Skip to main content

Advertisement

SpringerLink
Log in

The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Tumor cells are known to adapt to and utilize existing physiological mechanisms to promote survival and metastasis. The role of the microenvironment in the establishment of a metastatic lesion has become increasingly important as several factors secreted by stromal cells regulate metastatic pattern in a variety of tumor types. Tumor cells interact with osteoblasts, osteoclasts and bone matrix to form a vicious cycle that is essential for successful metastases. Here we review the current concepts regarding the role of an important chemokine/chemokine receptor (SDF-1 or CXCL12/CXCR4) pathway in tumor development and metastasis. CXCL12 secretion by stromal cells is known to attract cancer cells via stimulation of the CXCR4 receptor that is up regulated by tumor cells. CXCL12/CXCR4 activation regulates the pattern of metastatic spread with organs expressing high levels of CXCL12 developing secondary tumors (i.e., the bone marrow compartment). CXCL12 has a wide range of effects in regards to tumor development but the primary role of CXCL12 appears to be the mobilization of hematopoietic stem cells and the establishment of the cancer stem-like cell niche where high levels of CXCL12 recruit a highly tumorigenic population of tumor cells and promotes cell survival, proliferation, angiogenesis, and metastasis.

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

Access this article

Log in via an institution

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

  1. Addison, C. L., Arenberg, D. A., Morris, S. B., Xue, Y. Y., Burdick, M. D., Mulligan, M. S., et al. (2000). The CXC chemokine, monokine induced by interferon–gamma, inhibits non-small cell lung carcinoma tumor growth and metastasis. Human Gene Therapy, 11(2), 247–261.

    PubMed  CAS  Google Scholar 

  2. Schier, A. F. (2003). Chemokine signaling: Rules of attraction. Current Biology, 13(5), R192–R194.

    PubMed  CAS  Google Scholar 

  3. Proudfoot, A. E. (2002). Chemokine receptors: Multifaceted therapeutic targets Nature Reviews Immunology, 2(2), 106–115.

    PubMed  CAS  Google Scholar 

  4. Houshmand, P., & Zlotnik, A. (2003). Targeting tumor cells. Current Opinion in Cell Biology, 15(5), 640–644.

    PubMed  CAS  Google Scholar 

  5. 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.

    PubMed  CAS  Google Scholar 

  6. 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. Journal of Experimental Medicine, 185(1), 111–120.

    PubMed  CAS  Google Scholar 

  7. 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, 635–638.

    PubMed  CAS  Google Scholar 

  8. 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.

    PubMed  CAS  Google Scholar 

  9. 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.

    CAS  Google Scholar 

  10. Ponomaryov, T., Peled, A., Peled, I., Taichman, R. S., Habler, L., Sandbank, J., et al. (2000). Increased production of SDF-1 following treatment with DNA damaging agents: Relevance for human stem cell homing and repopulation of NOD/SCID Mice. Journal of Clinical Investigation, 106(11), 1331–1339.

    PubMed  CAS  Google Scholar 

  11. Sun, Y. X., Schneider, A., Jung, Y., Wang, J., Dai, J., Wang, J., 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, 2, 318–329.

    Google Scholar 

  12. 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.

    PubMed  CAS  Google Scholar 

  13. Jung, Y., Wang, J., Schneider, A., Sun, Y-X, Koh-Paige, A., Osman, N., et al. (2006) Regulation of SDF-1 (CXCL12) production by osteoblasts in the hematopoietic microenvironment and a possible mechanisms for stem cell homing. Bone, 38(4), 497–508.

    Google Scholar 

  14. Askari, A. T., Goldman, C. K., Forudi, F., Kiedrowski, M. J., & Ellis, S. G., DiCorleto, P. E., et al. (2002). Stromal cell-derived factor-1 mediates stem cell homing in ischemic cardiomyopathy. Circulation, 106(19), II-178.

    Google Scholar 

  15. Ratajczak, M. Z., Majka, M., Kucia, M., Drukala, J., Pietrzkowski, Z., Peiper, S., et al. (2003). Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells, 21(3), 363–371.

    PubMed  CAS  Google Scholar 

  16. Kollet, O., Shivtiel, S., Chen, Y. Q., Suriawinata, J., Thung, S. N., Dabeva, M. D., et al. (2003). HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34(+) stem cell recruitment to the liver. Journal of Clinical Investigation, 112(2), 160–169.

    PubMed  CAS  Google Scholar 

  17. Tachibana, K., Hirota, S., Iizasa, H., Yoshida, H., Kawabata, K., Kataoka, Y., et al. (1998). The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature, 393, 591–594.

