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CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Leukemia volume 23, pages 43–52 (2009)Cite this article

Abstract

Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor–stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.

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References

  1. Zlotnik A, Yoshie O . Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121–127.

    CAS  PubMed  Google Scholar 

  2. Loetscher P, Moser B, Baggiolini M . Chemokines and their receptors in lymphocyte traffic and HIV infection. Adv Immunol 2000; 74: 127–180.

    CAS  PubMed  Google Scholar 

  3. Baggiolini M . Chemokines and leukocyte traffic. Nature 1998; 392: 565–568.

    CAS  PubMed  Google Scholar 

  4. Moser B, Loetscher P . Lymphocyte traffic control by chemokines. Nat Immunol 2001; 2: 123–128.

    CAS  PubMed  Google Scholar 

  5. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382: 829–833.

    CAS  PubMed  Google Scholar 

  6. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1 [published erratum appears in Nature 1996;384: 288]. Nature 1996; 382: 833–835.

    CAS  PubMed  Google Scholar 

  7. Nagasawa T, Kikutani H, Kishimoto T . Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci USA 1994; 91: 2305–2309.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Feng Y, Broder CC, Kennedy PE, Berger EA . HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor [see comments]. Science 1996; 272: 872–877.

    CAS  PubMed  Google Scholar 

  9. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.

    CAS  PubMed  Google Scholar 

  10. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract [see comments]. Nature 1998; 393: 591–594.

    CAS  PubMed  Google Scholar 

  11. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development [see comments]. Nature 1998; 393: 595–599.

    CAS  PubMed  Google Scholar 

  12. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 1998; 95: 9448–9453.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 2008; 132: 463–473.

    Article  CAS  PubMed  Google Scholar 

  14. Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA 2007; 104: 14759–14764.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    CAS  PubMed  Google Scholar 

  16. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283: 845–848.

    CAS  PubMed  Google Scholar 

  17. Sugiyama T, Kohara H, Noda M, Nagasawa T . Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006; 25: 977–988.

    CAS  PubMed  Google Scholar 

  18. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 2005; 435: 969–973.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL . Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 2002; 195: 1145–1154.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Moore KA, Lemischka IR . Stem cells and their niches. Science 2006; 311: 1880–1885.

    CAS  PubMed  Google Scholar 

  21. Morrison SJ, Spradling AC . Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132: 598–611.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Laird DJ, von Andrian UH, Wagers AJ . Stem cell trafficking in tissue development, growth, and disease. Cell 2008; 132: 612–630.

    CAS  PubMed  Google Scholar 

  23. Honczarenko M, Douglas RS, Mathias C, Lee B, Ratajczak MZ, Silberstein LE . SDF-1 responsiveness does not correlate with CXCR4 expression levels of developing human bone marrow B cells. Blood 1999; 94: 2990–2998.

    CAS  PubMed  Google Scholar 

  24. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM . Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003; 19: 583–593.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  26. Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, Suzuki G et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J Exp Med 2001; 194: 45–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Cyster JG . Homing of antibody secreting cells. Immunol Rev 2003; 194: 48–60.

    CAS  PubMed  Google Scholar 

  28. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007; 109: 2708–2717.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    CAS  PubMed  Google Scholar 

  30. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    CAS  PubMed  Google Scholar 

  31. Lessard J, Sauvageau G . Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003; 423: 255–260.

    CAS  PubMed  Google Scholar 

  32. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11: 69–82.

    CAS  PubMed  Google Scholar 

  33. Yang ZJ, Wechsler-Reya RJ . Hit ‘em where they live: targeting the cancer stem cell niche. Cancer Cell 2007; 11: 3–5.

    CAS  PubMed  Google Scholar 

  34. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005; 201: 1307–1318.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cashen AF, Nervi B, DiPersio J . AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncol 2007; 3: 19–27.

    CAS  PubMed  Google Scholar 

  36. Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E et al. Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 antagonist 4F-benzoyl-TN14003. Stem Cells 2007; 25: 2158–2166.

    CAS  PubMed  Google Scholar 

  37. Burger JA, Kipps TJ . CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006; 107: 1761–1767.

    CAS  PubMed  Google Scholar 

  38. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

    CAS  PubMed  Google Scholar 

  39. Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ . Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 2004; 110: 3300–3305.

    PubMed  Google Scholar 

  40. Hu X, Dai S, Wu WJ, Tan W, Zhu X, Mu J et al. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation 2007; 116: 654–663.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Segers VF, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT . Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 2007; 116: 1683–1692.

