Cancer and Metastasis Reviews

, Volume 34, Issue 4, pp 575–591 | Cite as

Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis

  • Martin Schlesinger
  • Gerd Bendas
Non-Thematic Review


The integrin “very late antigen-4” (VLA-4) is expressed by numerous cells of hematopoietic origin and possesses a key function in the cellular immune response, e.g., by mediating leukocyte tethering, rolling, binding, and finally transmigration of the vascular wall at inflammatory sites. Thus, VLA-4 is a valuable target in medical sciences to interfere with pathological inflammations. In addition, leukemic cells and different solid tumors, which express VLA-4, make use of these adhesive functions and confer VLA-4 a progressive role in the metastatic spread. With a growing insight into the molecular mechanisms for creating a tumor-friendly microenvironment at metastatic sites and various tumor host interactions, the multiple functions of VLA-4 became evident recently, e.g., in leukocyte recruitment to micrometastases, the protection of tumors from immune surveillance, or contribution to a chemoresistance. Nevertheless, despite accumulating evidence for several functions of VLA-4 in tumorigenicity, a therapeutic interference with VLA-4 in cancer sciences has not been developed yet to the clinical level, undoubtedly by a marked impact on the physiological immune response. This review gives an up to date insight into the multiple functional role of VLA-4 in cancer and introduces this integrin as a promising target worthwhile to attract attention in biomedical cancer research.


VCAM-1 VLA-4 Integrin Metastasis Cancer Angiogenesis 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hemler, M. E. (1990). VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annual Review of Immunology, 8, 365–400.PubMedCrossRefGoogle Scholar
  2. 2.
    Kinashi, T. (2005). Intracellular signalling controlling integrin activation in lymphocytes. Nature Reviews Immunology, 5(7), 546–559.PubMedCrossRefGoogle Scholar
  3. 3.
    Phillips, D. R., Fitzgerald, L. A., Charo, I. F., & Parise, L. V. (1987). The platelet membrane glycoprotein IIb/IIIa complex. Structure, function, and relationship to adhesive protein receptors in nucleated cells. Annals of the New York Academy of Sciences, 509, 177–187.PubMedCrossRefGoogle Scholar
  4. 4.
    Phillips, D. R., Charo, I. F., Parise, L. V., & Fitzgerald, L. A. (1988). The platelet membrane glycoprotein IIb-IIIa complex. Blood, 71(4), 831–843.PubMedGoogle Scholar
  5. 5.
    Byron, A., Humphries, J. D., Craig, S. E., Knight, D., & Humphries, M. J. (2012). Proteomic analysis of α4β1 integrin adhesion complexes reveals α-subunit-dependent protein recruitment. Proteomics, 12(13), 2107–2114.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Humphries, J. D., Byron, A., & Humphries, M. J. (2006). Integrin ligands at a glance. Journal of Cell Science, 119(Pt 19), 3901–3903.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Luo, B.-H., & Springer, T. A. (2006). Integrin structures and conformational signaling. Current Opinion in Cell Biology, 18(5), 579–586.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Takada, Y., Strominger, J. L., & Hemler, M. E. (1987). The very late antigen family of heterodimers is part of a superfamily of molecules involved in adhesion and embryogenesis. Proceedings of the National Academy of Sciences of the United States of America, 84(10), 3239–3243.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Takada, Y., Ye, X., & Simon, S. (2007). The integrins. Genome Biology, 8(5), 215.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Hynes, R. O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell, 110(6), 673–687.PubMedCrossRefGoogle Scholar
  11. 11.
    Yang, J. T., Rayburn, H., & Hynes, R. O. (1995). Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development (Cambridge, England), 121(2), 549–560.Google Scholar
  12. 12.
    Luo, B.-H., Carman, C. V., & Springer, T. A. (2007). Structural basis of integrin regulation and signaling. Annual Review of Immunology, 25, 619–647.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Bayless, K. J., Meininger, G. A., Scholtz, J. M., & Davis, G. E. (1998). Osteopontin is a ligand for the alpha4beta1 integrin. Journal of Cell Science, 111(Pt 9), 1165–1174.PubMedGoogle Scholar
  14. 14.
    Clements, J. M., Newham, P., Shepherd, M., Gilbert, R., Dudgeon, T. J., Needham, L. A., & Humphries, M. J. (1994). Identification of a key integrin-binding sequence in VCAM-1 homologous to the LDV active site in fibronectin. Journal of Cell Science, 107(Pt 8), 2127–2135.PubMedGoogle Scholar
  15. 15.
    Hemler, M. E., Huang, C., & Schwarz, L. (1987). The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight beta subunit. The Journal of Biological Chemistry, 262(7), 3300–3309.PubMedGoogle Scholar
  16. 16.
    Hemler, M. E., Huang, C., Takada, Y., Schwarz, L., Strominger, J. L., & Clabby, M. L. (1987). Characterization of the cell surface heterodimer VLA-4 and related peptides. The Journal of Biological Chemistry, 262(24), 11478–11485.PubMedGoogle Scholar
  17. 17.