    PubMed  CAS  Google Scholar 

  18. Schrader, A. J., Lechner, O., Templin, M., Dittmar, K. E., Machtens, S., Mengel, M., et al. (2002). CXCR4/CXCL12 expression and signalling in kidney cancer. British Journal of Cancer, 86(8), 1250–1256.

    PubMed  CAS  Google Scholar 

  19. 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.

    PubMed  CAS  Google Scholar 

  20. Ratajczak, M. Z., 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(1), 29–40.

    PubMed  CAS  Google Scholar 

  21. Kucia, M., Reca, R., Miekus, K., Wanzeck, J., Wojakowski, W., Janowska-Wieczorek, A., 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), 879–894.

    PubMed  CAS  Google Scholar 

  22. Kucia, M., Ratajczak, J., Reca, R., Janowska-Wieczorek, A., & Ratajczak, M. Z. (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, Molecules & Diseases, 32(1), 52–57.

    CAS  Google Scholar 

  23. 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.

    PubMed  CAS  Google Scholar 

  24. 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. Nature Medicine, 10(8), 858–864.

    PubMed  CAS  Google Scholar 

  25. 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.

    PubMed  CAS  Google Scholar 

  26. 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. Journal of Biological Chemistry, 273(8), 4754–4760.

    PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  CAS  Google Scholar 

  28. 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. European Journal of Neuroscience, 12(1), 117–125.

    PubMed  CAS  Google Scholar 

  29. 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.

    PubMed  CAS  Google Scholar 

  30. 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.

    PubMed  CAS  Google Scholar 

  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, 595–599.

    PubMed  CAS  Google Scholar 

  32. 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.

    PubMed  CAS  Google Scholar 

  33. Sreedharan, S. P., Robichon, A., Peterson, K. E., & Goetzl, E. J. (1991). Cloning and expression of the human vasoactive intestinal peptide receptor. Proceedings of the National Academy of Sciences of the United States of America, 88(11), 4986–4990.

    PubMed  CAS  Google Scholar 

  34. Fredriksson, R., Lagerstrom, M. C., Lundin, L. G., & Schioth, H. B. (2003). The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Molecular Pharmacology, 63(6), 1256–1272.

    PubMed  CAS  Google Scholar 

  35. Shimizu, N., Soda, Y., Kanbe, K., Liu, H. Y., Mukai, R., Kitamura, T., et al. (2000). A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses. Journal of Virology, 74(2), 619–626.

    PubMed  CAS  Google Scholar 

  36. 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. Journal of Biological Chemistry, 280(42), 35760–35766.

    PubMed  CAS  Google Scholar 

  37. 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. Endocrinol, 141(1), 406–411.

    CAS  Google Scholar 

  38. Jones, S. W., Brockbank, S. M. V., 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.

    PubMed  CAS  Google Scholar 

  39. 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.

    PubMed  CAS  Google Scholar 

  40. Bernfield, M., Gotte, M., Park, P. W., Reizes, O., Fitzgerald, M. L., Lincecum, J., et al. (1999). Functions of cell surface heparan sulfate proteoglycans. Annual Review of Biochemistry, 68, 729–777.

    PubMed  CAS  Google Scholar 

  41. Hamon, M., Mbemba, E., Charnaux, N., Slimani, H., Brule, S., Saffar, L., et al. (2004). A syndecan-4/CXCR4 complex expressed on human primary lymphocytes and macrophages and HeLa cell line binds the CXC chemokine stromal cell-derived factor-1 (SDF-1). Glycobiology, 14(4), 311–323.

    PubMed  CAS  Google Scholar 

  42. Charnaux, N., Brule, S., Hamon, M., Chaigneau, T., Saffar, L., Prost, C., et al. (2005). Syndecan-4 is a signaling molecule for stromal cell-derived factor-1 (SDF-1)/CXCL12. FASEB Journal, 272(8), 1937–1951.

    CAS  Google Scholar 

  43. Balkwill, F. (2004). Cancer and the chemokine network. Nature Reviews. Cancer, 4(7), 540–550.

    PubMed  CAS  Google Scholar 

  44. Muller, C. A., Homey, B., Sato, H., Ge, N., Catron, D., Buchanan, M., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410, 50–56.

    PubMed  CAS  Google Scholar 

  45. 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.

    PubMed  CAS  Google Scholar 

  46. American Cancer Society (2003). American Cancer Society, Cancer Facts & Figures 2003. 1–52.

  47. Sun, Y-X, Wang, J., Shelburne, C. E., Lopatin, D. E., Chinnaiyan, A. M., Pienta, K. J., et al. (2003). The expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. Journal of Cellular Biochemistry, 89, 462–473.