    CAS  PubMed  Google Scholar 

  42. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W . Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 2003; 425: 307–311.

    CAS  PubMed  Google Scholar 

  43. Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA et al. Stromal cell-derived factor-1{alpha} and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel–Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 2005; 65: 6178–6188.

    CAS  PubMed  Google Scholar 

  44. Burger JA, Burkle A . The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. Br J Haematol 2007; 137: 288–296.

    CAS  PubMed  Google Scholar 

  45. Orimo A, Weinberg RA . Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006; 5: 1597–1601.

    CAS  PubMed  Google Scholar 

  46. Liotta LA . An attractive force in metastasis. Nature 2001; 410: 24–25.

    CAS  PubMed  Google Scholar 

  47. Burger JA, Burger M, Kipps TJ . Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 1999; 94: 3658–3667.

    CAS  PubMed  Google Scholar 

  48. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    CAS  PubMed  Google Scholar 

  49. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ . Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 2000; 96: 2655–2663.

    CAS  PubMed  Google Scholar 

  50. Burger M, Glodek A, Hartmann T, Schmitt-Graff A, Silberstein LE, Fujii N et al. Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. Oncogene 2003; 22: 8093–8101.

    CAS  PubMed  Google Scholar 

  51. Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 2005; 106: 1824–1830.

    CAS  PubMed  Google Scholar 

  52. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–1667.

    CAS  PubMed  Google Scholar 

  53. Li ZW, Dalton WS . Tumor microenvironment and drug resistance in hematologic malignancies. Blood Rev 2006; 20: 333–342.

    PubMed  Google Scholar 

  54. Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 2005; 106: 1824–1830.

    CAS  PubMed  Google Scholar 

  55. Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D, Dazzi F . Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 2007; 21: 304–310.

    CAS  PubMed  Google Scholar 

  56. Maestroni GJ, Hertens E, Galli P . Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cell Mol Life Sci 1999; 55: 663–667.

    CAS  PubMed  Google Scholar 

  57. Ohlsson LB, Varas L, Kjellman C, Edvardsen K, Lindvall M . Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp Mol Pathol 2003; 75: 248–255.

    CAS  PubMed  Google Scholar 

  58. Burger JA, Spoo A, Dwenger A, Burger M, Behringer D . CXCR4 chemokine receptors (CD184) and alpha4beta1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). Br J Haematol 2003; 122: 579–589.

    CAS  PubMed  Google Scholar 

  59. Pisati F, Belicchi M, Acerbi F, Marchesi C, Giussani C, Gavina M et al. Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models. Cancer Res 2007; 67: 3054–3063.

    CAS  PubMed  Google Scholar 

  60. Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 2006; 203: 1235–1247.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Nakashima H, Masuda M, Murakami T, Koyanagi Y, Matsumoto A, Fujii N et al. Anti-human immunodeficiency virus activity of a novel synthetic peptide, T22 ([Tyr-5,12, Lys-7]polyphemusin II): a possible inhibitor of virus-cell fusion. Antimicrob Agents Chemother 1992; 36: 1249–1255.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Masuda M, Nakashima H, Ueda T, Naba H, Ikoma R, Otaka A et al. A novel anti-HIV synthetic peptide, T-22 ([Tyr5,12,Lys7]-polyphemusin II). Biochem Biophys Res Commun 1992; 189: 845–850.

    CAS  PubMed  Google Scholar 

  63. De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H et al. Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci USA 1992; 89: 5286–5290.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M, De Vreese K et al. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother 1994; 38: 668–674.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Doranz BJ, Filion LG, Diaz-Mitoma F, Sitar DS, Sahai J, Baribaud F et al. Safe use of the CXCR4 inhibitor ALX40-4C in humans. AIDS Res Hum Retroviruses 2001; 17: 475–486.

    CAS  PubMed  Google Scholar 

  66. Doranz BJ, Grovit-Ferbas K, Sharron MP, Mao SH, Goetz MB, Daar ES et al. A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med 1997; 186: 1395–1400.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E . Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 1997; 186: 1383–1388.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Murakami T, Nakajima T, Koyanagi Y, Tachibana K, Fujii N, Tamamura H et al. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 1997; 186: 1389–1393.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Tamamura H, Xu Y, Hattori T, Zhang X, Arakaki R, Kanbara K et al. A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem Biophys Res Commun 1998; 253: 877–882.

    CAS  PubMed  Google Scholar 

  70. Tamamura H, Omagari A, Hiramatsu K, Gotoh K, Kanamoto T, Xu Y et al. Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140. Bioorg Med Chem Lett 2001; 11: 1897–1902.

