma-associated herpesvirus. Cancer Research, 65(12), 5084–5095.PubMedCrossRefGoogle Scholar
  51. 51.
    Martinez, A., Kapas, S., Miller, M. J., Ward, Y., & Cuttitta, F. (2000). Coexpression of receptors for adrenomedullin, calcitonin gene-related peptide, and amylin in pancreatic beta-cells. Endocrinology, 141(1), 406–411.PubMedCrossRefGoogle Scholar
  52. 52.
    Tripathi, V., Verma, R., Dinda, A., Malhotra, N., Kaur, J., & Luthra, K. (2009). Differential expression of rdc1/cxcr7 in the human placenta. Journal of Clinical Immunology, 29(3), 379–386.PubMedCrossRefGoogle Scholar
  53. 53.
    Miao, Z., Luker, K. E., Summers, B. C., Berahovich, R., Bhojani, M. S., Rehemtulla, A., et al. (2007). Cxcr7 (rdc1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proceedings of the National Academy of Sciences of the United States of America, 104(40), 15735–15740.PubMedCrossRefGoogle Scholar
  54. 54.
    Wang, J., Shiozawa, Y., Wang, Y., Jung, Y., Pienta, K. J., Mehra, R., et al. (2008). The role of cxcr7/rdc1 as a chemokine receptor for cxcl12/sdf-1 in prostate cancer. The Journal of Biological Chemistry, 283(7), 4283–4294.PubMedCrossRefGoogle Scholar
  55. 55.
    Begley, L. A., MacDonald, J. W., Day, M. L., & Macoska, J. A. (2007). Cxcl12 activates a robust transcriptional response in human prostate epithelial cells. The Journal of Biological Chemistry, 282(37), 26767–26774.PubMedCrossRefGoogle Scholar
  56. 56.
    Rajagopal, S., Kim, J., Ahn, S., Craig, S., Lam, C. M., Gerard, N. P., et al. (2010). Beta-arrestin- but not G protein-mediated signaling by the “Decoy” Receptor cxcr7. Proc Natl Acad Sci U S A, 107(2), 628–632.PubMedCrossRefGoogle Scholar
  57. 57.
    Boldajipour, B., Mahabaleshwar, H., Kardash, E., Reichman-Fried, M., Blaser, H., Minina, S., et al. (2008). Control of chemokine-guided cell migration by ligand sequestration. Cell, 132(3), 463–473.PubMedCrossRefGoogle Scholar
  58. 58.
    Dambly-Chaudiere, C., Cubedo, N., & Ghysen, A. (2007). Control of cell migration in the development of the posterior lateral line: Antagonistic interactions between the chemokine receptors cxcr4 and cxcr7/rdc1. BMC Developmental Biology, 7, 23.PubMedCrossRefGoogle Scholar
  59. 59.
    Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F., & Lagane, B. (2009). Cxcr7 heterodimerizes with cxcr4 and regulates cxcl12-mediated G protein signaling. Blood, 113(24), 6085–6093.PubMedCrossRefGoogle Scholar
  60. 60.
    Sierro, F., Biben, C., Martinez-Munoz, L., Mellado, M., Ransohoff, R. M., Li, M., et al. (2007). Disrupted cardiac development but normal hematopoiesis in mice deficient in the second cxcl12/sdf-1 receptor, cxcr7. Proceedings of the National Academy of Sciences of the United States of America, 104(37), 14759–14764.PubMedCrossRefGoogle Scholar
  61. 61.
    Hartmann, T. N., Grabovsky, V., Pasvolsky, R., Shulman, Z., Buss, E. C., Spiegel, A., et al. (2008). A crosstalk between intracellular cxcr7 and cxcr4 involved in rapid cxcl12-triggered integrin activation but not in chemokine-triggered motility of human t lymphocytes and cd34+ cells. Journal of Leukocyte Biology, 84(4), 1130–1140.PubMedCrossRefGoogle Scholar
  62. 62.
    Kalatskaya, I., Berchiche, Y. A., Gravel, S., Limberg, B. J., Rosenbaum, J. S., & Heveker, N. (2009). Amd3100 is a cxcr7 ligand with allosteric agonist properties. Molecular Pharmacology, 75(5), 1240–1247.PubMedCrossRefGoogle Scholar
  63. 63.