    PubMed  CAS  Google Scholar 

  48. Krempien, B. (1995). Pathogenesis of bone metastasis and tumor osteopathies. Radiologe, 35(1), 1–7.

    PubMed  CAS  Google Scholar 

  49. Weiss, L., Orr, F. W., & Honn, K. V. (1988). Interactions of cancer cells with the microvasculature during metastasis. FASEB Journal, 2(1), 12–21.

    PubMed  CAS  Google Scholar 

  50. Liu, A. Y., Roudier, M. P., & True, L. D. (2004). Heterogeneity in primary and metastatic prostate cancer as defined by cell surface CD profile. American Journal of Pathology, 165(5), 1543–1556.

    PubMed  Google Scholar 

  51. Keller, E. T., Zhang, J., Cooper, C. R., Smith, P. C., McCauley, L. K., & Pienta, K. J. (2001). Prostate carcinoma skeletal metastases: Cross-talk between tumor and bone. Cancer Metastasis Reviews, 20(3–4), 333–349.

    PubMed  CAS  Google Scholar 

  52. Glinsky, V. V., Glinsky, G. V., Rittenhouse-Olson, K., Huflejt, M. E., Glinskii, O. V., Deutscher, S. L., et al. (2001). The role of Thomsen–Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. Cancer Research, 61(12), 4851–4857.

    PubMed  CAS  Google Scholar 

  53. Cooper, C. R., Bhatia, J. K., Muenchen, H. J., McLean, L., Hayasaka, S., Taylor, J., et al. (2002). The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines. Clinical & Experimental Metastasis, 19(1), 25–33.

    CAS  Google Scholar 

  54. 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 alpha(5) and beta(3) integrins. Neoplasia, 8(4), 290–301.

    PubMed  CAS  Google Scholar 

  55. Sun, Y-X, Fang, M., Wang, J. H., Cooper, C. R., Pienta, K. J., & Taichman, R. S. (2007). Expression and activation of αvβ3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate, 67(1), 61–73.

    PubMed  CAS  Google Scholar 

  56. Thalmann, G. N., Anezinis, P. E., Chang, S. M., Zhau, H. E., Kim, E. E., Hopwood, V. L., et al. (1994). Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Research, 54(10), 2577–2581.

    PubMed  CAS  Google Scholar 

  57. Dhanasekaran, S. M., Barrette, T. R., Ghosh, D., Shah, R., Varambally, S., Kurachi, K., et al. (2001). Delineation of prognostic biomarkers in prostate cancer. Nature, 412, 822–826.

    PubMed  CAS  Google Scholar 

  58. Havens, A. M., Jung, Y., Sun, Y. X., & Taichman, R. S. (2006). The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis. BMC Cancer, 6(1), 195.

    PubMed  CAS  Google Scholar 

  59. Chan, J. Y-H., Lee-Prudhoe, J. E., Jorgensen, B., Ihrke, G., Doyonnas, R., Zannettino, A. C. W., et al. (2001). Relationship between novel isoforms, functionally important domains, and subcellular distribution of CD164/Endolyn. Journal of Biological Chemistry, 276(3), 2139–2152.

    PubMed  CAS  Google Scholar 

  60. Fernandis, A. Z., Cherla, R. P., & Ganju, R. K. (2003). Differential regulation of CXCR4-mediated T-cell chemotaxis and mitogen-activated protein kinase activation by the membrane tyrosine phosphatase, CD45. Journal of Biological Chemistry, 278(11), 9536–9543.

    PubMed  CAS  Google Scholar 

  61. Chinni, S. R., Sivalogan, S., Dong, Z., Filho, J. C., Deng, X., Bonfil, R. D., et al. (2006). CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: The role of bone microenvironment-associated CXCL12. Prostate, 66(1), 32–48.

    PubMed  CAS  Google Scholar 

  62. Wang, J. H., Wang, J., Sun, Y-X, Song, W., Nor, J., Wang, C. Y., et al. (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.

    PubMed  CAS  Google Scholar 

  63. Kukreja, P., Abdel-Mageed, A. B., Mondal, D., & Agrawal, K. C. (2004). SDF-1 alpha induced NF-kappa B activation promotes adhesion and trans-endothelial migration of prostate cancer cells by enhancing the expression of the chemokine receptor CXCR4. Blood, 104(11), 367A.

    Google Scholar 

  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. Journal of Biological Chemistry, 277(20), 18111–18117.