    CAS  PubMed  Google Scholar 

  71. Trent JO, Wang ZX, Murray JL, Shao W, Tamamura H, Fujii N et al. Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists. J Biol Chem 2003; 278: 47136–47144.

    CAS  PubMed  Google Scholar 

  72. Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A et al. A point 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 2002; 277: 24515–24521.

    CAS  PubMed  Google Scholar 

  73. Tamamura H, Hori A, Kanzaki N, Hiramatsu K, Mizumoto M, Nakashima H et al. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett 2003; 550: 79–83.

    CAS  PubMed  Google Scholar 

  74. Takenaga M, Tamamura H, Hiramatsu K, Nakamura N, Yamaguchi Y, Kitagawa A et al. A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma. Biochem Biophys Res Commun 2004; 320: 226–232.

    CAS  PubMed  Google Scholar 

  75. Tamamura H, Fujisawa M, Hiramatsu K, Mizumoto M, Nakashima H, Yamamoto N et al. Identification of a CXCR4 antagonist, a T140 analog, as an anti-rheumatoid arthritis agent. FEBS Lett 2004; 569: 99–104.

    CAS  PubMed  Google Scholar 

  76. Juarez J, Bradstock KF, Gottlieb DJ, Bendall LJ . Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 2003; 17: 1294–1300.

    CAS  PubMed  Google Scholar 

  77. Juarez J, Dela Pena A, Baraz R, Hewson J, Khoo M, Cisterne A et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 2007; 21: 1249–1257.

    CAS  PubMed  Google Scholar 

  78. Zannettino AC, Farrugia AN, Kortesidis A, Manavis J, To LB, Martin SK et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res 2005; 65: 1700–1709.

    CAS  PubMed  Google Scholar 

  79. Mori T, Doi R, Koizumi M, Toyoda E, Ito D, Kami K et al. CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther 2004; 3: 29–37.

    CAS  PubMed  Google Scholar 

  80. Kohara H, Omatsu Y, Sugiyama T, Noda M, Fujii N, Nagasawa T . Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling. Blood 2007; 110: 4153–4160.

    CAS  PubMed  Google Scholar 

  81. Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, Kobayashi M et al. CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol 2007; 171: 1249–1257.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 2004; 5: 943–952.

    CAS  PubMed  Google Scholar 

  83. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002; 3: 687–694.

    CAS  PubMed  Google Scholar 

  84. De Clercq E . The bicyclam AMD3100 story. Nat Rev Drug Discov 2003; 2: 581–587.

    CAS  PubMed  Google Scholar 

  85. Fricker SP, Anastassov V, Cox J, Darkes MC, Grujic O, Idzan SR et al. Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem Pharmacol 2006; 72: 588–596.

    CAS  PubMed  Google Scholar 

  86. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 1998; 4: 72–77.

    CAS  PubMed  Google Scholar 

  87. Hendrix CW, Flexner C, MacFarland RT, Giandomenico C, Fuchs EJ, Redpath E et al. Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 2000; 44: 1667–1673.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Hendrix CW, Collier AC, Lederman MM, Schols D, Pollard RB, Brown S et al. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 2004; 37: 1253–1262.

    CAS  PubMed  Google Scholar 

  89. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102: 2728–2730.

    CAS  PubMed  Google Scholar 

  90. Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K et al. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol 2004; 22: 1095–1102.

    CAS  PubMed  Google Scholar 

  91. Stone ND, Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S et al. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects. Antimicrob Agents Chemother 2007; 51: 2351–2358.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ichiyama K, Yokoyama-Kumakura S, Tanaka Y, Tanaka R, Hirose K, Bannai K et al. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 2003; 100: 4185–4190.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Endres MJ, Clapham PR, Marsh M, Ahuja M, Turner JD, McKnight A et al. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 1996; 87: 745–756.

    CAS  PubMed  Google Scholar 

  94. D'Apuzzo M, Rolink A, Loetscher M, Hoxie JA, Clark-Lewis I, Melchers F et al. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol 1997; 27: 1788–1793.

    CAS  PubMed  Google Scholar 

  95. Bertolini F, Dell'Agnola C, Mancuso P, Rabascio C, Burlini A, Monestiroli S et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res 2002; 62: 3106–3112.

    CAS  PubMed  Google Scholar 

  96. Chen GS, Yu HS, Lan CC, Chow KC, Lin TY, Kok LF et al. CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol 2006; 154: 910–918.