    Takada, Y., Elices, M. J., Crouse, C., & Hemler, M. E. (1989). The primary structure of the alpha 4 subunit of VLA-4: homology to other integrins and a possible cell-cell adhesion function. The EMBO Journal, 8(5), 1361–1368.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Chigaev, A., & Sklar, L. A. (2012). Aspects of VLA-4 and LFA-1 regulation that may contribute to rolling and firm adhesion. Frontiers in Immunology, 3, 242.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Elices, M. J., Osborn, L., Takada, Y., Crouse, C., Luhowskyj, S., Hemler, M. E., & Lobb, R. R. (1990). VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell, 60(4), 577–584.PubMedCrossRefGoogle Scholar
  20. 20.
    Shimizu, Y., van Seventer, G. A., Horgan, K. J., & Shaw, S. (1990). Costimulation of proliferative responses of resting CD4+ T cells by the interaction of VLA-4 and VLA-5 with fibronectin or VLA-6 with laminin. Journal of Immunology, 145(1), 59–67.Google Scholar
  21. 21.
    Bridges, L. C., Sheppard, D., & Bowditch, R. D. (2005). ADAM disintegrin-like domain recognition by the lymphocyte integrins alpha4beta1 and alpha4beta7. The Biochemical Journal, 387(Pt 1), 101–108.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Humphries, J. D., & Humphries, M. J. (2007). CD14 is a ligand for the integrin alpha4beta1. FEBS Letters, 581(4), 757–763.PubMedCrossRefGoogle Scholar
  23. 23.
    El Nemer, W., Wautier, M.-P., Rahuel, C., Gane, P., Hermand, P., Galactéros, F., & Le Van Kim, C. (2007). Endothelial Lu/BCAM glycoproteins are novel ligands for red blood cell alpha4beta1 integrin: role in adhesion of sickle red blood cells to endothelial cells. Blood, 109(8), 3544–3551.PubMedCrossRefGoogle Scholar
  24. 24.
    Huang, J., Filipe, A., Rahuel, C., Bonnin, P., Mesnard, L., Guérin, C., & Tharaux, P.-L. (2014). Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice. Kidney International, 85(5), 1123–1136.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Yang, Y., Harrison, J. E., Print, C. G., Lehnert, K., Sammar, M., Lazarovits, A., & Krissansen, G. W. (1996). Interaction of monocytoid cells with the mucosal addressin MAdCAM-1 via the integrins VLA-4 and LPAM-1. Immunology and Cell Biology, 74(5), 383–393.PubMedCrossRefGoogle Scholar
  26. 26.
    Lehnert, K., Print, C. G., Yang, Y., & Krissansen, G. W. (1998). MAdCAM-1 costimulates T cell proliferation exclusively through integrin alpha4beta7, whereas VCAM-1 and CS-1 peptide use alpha4beta1: evidence for “remote” costimulation and induction of hyperresponsiveness to B7 molecules. European Journal of Immunology, 28(11), 3605–3615.PubMedCrossRefGoogle Scholar
  27. 27.
    Berlin, C., Berg, E. L., Briskin, M. J., Andrew, D. P., Kilshaw, P. J., Holzmann, B., & Butcher, E. C. (1993). Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell, 74(1), 185–195.PubMedCrossRefGoogle Scholar
  28. 28.
    Alon, R., Kassner, P. D., Carr, M. W., Finger, E. B., Hemler, M. E., & Springer, T. A. (1995). The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. The Journal of Cell Biology, 128(6), 1243–1253.PubMedCrossRefGoogle Scholar
  29. 29.
    Berlin, C., Bargatze, R. F., Campbell, J. J., von Andrian, U. H., Szabo, M. C., Hasslen, S. R., & Butcher, E. C. (1995). Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell, 80(3), 413–422.PubMedCrossRefGoogle Scholar
  30. 30.
    Chen, C., Mobley, J. L., Dwir, O., Shimron, F., Grabovsky, V., Lobb, R. R., & Alon, R. (1999). High affinity very late antigen-4 subsets expressed on T cells are mandatory for spontaneous adhesion strengthening but not for rolling on VCAM-1 in shear flow. Journal of immunology (Baltimore, Md.: 1950), 162(2), 1084–1095.Google Scholar
  31. 31.
    Grabovsky, V., Feigelson, S., Chen, C., Bleijs, D. A., Peled, A., Cinamon, G., & Alon, R. (2000). Subsecond induction of alpha4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions. The Journal of Experimental Medicine, 192(4), 495–506.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Ding, Z., Xiong, K., & Issekutz, T. B. (2001). Chemokines stimulate human T lymphocyte transendothelial migration to utilize VLA-4 in addition to LFA-1. Journal of Leukocyte Biology, 69(3), 458–466.PubMedGoogle Scholar
  33. 33.