    Luker, K. E., Gupta, M., Steele, J. M., Foerster, B. R., & Luker, G. D. (2009). Imaging ligand-dependent activation of cxcr7. Neoplasia, 11(10), 1022–1035.PubMedGoogle Scholar
  64. 64.
    Fernandis, A. Z., Cherla, R. P., Chernock, R. D., & Ganju, R. K. (2002). Cxcr4/ccr5 down-modulation and chemotaxis are regulated by the proteasome pathway. The Journal of Biological Chemistry, 277(20), 18111–18117.PubMedCrossRefGoogle Scholar
  65. 65.
    Sun, Y. X., Schneider, A., Jung, Y., Wang, J., Dai, J., Cook, K., et al. (2005). Skeletal localization and neutralization of the sdf-1(cxcl12)/cxcr4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. Journal of Bone and Mineral Research, 20(2), 318–329.PubMedCrossRefGoogle Scholar
  66. 66.
    Engl, T., Relja, B., Marian, D., Blumenberg, C., Muller, I., Beecken, W. D., et al. (2006). Cxcr4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia, 8(4), 290–301.PubMedCrossRefGoogle Scholar
  67. 67.
    Kukreja, P., Abdel-Mageed, A. B., Mondal, D., Liu, K., & Agrawal, K. C. (2005). Up-regulation of cxcr4 expression in pc-3 cells by stromal-derived factor-1alpha (cxcl12) increases endothelial adhesion and transendothelial migration: Role of mek/erk signaling pathway-dependent nf-kappab activation. Cancer Research, 65(21), 9891–9898.PubMedCrossRefGoogle Scholar
  68. 68.
    Sun, Y. X., Wang, J., Shelburne, C. E., Lopatin, D. E., Chinnaiyan, A. M., Rubin, M. A., et al. (2003). Expression of cxcr4 and cxcl12 (sdf-1) in human prostate cancers (pca) in vivo. Journal of Cellular Biochemistry, 89(3), 462–473.PubMedCrossRefGoogle Scholar
  69. 69.
    Darash-Yahana, M., Pikarsky, E., Abramovitch, R., Zeira, E., Pal, B., Karplus, R., et al. (2004). Role of high expression levels of cxcr4 in tumor growth, vascularization, and metastasis. The FASEB Journal, 18(11), 1240–1242.PubMedGoogle Scholar
  70. 70.
    Wang, J., Sun, Y., Song, W., Nor, J. E., Wang, C. Y., & Taichman, R. S. (2005). Diverse signaling pathways through the sdf-1/cxcr4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cellular Signalling, 17(12), 1578–1592.PubMedCrossRefGoogle Scholar
  71. 71.
    Wang, J., Dai, J., Jung, Y., Wei, C. L., Wang, Y., Havens, A. M., et al. (2007). A glycolytic mechanism regulating an angiogenic switch in prostate cancer. Cancer Research, 67(1), 149–159.PubMedCrossRefGoogle Scholar
  72. 72.
    Zhao, H., & Peehl, D. M. (2009). Tumor-promoting phenotype of cd90hi prostate cancer-associated fibroblasts. The Prostate, 69(9), 991–1000.PubMedCrossRefGoogle Scholar
  73. 73.
    Ratajczak, M. Z., Reca, R., Wysoczynski, M., Yan, J., & Ratajczak, J. (2006). Modulation of the sdf-1-cxcr4 axis by the third complement component (c3)—Implications for trafficking of cxcr4+ stem cells. Experimental Hematology, 34(8), 986–995.PubMedCrossRefGoogle Scholar
  74. 74.
    Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M., et al. (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1(3), 313–323.PubMedCrossRefGoogle Scholar
  75. 75.
    Mazzinghi, B., Ronconi, E., Lazzeri, E., Sagrinati, C., Ballerini, L., Angelotti, M. L., et al. (2008). Essential but differential role for cxcr4 and cxcr7 in the therapeutic homing of human renal progenitor cells. The Journal of Experimental Medicine, 205(2), 479–490.PubMedCrossRefGoogle Scholar
  76. 76.
    Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C., et al. (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3(6), 537–549.PubMedCrossRefGoogle Scholar
  77. 77.
    Liang, Z., Yoon, Y., Votaw, J., Goodman, M. M., Williams, L., & Shim, H. (2005). Silencing of cxcr4 blocks breast cancer metastasis. Cancer Research, 65(3), 967–971.PubMedGoogle Scholar
  78. 78.