    CAS  PubMed  Google Scholar 

  97. Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP, Strieter RM . The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 2003; 167: 1676–1686.

    PubMed  Google Scholar 

  98. Engl T, Relja B, Marian D, Blumenberg C, Muller I, Beecken WD et al. CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 2006; 8: 290–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Baribaud F, Edwards TG, Sharron M, Brelot A, Heveker N, Price K et al. Antigenically distinct conformations of CXCR4. J Virol 2001; 75: 8957–8967.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Farzan M, Babcock GJ, Vasilieva N, Wright PL, Kiprilov E, Mirzabekov T et al. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1 alpha association and HIV-1 entry. J Biol Chem 2002; 277: 29484–29489.

    CAS  PubMed  Google Scholar 

  101. Kim SY, Lee CH, Midura BV, Yeung C, Mendoza A, Hong SH et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis 2008; 25: 201–211.

    CAS  PubMed  Google Scholar 

  102. Mohle R, Failenschmid C, Bautz F, Kanz L . Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia 1999; 13: 1954–1959.

    CAS  PubMed  Google Scholar 

  103. Scholzel C, Lowenberg B . Stimulation of proliferation and differentiation of acute myeloid leukemia cells on a bone marrow stroma in culture. Exp Hematol 1985; 13: 664–669.

    CAS  PubMed  Google Scholar 

  104. Bendall LJ, Daniel A, Kortlepel K, Gottlieb DJ . Bone marrow adherent layers inhibit apoptosis of acute myeloid leukemia cells. Exp Hematol 1994; 22: 1252–1260.

    CAS  PubMed  Google Scholar 

  105. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M . Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 2002; 16: 1713–1724.

    CAS  PubMed  Google Scholar 

  106. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9: 1158–1165.

    CAS  PubMed  Google Scholar 

  107. Bendall LJ, Kortlepel K, Gottlieb DJ . Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms. Blood 1993; 82: 3125–3132.

    CAS  PubMed  Google Scholar 

  108. Delforge M, Raets V, Van Duppen V, Vandenberghe P, Boogaerts M . CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of alpha4beta1 and alpha5beta1 integrins. Leukemia 2005; 19: 57–63.

    CAS  PubMed  Google Scholar 

  109. Hamada T, Mohle R, Hesselgesser J, Hoxie J, Nachman RL, Moore MA et al. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 1998; 188: 539–548.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Mohle R, Schittenhelm M, Failenschmid C, Bautz F, Kratz-Albers K, Serve H et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol 2000; 110: 563–572.

    CAS  PubMed  Google Scholar 

  111. Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004; 64: 2817–2824.

    CAS  PubMed  Google Scholar 

  112. Tavor S, Petit I, Porozov S, Goichberg P, Avigdor A, Sagiv S et al. Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice. Blood 2005; 106: 2120–2127.

    CAS  PubMed  Google Scholar 

  113. Hope KJ, Jin L, Dick JE . Human acute myeloid leukemia stem cells. Arch Med Res 2003; 34: 507–514.

    CAS  PubMed  Google Scholar 

  114. Spoo AC, Lubbert M, Wierda WG, Burger JA . CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007; 109: 786–791.

    CAS  PubMed  Google Scholar 

  115. Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE . Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004; 104: 550–557.

    CAS  PubMed  Google Scholar 

  116. Konoplev S, Rassidakis GZ, Estey E, Kantarjian H, Liakou CI, Huang X et al. Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype. Cancer 2007; 109: 1152–1156.

    CAS  PubMed  Google Scholar 

  117. Uy GL, Rettig MP, Ramirez P, Nervi B, Abboud CN, DiPersio JF . Kinetics of human and murine mobilization of acute myelogenous leukemia in response to AMD3100. Blood 2007; 110: 265a.

    Google Scholar 

  118. Andreeff M, Konoplev S, Wang RY, Zeng Z, McQueen T, Shi YX et al. Massive mobilization of AML cells into circulation by disruption of leukemia/stroma cell interactions using CXCR4 antagonist AMD3100: first evidence in patients and potential for abolishing bone marrow microenvironment-mediated resistance. Blood 2006; 108 (ASH Annual Meeting Abstracts): 176a (Abstract 568).

    Google Scholar 

  119. Nagasawa T . Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 2006; 6: 107–116.

    CAS  PubMed  Google Scholar 

  120. Burger JA, Zvaifler NJ, Tsukada N, Firestein GS, Kipps TJ . Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J Clin Invest 2001; 107: 305–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Bradstock KF, Makrynikola V, Bianchi A, Shen W, Hewson J, Gottlieb DJ . 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 [in process citation]. Leukemia 2000; 14: 882–888.