    PubMed  CAS  Google Scholar 

  65. Zhou, Y., Larsen, P. H., Hao, C., & Yong, V. W. (2002). CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. Journal of Biological Chemistry, 277(51), 49481–49487.

    PubMed  CAS  Google Scholar 

  66. 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.

    PubMed  CAS  Google Scholar 

  67. 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.

    PubMed  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. Libura, J. D. (2002). CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood, 100(7), 2597–2606.

    PubMed  CAS  Google Scholar 

  70. Rossi, D., & Zlotnik, A. (2000). The biology of chemokines and their receptors. Annual Review of Immunology, 18, 217–242.

    PubMed  CAS  Google Scholar 

  71. Strieter, R. M., Polverini, P. J., Arenberg, D. A., Walz, A., Opdenakker, G., Van, D., et al. (1995). Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. Journal of Leukocyte Biology, 57(5), 752–762.

    PubMed  CAS  Google Scholar 

  72. Salvucci, O., Yao, L., Villalba, S., Sajewicz, A., Pittaluga, S., & Tosato, G. (2002). Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood, 99(8), 2703–2711.

    PubMed  CAS  Google Scholar 

  73. Mirshahi, F., Pourtau, J., Li, H., Muraine, M., Trochon, V., Legrand, E., et al. (2000). SDF-1 activity on microvascular endothelial cells: Consequences on angiogenesis in in vitro and in vivo models. Thrombosis Research, 99(6), 587–594.

    PubMed  CAS  Google Scholar 

  74. Bautz, F., Rafii, S., Kanz, L., & Mohle, R. (2000). Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment. Experimental Hematology, 28(6), 700–706.

    PubMed  CAS  Google Scholar 

  75. 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. FASEB Journal, 18(11), 1240–1242.

    PubMed  CAS  Google Scholar 

  76. Seo, D. W., Li, H., Guedez, L., Wingfield, P. T., Diaz, T., Salloum, R., et al. (2003). TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell, 114(2), 171–180.

    PubMed  CAS  Google Scholar 

  77. 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.

    PubMed  CAS  Google Scholar 

  78. Li, Y. M., Pan, Y., Wei, Y., Cheng, X., Zhou, B. P., Tan, M., et al. (2004). Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell, 6(5), 459–469.

    PubMed  CAS  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. Kang, Y. B., Siegel, P. M., Shu, W. P., 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.

    PubMed  CAS  Google Scholar 

  81. 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.

    PubMed  CAS  Google Scholar 

  82. 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.

    PubMed  CAS  Google Scholar 

  83. Salvucci, O., Bouchard, A., Baccarelli, A., Deschenes, J., Sauter, G., Simon, R., et al. (2006). The role of CXCR4 receptor expression in breast cancer: A large tissue microarray study. Breast Cancer Research and Treatment, 97(3), 275–283.

    PubMed  CAS  Google Scholar 

  84. Kato, M., Kitayama, J., Kazama, S., & Nagawa, H. (2003). Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Research, 5(5), R144–R150.

    PubMed  CAS  Google Scholar 

  85. 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.

    PubMed  CAS  Google Scholar 

  86. 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.

    PubMed  CAS  Google Scholar 

  87. 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 Yixue Zazhi, 85(17), 1190–1194.

    PubMed  CAS  Google Scholar 

  88. 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.

    PubMed  CAS  Google Scholar 

  89. Phillips, R. J., Mestas, J., Gharee-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-1 alpha. Journal of Biological Chemistry, 280(23), 22473–22481.

    PubMed  CAS  Google Scholar 

  90. 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.

    PubMed  CAS  Google Scholar 

  91. 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.

    CAS  Google Scholar 

  92. 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.

    PubMed  CAS  Google Scholar 

  93. 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. Nature Medicine, 9(9), 1158–1165.

    PubMed  CAS  Google Scholar 

  94. Sanz-Rodriguez, F., Hidalgo, A., & Teixido, J. (2001). Chemokine stromal cell-derived factor-1 alpha modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1. Blood, 97(2), 346–351.

    PubMed  CAS  Google Scholar 

  95. 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.

    PubMed  CAS  Google Scholar 

  96. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.

    Google Scholar 

  97. Li, L., & Neaves, W. B. (2006). Normal stem cells and cancer stem cells: The niche matters. Cancer Research, 66(9), 4553–4557.

    PubMed  CAS  Google Scholar 

  98. 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, 475–482.