    Ueda, Y., Neel, N. F., Schutyser, E., Raman, D., & Richmond, A. (2006). Deletion of the cooh-terminal domain of cxc chemokine receptor 4 leads to the down-regulation of cell-to-cell contact, enhanced motility and proliferation in breast carcinoma cells. Cancer Research, 66(11), 5665–5675.PubMedCrossRefGoogle Scholar
  79. 79.
    Holland, J. D., Kochetkova, M., Akekawatchai, C., Dottore, M., Lopez, A., & McColl, S. R. (2006). Differential functional activation of chemokine receptor cxcr4 is mediated by G proteins in breast cancer cells. Cancer Research, 66(8), 4117–4124.PubMedCrossRefGoogle Scholar
  80. 80.
    Fulton, A. M. (2009). The chemokine receptors cxcr4 and cxcr3 in cancer. Current Oncology Reports, 11(2), 125–131.PubMedCrossRefGoogle Scholar
  81. 81.
    Akekawatchai, C., Holland, J. D., Kochetkova, M., Wallace, J. C., & McColl, S. R. (2005). Transactivation of cxcr4 by the insulin-like growth factor-1 receptor (igf-1r) in human mda-mb-231 breast cancer epithelial cells. The Journal of Biological Chemistry, 280(48), 39701–39708.PubMedCrossRefGoogle Scholar
  82. 82.
    Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated sdf-1/cxcl12 secretion. Cell, 121(3), 335–348.PubMedCrossRefGoogle Scholar
  83. 83.
    Razmkhah, M., Talei, A. R., Doroudchi, M., Khalili-Azad, T., & Ghaderi, A. (2005). Stromal cell-derived factor-1 (sdf-1) alleles and susceptibility to breast carcinoma. Cancer Letters, 225(2), 261–266.PubMedCrossRefGoogle Scholar
  84. 84.
    Cabioglu, N., Summy, J., Miller, C., Parikh, N. U., Sahin, A. A., Tuzlali, S., et al. (2005). Cxcl-12/stromal cell-derived factor-1alpha transactivates her2-neu in breast cancer cells by a novel pathway involving src kinase activation. Cancer Research, 65(15), 6493–6497.PubMedCrossRefGoogle Scholar
  85. 85.
    Salmaggi, A., Maderna, E., Calatozzolo, C., Gaviani, P., Canazza, A., Milanesi, I., et al. (2009). Cxcl12, cxcr4 and cxcr7 expression in brain metastases. Cancer Biology & Therapy, 8(17), 1608–1614.CrossRefGoogle Scholar
  86. 86.
    Burger, J. A., & Kipps, T. J. (2006). Cxcr4: A key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 107(5), 1761–1767.PubMedCrossRefGoogle Scholar
  87. 87.
    Burger, M., Glodek, A., Hartmann, T., Schmitt-Graff, A., Silberstein, L. E., Fujii, N., et al. (2003). Functional expression of cxcr4 (cd184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. Oncogene, 22(50), 8093–8101.PubMedCrossRefGoogle Scholar
  88. 88.
    Hartmann, T. N., Burger, J. A., Glodek, A., Fujii, N., & Burger, M. (2005). Cxcr4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (sclc) cells. Oncogene, 24(27), 4462–4471.PubMedCrossRefGoogle Scholar
  89. 89.
    Su, L. P., Zhang, J. P., Xu, H. B., Chen, J., Wang, Y., & Xiong, S. D. (2005). the role of cxcr4 in lung cancer metastasis and its possible mechanism. Zhonghua Yi Xue Za Zhi, 85(17), 1190–1194.PubMedGoogle Scholar
  90. 90.
    Kijima, T., Maulik, G., Ma, P. C., Tibaldi, E. V., Turner, R. E., Rollins, B., et al. (2002). Regulation of cellular proliferation, cytoskeletal function, and signal transduction through cxcr4 and c-kit in small cell lung cancer cells. Cancer Research, 62(21), 6304–6311.PubMedGoogle Scholar
  91. 91.
    Phillips, R. J., Mestas, J., Gharaee-Kermani, M., Burdick, M. D., Sica, A., Belperio, J. A., et al. (2005). Epidermal growth factor and hypoxia-induced expression of cxc chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/pten/akt/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. The Journal of Biological Chemistry, 280(23), 22473–22481.PubMedCrossRefGoogle Scholar
  92. 92.