    Nguyen, K., Sylvain, N. R., & Bunnell, S. C. (2008). T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76. Immunity, 28(6), 810–821.PubMedCrossRefGoogle Scholar
  34. 34.
    Burkhardt, J. K. (2008). Integrins put the brakes on microcluster dynamics at the immunological synapse. Immunity, 28(6), 732–734.PubMedCrossRefGoogle Scholar
  35. 35.
    Carrasco, Y. R., & Batista, F. D. (2006). B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. The EMBO Journal, 25(4), 889–899.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Wang, Q.-Q., Li, H., Oliver, T., Glogauer, M., Guo, J., & He, Y.-W. (2008). Integrin beta 1 regulates phagosome maturation in macrophages through Rac expression. Journal of Immunology (Baltimore, Md.: 1950), 180(4), 2419–2428.CrossRefGoogle Scholar
  37. 37.
    Milner, R., & Campbell, I. L. (2002). Developmental regulation of beta1 integrins during angiogenesis in the central nervous system. Molecular and Cellular Neurosciences, 20(4), 616–626.PubMedCrossRefGoogle Scholar
  38. 38.
    Lawrence, M. B., & Springer, T. A. (1991). Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell, 65(5), 859–873.PubMedCrossRefGoogle Scholar
  39. 39.
    Von Andrian, U. H., Chambers, J. D., McEvoy, L. M., Bargatze, R. F., Arfors, K. E., & Butcher, E. C. (1991). Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proceedings of the National Academy of Sciences of the United States of America, 88(17), 7538–7542.CrossRefGoogle Scholar
  40. 40.
    Masumoto, A., & Hemler, M. E. (1993). Multiple activation states of VLA-4. Mechanistic differences between adhesion to CS1/fibronectin and to vascular cell adhesion molecule-1. The Journal of Biological Chemistry, 268(1), 228–234.PubMedGoogle Scholar
  41. 41.
    Chigaev, A., Waller, A., Zwartz, G. J., Buranda, T., & Sklar, L. A. (2007). Regulation of cell adhesion by affinity and conformational unbending of alpha4beta1 integrin. Journal of Immunology, 178(11), 6828–6839.CrossRefGoogle Scholar
  42. 42.
    Chigaev, A., Waller, A., Amit, O., Halip, L., Bologa, C. G., & Sklar, L. A. (2009). Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation. The Journal of Biological Chemistry, 284(21), 14337–14346.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Zwartz, G. J., Chigaev, A., Dwyer, D. C., Foutz, T. D., Edwards, B. S., & Sklar, L. A. (2004). Real-time analysis of very late antigen-4 affinity modulation by shear. The Journal of Biological Chemistry, 279(37), 38277–38286.PubMedCrossRefGoogle Scholar
  44. 44.
    Chigaev, A., Waller, A., Amit, O., & Sklar, L. A. (2008). Galphas-coupled receptor signaling actively down-regulates alpha4beta1-integrin affinity: a possible mechanism for cell de-adhesion. BMC Immunology, 9, 26.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Chigaev, A., Smagley, Y., & Sklar, L. A. (2011). Nitric oxide/cGMP pathway signaling actively down-regulates α4β1-integrin affinity: an unexpected mechanism for inducing cell de-adhesion. BMC Immunology, 12, 28.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Fujita, M., Takada, Y. K., Izumiya, Y., & Takada, Y. (2014). The binding of monomeric C-reactive protein (mCRP) to Integrins αvβ3 and α4β1 is related to its pro-inflammatory action. PLoS ONE, 9(4), e93738.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Schmitz, P., Gerber, U., Schütze, N., Jüngel, E., Blaheta, R., Naggi, A., & Bendas, G. (2013). Cyr61 is a target for heparin in reducing MV3 melanoma cell adhesion and migration via the integrin VLA-4. Thrombosis and Haemostasis, 110(5), 1046–1054.PubMedCrossRefGoogle Scholar
  48. 48.
    Fujita, M., Takada, Y. K., & Takada, Y. (2014). The chemokine fractalkine can activate integrins without CX3CR1 through direct binding to a ligand-binding site distinct from the classical RGD-binding site. PLoS ONE, 9(5), e96372.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Fiorcari, S., Brown, W. S., McIntyre, B. W., Estrov, Z., Maffei, R., O’Brien, S., & Burger, J. A. (2013). The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells. PLoS ONE, 8(12), e83830.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Schmid, M. C., Franco, I., Kang, S. W., Hirsch, E., Quilliam, L. A., & Varner, J. A. (2013). PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth. PLoS ONE, 8(4), e60226.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Feigelson, S. W., Grabovsky, V., Winter, E., Chen, L. L., Pepinsky, R. B., Yednock, T., & Alon, R. (2001). The Src kinase p56(lck) up-regulates VLA-4 integrin affinity. Implications for rapid spontaneous and chemokine-triggered T cell adhesion to VCAM-1 and fibronectin. The Journal of Biological Chemistry, 276(17), 13891–13901.PubMedGoogle Scholar
  52. 52.