    PubMed  CAS  Google Scholar 

  99. Rak, J. (2006). Is cancer stem cell a cell, or a multicellular unit capable of inducing angiogenesis? Medical Hypotheses, 66(3), 601–604.

    PubMed  CAS  Google Scholar 

  100. Polyak, K., & Hahn, W. C. (2006). Roots and stems: Stem cells in cancer. Nature Medicine, 12(3), 296–300.

    CAS  Google Scholar 

  101. Clarke, M. F., & Fuller, M. (2006). Stem cells and cancer: Two faces of eve. Cell, 124(6), 1111–1115.

    PubMed  CAS  Google Scholar 

  102. 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.

    PubMed  CAS  Google Scholar 

  103. 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.

    PubMed  CAS  Google Scholar 

  104. Bradstock, K. F., Makrynikola, V., Bianchi, A., Shen, W., Hewson, J., & Gottlieb, D. J. (2000). Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers. Leukemia, 14(5), 882–888.

    PubMed  CAS  Google Scholar 

  105. Loetscher, P., Gong, J. H., Dewald, B., Baggiolini, M., & Clark-Lewis, I. (1998). N-terminal peptides of stromal cell-derived factor-1 with CXC chemokine receptor 4 agonist and antagonist activities. Journal of Biological Chemistry, 273(35), 22279–22283.

    PubMed  CAS  Google Scholar 

  106. Obrien, W. A., SumnerSmith, M., Mao, S. H., Sadeghi, S., Zhao, J. Q., & Chen, I. Y. (1996). Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions. Journal of Virology, 70(5), 2825–2831.

    CAS  Google Scholar 

  107. Tamamura, H., Sugioka, M., Odagaki, Y., Omagari, A., Kan, Y., Oishi, S., et al. (2001). Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity. Bioorganic & Medicinal Chemistry Letters, 11(3), 359–362.

    CAS  Google Scholar 

  108. Liang, Z. X., Wu, T., Lou, H., Yu, X. W., Taichman, R. S., Lau, S. K., et al. (2004). Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Research, 64(12), 4302–4308.

    PubMed  CAS  Google Scholar 

  109. Jordan, N. J., Kolios, G., Abbot, S. E., Sinai, M. A., Thompson, D. A., Petraki, K., et al. (1999). Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. Journal of Clinical Investigation, 104(8), 1061–1069.

    Article  PubMed  CAS  Google Scholar 

  110. Rubin, J. B., Kung, A. L., Klein, R. S., Chan, J. A., Sun, Y. P., 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.

    PubMed  CAS  Google Scholar 

  111. Taichman, R. S., Cooper, C., Keller, E. T., Pienta, K. J., Taichman, N., & McCauley, L. K. (2002). Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Research, 62, 1832–1837.

    PubMed  CAS  Google Scholar 

  112. Cooper, C. R., Sikes, R. A., Nicholson, B. E., Sun, Y. X., Pienta, K. J., & Taichman, R. S. (2004). Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Cancer Treatment and Research, 118, 291–309.

    PubMed  CAS  Google Scholar 

  113. 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, 600–603.

    PubMed  CAS  Google Scholar 

  114. 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. Developments in Biologicals, 213(2), 442–456.

    CAS  Google Scholar 

  115. 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.

    PubMed  CAS  Google Scholar 

  116. Robledo, M. M., Bartolome, R. A., Longo, N., Rodriguez-Frade, J. M., Mellado, M., Longo, I., et al. (2001). Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. Journal of Biological Chemistry, 276(48), 45098–45105.

    PubMed  CAS  Google Scholar 

  117. Gerritsen, M. E., Peale, F. V. Jr., & Wu, T. (2002). Gene expression profiling in silico: Relative expression of candidate angiogenesis associated genes in renal cell carcinomas. Experimental Nephrology, 10(2), 114–119.

    PubMed  CAS  Google Scholar 

  118. 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.

    PubMed  CAS  Google Scholar 

  119. Eitner, F., Cui, Y., Hudkins, K. L., & Alpers, C. E. (1998). Chemokine receptor (CXCR4) mRNA-expressing leukocytes are increased in human renal allograft rejection. Transplantation, 66(11), 1551–1557.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, MI, 48109-1078, USA

    Jianhua Wang & Russell S. Taichman

  2. Department of Internal Medicine, Division of Hemotology/Oncology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA

    Robert Loberg

Authors
  1. Jianhua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Loberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Russell S. Taichman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Russell S. Taichman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Loberg, R. & Taichman, R.S. The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Rev 25, 573–587 (2006). https://doi.org/10.1007/s10555-006-9019-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-006-9019-x

Keywords

Search

Navigation