    Iwakiri, S., Mino, N., Takahashi, T., Sonobe, M., Nagai, S., Okubo, K., et al. (2009). Higher expression of chemokine receptor cxcr7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer, 115(11), 2580–2593.PubMedCrossRefGoogle Scholar
  93. 93.
    Billadeau, D. D., Chatterjee, S., Bramati, P., Sreekumar, R., Shah, V., Hedin, K., et al. (2006). Characterization of the cxcr4 signaling in pancreatic cancer cells. International Journal of Gastrointestinal Cancer, 37(4), 110–119.PubMedGoogle Scholar
  94. 94.
    Mori, T., Doi, R., Koizumi, M., Toyoda, E., Ito, D., Kami, K., et al. (2004). Cxcr4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. Molecular Cancer Therapeutics, 3(1), 29–37.PubMedGoogle Scholar
  95. 95.
    Koshiba, T., Hosotani, R., Miyamoto, Y., Ida, J., Tsuji, S., Nakajima, S., et al. (2000). Expression of stromal cell-derived factor 1 and cxcr4 ligand receptor system in pancreatic cancer: A possible role for tumor progression. Clinical Cancer Research, 6(9), 3530–3535.PubMedGoogle Scholar
  96. 96.
    Marchesi, F., Monti, P., Leone, B. E., Zerbi, A., Vecchi, A., Piemonti, L., et al. (2004). Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional cxcr4. Cancer Research, 64(22), 8420–8427.PubMedCrossRefGoogle Scholar
  97. 97.
    Gao, Z., Wang, X., Wu, K., Zhao, Y., & Hu, G. (2010). Pancreatic stellate cells increase the invasion of human pancreatic cancer cells through the stromal cell-derived factor-1/cxcr4 axis. Pancreatology, 10(2–3), 186–193.PubMedCrossRefGoogle Scholar
  98. 98.
    Marechal, R., Demetter, P., Nagy, N., Berton, A., Decaestecker, C., Polus, M., et al. (2009). High expression of cxcr4 may predict poor survival in resected pancreatic adenocarcinoma. British Journal of Cancer, 100(9), 1444–1451.PubMedCrossRefGoogle Scholar
  99. 99.
    Jankowski, K., Kucia, M., Wysoczynski, M., Reca, R., Zhao, D., Trzyna, E., et al. (2003). Both hepatocyte growth factor (hgf) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only hgf enhances their resistance to radiochemotherapy. Cancer Research, 63(22), 7926–7935.PubMedGoogle Scholar
  100. 100.
    Balkwill, F. (2004). The significance of cancer cell expression of the chemokine receptor cxcr4. Seminars in Cancer Biology, 14(3), 171–179.PubMedCrossRefGoogle Scholar
  101. 101.
    Bertolini, F., Dell’Agnola, C., Mancuso, P., Rabascio, C., Burlini, A., Monestiroli, S., et al. (2002). Cxcr4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma. Cancer Research, 62(11), 3106–3112.PubMedGoogle Scholar
  102. 102.
    Scotton, C. J., Wilson, J. L., Scott, K., Stamp, G., Wilbanks, G. D., Fricker, S., et al. (2002). Multiple actions of the chemokine cxcl12 on epithelial tumor cells in human ovarian cancer. Cancer Research, 62(20), 5930–5938.PubMedGoogle Scholar
  103. 103.
    Zhou, Y., Larsen, P. H., Hao, C., & Yong, V. W. (2002). Cxcr4 is a major chemokine receptor on glioma cells and mediates their survival. The Journal of Biological Chemistry, 277(51), 49481–49487.PubMedCrossRefGoogle Scholar
  104. 104.
    Rubin, J. B., Kung, A. L., Klein, R. S., Chan, J. A., Sun, Y., Schmidt, K., et al. (2003). A small-molecule antagonist of cxcr4 inhibits intracranial growth of primary brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100(23), 13513–13518.PubMedCrossRefGoogle Scholar
  105. 105.
    Sehgal, A., Keener, C., Boynton, A. L., Warrick, J., & Murphy, G. P. (1998). Cxcr-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. Journal of Surgical Oncology, 69(2), 99–104.PubMedCrossRefGoogle Scholar
  106. 106.
    Kim, J., Mori, T., Chen, S. L., Amersi, F. F., Martinez, S. R., Kuo, C., et al. (2006). Chemokine receptor cxcr4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Annals of Surgery, 244(1), 113–120.PubMedCrossRefGoogle Scholar
  107. 107.