    Brown, W. S., Khalili, J. S., Rodriguez-Cruz, T. G., Lizee, G., & McIntyre, B. W. (2014). B-Raf regulation of integrin α4β1-mediated resistance to shear stress through changes in cell spreading and cytoskeletal association in T cells. The Journal of Biological Chemistry. doi: 10.1074/jbc.M114.562918.Google Scholar
  53. 53.
    De Bruyn, K. M. T., Rangarajan, S., Reedquist, K. A., Figdor, C. G., & Bos, J. L. (2002). The small GTPase Rap1 is required for Mn(2+)- and antibody-induced LFA-1- and VLA-4-mediated cell adhesion. The Journal of Biological Chemistry, 277(33), 29468–29476.PubMedCrossRefGoogle Scholar
  54. 54.
    Sánchez-Mateos, P., Campanero, M. R., Balboa, M. A., & Sánchez-Madrid, F. (1993). Co-clustering of beta 1 integrins, cytoskeletal proteins, and tyrosine-phosphorylated substrates during integrin-mediated leukocyte aggregation. Journal of Immunology, 151(7), 3817–3828.Google Scholar
  55. 55.
    Alon, R., Feigelson, S. W., Manevich, E., Rose, D. M., Schmitz, J., Overby, D. R., & Ginsberg, M. H. (2005). Alpha4beta1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the alpha4-cytoplasmic domain. The Journal of Cell Biology, 171(6), 1073–1084.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Manevich, E., Grabovsky, V., Feigelson, S. W., & Alon, R. (2007). Talin 1 and paxillin facilitate distinct steps in rapid VLA-4-mediated adhesion strengthening to vascular cell adhesion molecule 1. The Journal of Biological Chemistry, 282(35), 25338–25348.PubMedCrossRefGoogle Scholar
  57. 57.
    Hyduk, S. J., Rullo, J., Cano, A. P., Xiao, H., Chen, M., Moser, M., & Cybulsky, M. I. (2011). Talin-1 and kindlin-3 regulate alpha4beta1 integrin-mediated adhesion stabilization, but not G protein-coupled receptor-induced affinity upregulation. Journal of Immunology, 187(8), 4360–4368.CrossRefGoogle Scholar
  58. 58.
    Poste, G., & Fidler, I. J. (1980). The pathogenesis of cancer metastasis. Nature, 283(5743), 139–146.PubMedCrossRefGoogle Scholar
  59. 59.
    Rice, G. E., Gimbrone, M. A., Jr., & Bevilacqua, M. P. (1988). Tumor cell-endothelial interactions. Increased adhesion of human melanoma cells to activated vascular endothelium. The American Journal of Pathology, 133(2), 204–210.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Rice, G. E., & Bevilacqua, M. P. (1989). An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science, 246(4935), 1303–1306.PubMedCrossRefGoogle Scholar
  61. 61.
    Taichman, D. B., Cybulsky, M. I., Djaffar, I., Longenecker, B. M., Teixidó, J., Rice, G. E., & Bevilacqua, M. P. (1991). Tumor cell surface alpha 4 beta 1 integrin mediates adhesion to vascular endothelium: demonstration of an interaction with the N-terminal domains of INCAM-110/VCAM-1. Cell Regulation, 2(5), 347–355.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Juneja, H. S., Schmalsteig, F. C., Lee, S., & Chen, J. (1993). Vascular cell adhesion molecule-1 and VLA-4 are obligatory adhesion proteins in the heterotypic adherence between human leukemia/lymphoma cells and marrow stromal cells. Experimental Hematology, 21(3), 444–450.PubMedGoogle Scholar
  63. 63.
    Csanaky, G., Matutes, E., Vass, J. A., Morilla, R., & Catovsky, D. (1997). Adhesion receptors on peripheral blood leukemic B cells. A comparative study on B cell chronic lymphocytic leukemia and related lymphoma/leukemias. Leukemia, 11(3), 408–415.PubMedCrossRefGoogle Scholar
  64. 64.
    Martìn-Padura, I., Mortarini, R., Lauri, D., Bernasconi, S., Sanchez-Madrid, F., Parmiani, G., & Dejana, E. (1991). Heterogeneity in human melanoma cell adhesion to cytokine activated endothelial cells correlates with VLA-4 expression. Cancer Research, 51(8), 2239–2241.PubMedGoogle Scholar
  65. 65.
    Zhu, N. W., Perks, C. M., Burd, A. R., & Holly, J. M. (1999). Changes in the levels of integrin and focal adhesion kinase (FAK) in human melanoma cells following 532 nm laser treatment. International Journal of Cancer. Journal International Du Cancer, 82(3), 353–358.PubMedCrossRefGoogle Scholar
  66. 66.