    CAS  PubMed  Google Scholar 

  122. Corcione A, Arduino N, Ferretti E, Pistorio A, Spinelli M, Ottonello L et al. Chemokine receptor expression and function in childhood acute lymphoblastic leukemia of B-lineage. Leuk Res 2006; 30: 365–372.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  124. Spiegel A, Kollet O, Peled A, Abel L, Nagler A, Bielorai B et al. Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 2004; 103: 2900–2907.

    CAS  PubMed  Google Scholar 

  125. Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D . Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest 2007; 117: 1049–1057.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Williams DA . A new mechanism of leukemia drug resistance? N Engl J Med 2007; 357: 77–78.

    CAS  PubMed  Google Scholar 

  127. Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 2004; 6: 459–469.

    CAS  PubMed  Google Scholar 

  128. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 2004; 64: 8604–8612.

    CAS  PubMed  Google Scholar 

  129. Kijima T, Maulik G, Ma PC, Tibaldi EV, Turner RE, Rollins B et al. Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 2002; 62: 6304–6311.

    CAS  PubMed  Google Scholar 

  130. Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M . CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 2005; 24: 4462–4471.

    CAS  PubMed  Google Scholar 

  131. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 1999; 5: 662–668.

    CAS  PubMed  Google Scholar 

  132. Ara T, Itoi M, Kawabata K, Egawa T, Tokoyoda K, Sugiyama T et al. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J Immunol 2003; 170: 4649–4655.

    CAS  PubMed  Google Scholar 

  133. Cabioglu N, Summy J, Miller C, Parikh NU, Sahin AA, Tuzlali S et al. CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation. Cancer Res 2005; 65: 6493–6497.

    CAS  PubMed  Google Scholar 

  134. Marchesi F, Monti P, Leone BE, Zerbi A, Vecchi A, Piemonti L et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer Res 2004; 64: 8420–8427.

    CAS  PubMed  Google Scholar 

  135. Ohira S, Sasaki M, Harada K, Sato Y, Zen Y, Isse K et al. Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of CXCR4 expressed in carcinoma cells with tumor necrosis factor-alpha and stromal-derived factor-1 released in stroma. Am J Pathol 2006; 168: 1155–1168.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Yasumoto K, Koizumi K, Kawashima A, Saitoh Y, Arita Y, Shinohara K et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res 2006; 66: 2181–2187.

    CAS  PubMed  Google Scholar 

  137. Ottaiano A, Franco R, Aiello Talamanca A, Liguori G, Tatangelo F, Delrio P et al. Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II–III colorectal cancer patients. Clin Cancer Res 2006; 12: 2795–2803.

    CAS  PubMed  Google Scholar 

  138. Scala S, Giuliano P, Ascierto PA, Ierano C, Franco R, Napolitano M et al. Human melanoma metastases express functional CXCR4. Clin Cancer Res 2006; 12: 2427–2433.

    CAS  PubMed  Google Scholar 

  139. Lee CH, Kakinuma T, Wang J, Zhang H, Palmer DC, Restifo NP et al. Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases. Mol Cancer Ther 2006; 5: 2592–2599.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Hong X, Jiang F, Kalkanis SN, Zhang ZG, Zhang XP, DeCarvalho AC et al. SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion. Cancer Lett 2006; 236: 39–45.

    CAS  PubMed  Google Scholar 

  141. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 2003; 100: 13513–13518.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 2002; 62: 5930–5938.

    CAS  PubMed  Google Scholar 

  143. Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M et al. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood 2002; 100: 2597–2606.

    CAS  PubMed  Google Scholar 

  144. Hart CA, Brown M, Bagley S, Sharrard M, Clarke NW . Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process. Br J Cancer 2005; 92: 503–512.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Zeng Z, Samudio IJ, Munsell M, An J, Huang Z, Estey E et al. Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. Mol Cancer Ther 2006; 5: 3113–3121.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize that due to space limitation we were not able to discuss and cite a number of additional studies of other investigators that are related to CXCR4 antagonists in leukemia and other neoplastic diseases. This study was supported by an ASCO Career Development Award (to JAB), a Kimmel Scholar Award by the Sidney Kimmel Foundation for Cancer Research (to JAB) and a CLL Global Research Foundation grant (to JAB).

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  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J A Burger

  2. Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel

    A Peled

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Correspondence to J A Burger.

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Burger, J., Peled, A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23, 43–52 (2009). https://doi.org/10.1038/leu.2008.299

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