    Geminder, H., Sagi-Assif, O., Goldberg, L., Meshel, T., Rechavi, G., Witz, I. P., et al. (2001). A possible role for cxcr4 and its ligand, the cxc chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. Journal of Immunology, 167(8), 4747–4757.Google Scholar
  108. 108.
    Scala, S., Ottaiano, A., Ascierto, P. A., Cavalli, M., Simeone, E., Giuliano, P., et al. (2005). Expression of cxcr4 predicts poor prognosis in patients with malignant melanoma. Clinical Cancer Research, 11(5), 1835–1841.PubMedCrossRefGoogle Scholar
  109. 109.
    Zeelenberg, I. S., Ruuls-Van Stalle, L., & Roos, E. (2003). The chemokine receptor cxcr4 is required for outgrowth of colon carcinoma micrometastases. Cancer Research, 63(13), 3833–3839.PubMedGoogle Scholar
  110. 110..
    Grymula, K., Tarnowski, M., Wysoczynski, M., Drukala, J., Barr, F. G., Ratajczak, J., et al. (2010) Overlapping and distinct role of cxcr7-sdf-1/itac and cxcr4-sdf-1 axes in regulating metastatic behavior of human rhabdomyosarcomas. Int J Cancer (in press).Google Scholar
  111. 111.
    Libura, J., Drukala, J., Majka, M., Tomescu, O., Navenot, J. M., Kucia, M., et al. (2002). Cxcr4-sdf-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood, 100(7), 2597–2606.PubMedCrossRefGoogle Scholar
  112. 112.
    Tarnowski, M., Grymula, K., Reca, R., Jankowski, K., Maksym, R., Tarnowska, J., et al. (2010). Regulation of expression of stromal-derived factor-1 receptors: Cxcr4 and cxcr7 in human rhabdomyosarcomas. Mol Cancer Res, 8(1), 1–14.PubMedCrossRefGoogle Scholar
  113. 113.
    Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., et al. (2003). Interaction between leukemic-cell vla-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Natural Medicines, 9(9), 1158–1165.CrossRefGoogle Scholar
  114. 114.
    Sanz-Rodriguez, F., Hidalgo, A., & Teixido, J. (2001). Chemokine stromal cell-derived factor-1alpha modulates vla-4 integrin-mediated multiple myeloma cell adhesion to cs-1/fibronectin and vcam-1. Blood, 97(2), 346–351.PubMedCrossRefGoogle Scholar
  115. 115.
    Dvorak, H. F. (1986). Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England journal of medicine, 315(26), 1650–1659.PubMedCrossRefGoogle Scholar
  116. 116.
    Horgan, K., Jones, D. L., & Mansel, R. E. (1987). Mitogenicity of human fibroblasts in vivo for human breast cancer cells. The British Journal of Surgery, 74(3), 227–229.PubMedCrossRefGoogle Scholar
  117. 117.
    Ronnov-Jessen, L., Petersen, O. W., Koteliansky, V. E., & Bissell, M. J. (1995). The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. The Journal of clinical investigation, 95(2), 859–873.PubMedCrossRefGoogle Scholar
  118. 118.
    Clarke, M. F., & Fuller, M. (2006). Stem cells and cancer: Two faces of eve. Cell, 124(6), 1111–1115.PubMedCrossRefGoogle Scholar
  119. 119.
    Li, L., & Neaves, W. B. (2006). Normal stem cells and cancer stem cells: The niche matters. Cancer Research, 66(9), 4553–4557.PubMedCrossRefGoogle Scholar
  120. 120.
    Polyak, K., & Hahn, W. C. (2006). Roots and stems: Stem cells in cancer. Natural Medicines, 12(3), 296–300.CrossRefGoogle Scholar
  121. 121.
    Rak, J. (2006). Is cancer stem cell a cell, or a multicellular unit capable of inducing angiogenesis? Medical Hypotheses, 66(3), 601–604.PubMedCrossRefGoogle Scholar
  122. 122.
    Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., et al. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 441(7092), 475–482.PubMedCrossRefGoogle Scholar
  123. 123.
    Begley, L., Monteleon, C., Shah, R. B., Macdonald, J. W., & Macoska, J. A. (2005). Cxcl12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro. Aging Cell, 4(6), 291–298.PubMedCrossRefGoogle Scholar
  124. 124.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., et al. (2005). Vegfr1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827.PubMedCrossRefGoogle Scholar
  125. 125.