    Zhu, N., Eves, P. C., Katerinaki, E., Szabo, M., Morandini, R., Ghanem, G., & Haycock, J. W. (2002). Melanoma cell attachment, invasion, and integrin expression is upregulated by tumor necrosis factor alpha and suppressed by alpha melanocyte stimulating hormone. The Journal of Investigative Dermatology, 119(5), 1165–1171.PubMedCrossRefGoogle Scholar
  67. 67.
    Klemke, M., Weschenfelder, T., Konstandin, M. H., & Samstag, Y. (2007). High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. Journal of Cellular Physiology, 212(2), 368–374.PubMedCrossRefGoogle Scholar
  68. 68.
    Okahara, H., Yagita, H., Miyake, K., & Okumura, K. (1994). Involvement of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) in tumor necrosis factor alpha enhancement of experimental metastasis. Cancer Research, 54(12), 3233–3236.PubMedGoogle Scholar
  69. 69.
    Garofalo, A., Chirivi, R. G., Foglieni, C., Pigott, R., Mortarini, R., Martin-Padura, I., & Dejana, E. (1995). Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. Cancer Research, 55(2), 414–419.PubMedGoogle Scholar
  70. 70.
    Higashiyama, A., Watanabe, H., Okumura, K., & Yagita, H. (1996). Involvement of tumor necrosis factor alpha and very late activation antigen 4/vascular cell adhesion molecule 1 interaction in surgical-stress-enhanced experimental metastasis. Cancer Immunology, Immunotherapy: CII, 42(4), 231–236.PubMedCrossRefGoogle Scholar
  71. 71.
    Cardones, A. R., Murakami, T., & Hwang, S. T. (2003). CXCR4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta(1) integrin. Cancer Research, 63(20), 6751–6757.PubMedGoogle Scholar
  72. 72.
    Rebhun, R. B., Cheng, H., Gershenwald, J. E., Fan, D., Fidler, I. J., & Langley, R. R. (2010). Constitutive expression of the alpha4 integrin correlates with tumorigenicity and lymph node metastasis of the B16 murine melanoma. Neoplasia, 12(2), 173–182.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Khatib, A.-M., Auguste, P., Fallavollita, L., Wang, N., Samani, A., Kontogiannea, M., & Brodt, P. (2005). Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. The American Journal of Pathology, 167(3), 749–759.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Sipos, E., Chen, L., András, I. E., Wrobel, J., Zhang, B., Pu, H., & Toborek, M. (2012). Proinflammatory adhesion molecules facilitate polychlorinated biphenyl-mediated enhancement of brain metastasis formation. Toxicological Sciences, 126(2), 362–371.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Langley, R. R., Carlisle, R., Ma, L., Specian, R. D., Gerritsen, M. E., & Granger, D. N. (2001). Endothelial expression of vascular cell adhesion molecule-1 correlates with metastatic pattern in spontaneous melanoma. Microcirculation, 8(5), 335–345.PubMedCrossRefGoogle Scholar
  76. 76.
    Haddad, O., Chotard-Ghodsnia, R., Verdier, C., & Duperray, A. (2010). Tumor cell/endothelial cell tight contact upregulates endothelial adhesion molecule expression mediated by NFkappaB: differential role of the shear stress. Experimental Cell Research, 316(4), 615–626.PubMedCrossRefGoogle Scholar
  77. 77.
    Chiu, J.-J., Chen, L.-J., Lee, P.-L., Lee, C.-I., Lo, L.-W., Usami, S., & Chien, S. (2003). Shear stress inhibits adhesion molecule expression in vascular endothelial cells induced by coculture with smooth muscle cells. Blood, 101(7), 2667–2674.PubMedCrossRefGoogle Scholar
  78. 78.
    Chiu, J.-J., Lee, P.-L., Chen, C.-N., Lee, C.-I., Chang, S.-F., Chen, L.-J., & Chien, S. (2004). Shear stress increases ICAM-1 and decreases VCAM-1 and E-selectin expressions induced by tumor necrosis factor-[alpha] in endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(1), 73–79.PubMedCrossRefGoogle Scholar
  79. 79.
    Partridge, J., Carlsen, H., Enesa, K., Chaudhury, H., Zakkar, M., Luong, L., & Evans, P. C. (2007). Laminar shear stress acts as a switch to regulate divergent functions of NF-kappaB in endothelial cells. FASEB Journal, 21(13), 3553–3561.PubMedCrossRefGoogle Scholar
  80. 80.
    Qian, F., Vaux, D. L., & Weissman, I. L. (1994). Expression of the integrin alpha 4 beta 1 on melanoma cells can inhibit the invasive stage of metastasis formation. Cell, 77(3), 335–347.PubMedCrossRefGoogle Scholar
  81. 81.
    Johnson, J. P. (1999). Cell adhesion molecules in the development and progression of malignant melanoma. Cancer Metastasis Reviews, 18(3), 345–357.PubMedCrossRefGoogle Scholar
  82. 82.