    Houshmand, P., & Zlotnik, A. (2003). Targeting tumor cells. Current Opinion in Cell Biology, 15(5), 640–644.PubMedCrossRefGoogle Scholar
  126. 126.
    Ao, M., Franco, O. E., Park, D., Raman, D., Williams, K., & Hayward, S. W. (2007). Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Research, 67(9), 4244–4253.PubMedCrossRefGoogle Scholar
  127. 127.
    Zhang, L., Yeger, H., Das, B., Irwin, M. S., & Baruchel, S. (2007). Tissue microenvironment modulates cxcr4 expression and tumor metastasis in neuroblastoma. Neoplasia, 9(1), 36–46.PubMedCrossRefGoogle Scholar
  128. 128.
    Donahue, R. E., Jin, P., Bonifacino, A. C., Metzger, M. E., Ren, J., Wang, E., et al. (2009). Plerixafor (amd3100) and granulocyte colony-stimulating factor (g-csf) mobilize different cd34+ cell populations based on global gene and microrna expression signatures. Blood, 114(12), 2530–2541.PubMedCrossRefGoogle Scholar
  129. 129.
    Kim, S. Y., Lee, C. H., Midura, B. V., Yeung, C., Mendoza, A., Hong, S. H., et al. (2008). Inhibition of the cxcr4/cxcl12 chemokine pathway reduces the development of murine pulmonary metastases. Clinical & Experimental Metastasis, 25(3), 201–211.CrossRefGoogle Scholar
  130. 130.
    Porvasnik, S., Sakamoto, N., Kusmartsev, S., Eruslanov, E., Kim, W. J., Cao, W., et al. (2009). Effects of cxcr4 antagonist ctce-9908 on prostate tumor growth. The Prostate, 69(13), 1460–1469.PubMedCrossRefGoogle Scholar
  131. 131.
    Richert, M. M., Vaidya, K. S., Mills, C. N., Wong, D., Korz, W., Hurst, D. R., et al. (2009). Inhibition of cxcr4 by ctce-9908 inhibits breast cancer metastasis to lung and bone. Oncology Reports, 21(3), 761–767.PubMedGoogle Scholar
  132. 132.
    Hojo, S., Koizumi, K., Tsuneyama, K., Arita, Y., Cui, Z., Shinohara, K., et al. (2007). High-level expression of chemokine cxcl16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Research, 67(10), 4725–4731.PubMedCrossRefGoogle Scholar
  133. 133.
    Wysoczynski, M., Kucia, M., Ratajczak, J., & Ratajczak, M. Z. (2007). Cleavage fragments of the third complement component (c3) enhance stromal derived factor-1 (sdf-1)-mediated platelet production during reactive postbleeding thrombocytosis. Leukemia, 21(5), 973–982.PubMedGoogle Scholar
  134. 134.
    Wysoczynski, M., Miekus, K., Jankowski, K., Wanzeck, J., Bertolone, S., Janowska-Wieczorek, A., et al. (2007). Leukemia inhibitory factor: A newly identified metastatic factor in rhabdomyosarcomas. Cancer Research, 67(5), 2131–2140.PubMedCrossRefGoogle Scholar
  135. 135.
    McGrath, K. E., Koniski, A. D., Maltby, K. M., McGann, J. K., & Palis, J. (1999). Embryonic expression and function of the chemokine sdf-1 and its receptor, cxcr4. Developmental Biology, 213(2), 442–456.PubMedCrossRefGoogle Scholar
  136. 136.
    Mohle, R., Moore, M. A., Nachman, R. L., & Rafii, S. (1997). Transendothelial migration of cd34+ and mature hematopoietic cells: An in vitro study using a human bone marrow endothelial cell line. Blood, 89(1), 72–80.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Xueqing Sun
    • 1
  • Guangcun Cheng
    • 1
  • Mingang Hao
    • 1
  • Jianghua Zheng
    • 1
  • Xiaoming Zhou
    • 1
  • Jian Zhang
    • 2
  • Russell S. Taichman
    • 3
  • Kenneth J. Pienta
    • 2
  • Jianhua Wang
    • 1
  1. 1.Department of Biochemistry and Molecular & Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Medical ScienceShanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Department of Internal Medicine and UrologyUniversity of MichiganAnn ArborUSA
  3. 3.Department of Periodontics & Oral MedicineUniversity of Michigan School of DentistryAnn ArborUSA

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