    Huhtala, P., Humphries, M. J., McCarthy, J. B., Tremble, P. M., Werb, Z., & Damsky, C. H. (1995). Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. The Journal of Cell Biology, 129(3), 867–879.PubMedCrossRefGoogle Scholar
  83. 83.
    Altevogt, P., Hubbe, M., Ruppert, M., Lohr, J., von Hoegen, P., Sammar, M., & Butcher, E. C. (1995). The alpha 4 integrin chain is a ligand for alpha 4 beta 7 and alpha 4 beta 1. The Journal of Experimental Medicine, 182(2), 345–355.PubMedCrossRefGoogle Scholar
  84. 84.
    Campanero, M. R., Arroyo, A. G., Pulido, R., Ursa, A., de Matías, M. S., Sánchez-Mateos, P., & Corbí, A. L. (1992). Functional role of alpha 2/beta 1 and alpha 4/beta 1 integrins in leukocyte intercellular adhesion induced through the common beta 1 subunit. European Journal of Immunology, 22(12), 3111–3119.PubMedCrossRefGoogle Scholar
  85. 85.
    Bednarczyk, J. L., & McIntyre, B. W. (1990). A monoclonal antibody to VLA-4 alpha-chain (CDw49d) induces homotypic lymphocyte aggregation. Journal of Immunology, 144(3), 777–784.Google Scholar
  86. 86.
    Bednarczyk, J. L., Wygant, J. N., Szabo, M. C., Molinari-Storey, L., Renz, M., Fong, S., & McIntyre, B. W. (1993). Homotypic leukocyte aggregation triggered by a monoclonal antibody specific for a novel epitope expressed by the integrin beta 1 subunit: conversion of nonresponsive cells by transfecting human integrin alpha 4 subunit cDNA. Journal of Cellular Biochemistry, 51(4), 465–478.PubMedCrossRefGoogle Scholar
  87. 87.
    Pulido, R., Elices, M. J., Campanero, M. R., Osborn, L., Schiffer, S., García-Pardo, A., & Sánchez-Madrid, F. (1991). Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. Correlation with distinct alpha 4 epitopes. The Journal of Biological Chemistry, 266(16), 10241–10245.PubMedGoogle Scholar
  88. 88.
    Hart, I. R., Birch, M., & Marshall, J. F. (1991). Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Reviews, 10(2), 115–128.PubMedCrossRefGoogle Scholar
  89. 89.
    Moretti, S., Martini, L., Berti, E., Pinzi, C., & Giannotti, B. (1993). Adhesion molecule profile and malignancy of melanocytic lesions. Melanoma Research, 3(4), 235–239.PubMedGoogle Scholar
  90. 90.
    Schadendorf, D., Gawlik, C., Haney, U., Ostmeier, H., Suter, L., & Czarnetzki, B. M. (1993). Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. The Journal of Pathology, 170(4), 429–434.PubMedCrossRefGoogle Scholar
  91. 91.
    Schadendorf, D., Heidel, J., Gawlik, C., Suter, L., & Czarnetzki, B. M. (1995). Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels. Journal of the National Cancer Institute, 87(5), 366–371.PubMedCrossRefGoogle Scholar
  92. 92.
    Chen, Q., Zhang, X. H.-F., & Massagué, J. (2011). Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell, 20(4), 538–549.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Lin, K.-Y., Lu, D., Hung, C.-F., Peng, S., Huang, L., Jie, C., & Wu, T.-C. (2007). Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer Research, 67(4), 1832–1841.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Kuai, W.-X., Wang, Q., Yang, X.-Z., Zhao, Y., Yu, R., & Tang, X.-J. (2012). Interleukin-8 associates with adhesion, migration, invasion and chemosensitivity of human gastric cancer cells. World Journal of Gastroenterology: WJG, 18(9), 979–985.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Ruco, L. P., de Laat, P. A., Matteucci, C., Bernasconi, S., Sciacca, F. M., van der Kwast, T. H., & Versnel, M. A. (1996). Expression of ICAM-1 and VCAM-1 in human malignant mesothelioma. The Journal of Pathology, 179(3), 266–271.PubMedCrossRefGoogle Scholar
  96. 96.
    Ding, Y.-B., Chen, G.-Y., Xia, J.-G., Zang, X.-W., Yang, H.-Y., & Yang, L. (2003). Association of VCAM-1 overexpression with oncogenesis, tumor angiogenesis and metastasis of gastric carcinoma. World Journal of Gastroenterology: WJG, 9(7), 1409–1414.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Gupta, G. P., Minn, A. J., Kang, Y., Siegel, P. M., Serganova, I., Cordón-Cardo, C., & Massagué, J. (2005). Identifying site-specific metastasis genes and functions. Cold Spring Harbor Symposia on Quantitative Biology, 70, 149–158.PubMedCrossRefGoogle Scholar
  98. 98.
    Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., & Massagué, J. (2005). Genes that mediate breast cancer metastasis to lung. Nature, 436(7050), 518–524.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Vanharanta, S., & Massagué, J. (2013). Origins of metastatic traits. Cancer Cell, 24(4), 410–421.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Chen, Q., & Massagué, J. (2012). Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis. Clinical Cancer Research, 18(20), 5520–5525.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Lu, X., Mu, E., Wei, Y., Riethdorf, S., Yang, Q., Yuan, M., & Kang, Y. (2011). VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell, 20(6), 701–714.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Hynes, R. O. (2011). Metastatic cells will take any help they can get. Cancer Cell, 20(6), 689–690.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Lin, K. Y., Guarnieri, F. G., Staveley-O’Carroll, K. F., Levitsky, H. I., August, J. T., Pardoll, D. M., & Wu, T. C. (1996). Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Research, 56(1), 21–26.PubMedGoogle Scholar
  104. 104.
    Wu, T. C., Guarnieri, F. G., Staveley-O’Carroll, K. F., Viscidi, R. P., Levitsky, H. I., Hedrick, L., & Pardoll, D. M. (1995). Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens. Proceedings of the National Academy of Sciences of the United States of America, 92(25), 11671–11675.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Wu, T.-C. (2007). The role of vascular cell adhesion molecule-1 in tumor immune evasion. Cancer Research, 67(13), 6003–6006.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Rose, D. M., Grabovsky, V., Alon, R., & Ginsberg, M. H. (2001). The affinity of integrin alpha(4)beta(1) governs lymphocyte migration. Journal of Immunology, 167(5), 2824–2830.CrossRefGoogle Scholar
  107. 107.
    Rose, D. M., Han, J., & Ginsberg, M. H. (2002). Alpha4 integrins and the immune response. Immunological Reviews, 186, 118–124.PubMedCrossRefGoogle Scholar
  108. 108.
    Liu, S., Thomas, S. M., Woodside, D. G., Rose, D. M., Kiosses, W. B., Pfaff, M., & Ginsberg, M. H. (1999). Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature, 402(6762), 676–681.PubMedCrossRefGoogle Scholar
  109. 109.
    Rose, D. M., Liu, S., Woodside, D. G., Han, J., Schlaepfer, D. D., & Ginsberg, M. H. (2003). Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. Journal of Immunology, 170(12), 5912–5918.CrossRefGoogle Scholar
  110. 110.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., & Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., & Zlotnik, A. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56.PubMedCrossRefGoogle Scholar
  112. 112.
    Zlotnik, A., Burkhardt, A. M., & Homey, B. (2011). Homeostatic chemokine receptors and organ-specific metastasis. Nature Reviews Immunology, 11(9), 597–606.PubMedCrossRefGoogle Scholar
  113. 113.
    Williams, S. A., Harata-Lee, Y., Comerford, I., Anderson, R. L., Smyth, M. J., & McColl, S. R. (2010). Multiple functions of CXCL12 in a syngeneic model of breast cancer. Molecular Cancer, 9, 250.PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Koizumi, K., Kozawa, Y., Ohashi, Y., Nakamura, E. S., Aozuka, Y., Sakurai, H., & Saiki, I. (2007). CCL21 promotes the migration and adhesion of highly lymph node metastatic human non-small cell lung cancer Lu-99 in vitro. Oncology Reports, 17(6), 1511–1516.PubMedGoogle Scholar
  115. 115.
    Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S., & Ruco, L. (1992). The origin and function of tumor-associated macrophages. Immunology Today, 13(7), 265–270.PubMedCrossRefGoogle Scholar
  116. 116.
    Conti, I., & Rollins, B. J. (2004). CCL2 (monocyte chemoattractant protein-1) and cancer. Seminars in Cancer Biology, 14(3), 149–154.PubMedCrossRefGoogle Scholar
  117. 117.
    Zhao, L., Lim, S. Y., Gordon-Weeks, A. N., Tapmeier, T. T., Im, J. H., Cao, Y., & Muschel, R. J. (2013). Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology, 57(2), 829–839.PubMedCrossRefGoogle Scholar
  118. 118.
    Lim, S. Y., Gordon-Weeks, A. N., Zhao, L., Tapmeier, T. T., Im, J. H., Cao, Y., & Muschel, R. J. (2013). Recruitment of myeloid cells to the tumor microenvironment supports liver metastasis. Oncoimmunology, 2(3), e23187.PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Qian, B.-Z., Li, J., Zhang, H., Kitamura, T., Zhang, J., Campion, L. R., & Pollard, J. W. (2011). CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature, 475(7355), 222–225.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Qian, B., Deng, Y., Im, J. H., Muschel, R. J., Zou, Y., Li, J., & Pollard, J. W. (2009). A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PloS One, 4(8), e6562.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Gil-Bernabé, A. M., Ferjancic, S., Tlalka, M., Zhao, L., Allen, P. D., Im, J. H., & Muschel, R. J. (2012). Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood, 119(13), 3164–3175.PubMedCrossRefGoogle Scholar
  122. 122.
    Ferjancic, S., Gil-Bernabé, A. M., Hill, S. A., Allen, P. D., Richardson, P., Sparey, T., & Muschel, R. J. (2013). VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice. Blood, 121(16), 3289–3297.PubMedCrossRefGoogle Scholar
  123. 123.
    Murdoch, C., Muthana, M., Coffelt, S. B., & Lewis, C. E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nature Reviews Cancer, 8(8), 618–631.PubMedCrossRefGoogle Scholar
  124. 124.
    Tazzyman, S., Lewis, C. E., & Murdoch, C. (2009). Neutrophils: key mediators of tumour angiogenesis. International Journal of Experimental Pathology, 90(3), 222–231.PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Lindau, D., Gielen, P., Kroesen, M., Wesseling, P., & Adema, G. J. (2013). The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology, 138(2), 105–115.PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Yang, L., DeBusk, L. M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., & Lin, P. C. (2004). Expansion of myeloid immune suppressor Gr+CD11b+cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell, 6(4), 409–421.PubMedCrossRefGoogle Scholar
  127. 127.
    Jin, H., Su, J., Garmy-Susini, B., Kleeman, J., & Varner, J. (2006). Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Research, 66(4), 2146–2152.PubMedCrossRefGoogle Scholar
  128. 128.
    Joshi, S., Singh, A. R., Zulcic, M., Bao, L., Messer, K., Ideker, T., & Durden, D. L. (2014). Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS ONE, 9(4), e95893.PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. The New England Journal of Medicine, 285(21), 1182–1186.PubMedCrossRefGoogle Scholar
  130. 130.
    Ide, A. G., Baker, N. H., & Warren, S. L. (1939). Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. American Journal of Roentgenology, 42, 891–899.Google Scholar
  131. 131.
    Algire, G. H., Chalkley, H. W., Legallais, F. Y., & Park, H. D. (1945). Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. Journal of the National Cancer Institute, 6(1), 73–85.Google Scholar
  132. 132.
    Folkman, J., Merler, E., Abernathy, C., & Williams, G. (1971). Isolation of a tumor factor responsible for angiogenesis. The Journal of Experimental Medicine, 133(2), 275–288.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Gimbrone, M. A., Jr., Leapman, S. B., Cotran, R. S., & Folkman, J. (1972). Tumor dormancy in vivo by prevention of neovascularization. The Journal of Experimental Medicine, 136(2), 261–276.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Avraamides, C. J., Garmy-Susini, B., & Varner, J. A. (2008). Integrins in angiogenesis and lymphangiogenesis. Nature Reviews Cancer, 8(8), 604–617.PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Garmy-Susini, B., & Varner, J. A. (2008). Roles of integrins in tumor angiogenesis and lymphangiogenesis. Lymphatic Research and Biology, 6(3–4), 155–163.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Grant, M. B., May, W. S., Caballero, S., Brown, G. A. J., Guthrie, S. M., Mames, R. N., & Scott, E. W. (2002). Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nature Medicine, 8(6), 607–612.PubMedCrossRefGoogle Scholar
  137. 137.
    Patterson, L. J., Gering, M., & Patient, R. (2005). Scl is required for dorsal aorta as well as blood formation in zebrafish embryos. Blood, 105(9), 3502–3511.PubMedCrossRefGoogle Scholar
  138. 138.
    Wang, L., Li, L., Shojaei, F., Levac, K., Cerdan, C., Menendez, P., & Bhatia, M. (2004). Endothelial and hematopoietic cell fate of human embryonic stem cells originates from primitive endothelium with hemangioblastic properties. Immunity, 21(1), 31–41.PubMedCrossRefGoogle Scholar
  139. 139.
    Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., & Rafii, S. (2001). Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Medicine, 7(11), 1194–1201.PubMedCrossRefGoogle Scholar
  140. 140.
    Chen, L., Ackerman, R., Saleh, M., Gotlinger, K. H., Kessler, M., Mendelowitz, L. G., & Guo, A. M. (2014). 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. The Journal of Pharmacology and Experimental Therapeutics, 348(3), 442–451.PubMedCentralPubMedCrossRefGoogle Scholar
  141. 141.
    Jin, H., Aiyer, A., Su, J., Borgstrom, P., Stupack, D., Friedlander, M., & Varner, J. (2006). A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. The Journal of Clinical Investigation, 116(3), 652–662.PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Schmid, M. C., & Varner, J. A. (2009). Circulating endothelial progenitor cells. Methods in Molecular Biology, 467, 139–155.PubMedCrossRefGoogle Scholar
  143. 143.
    Ruzinova, M. B., Schoer, R. A., Gerald, W., Egan, J. E., Pandolfi, P. P., Rafii, S., & Benezra, R. (2003). Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell, 4(4), 277–289.PubMedCrossRefGoogle Scholar
  144. 144.
    Ono, M., Torisu, H., Fukushi, J., Nishie, A., & Kuwano, M. (1999). Biological implications of macrophage infiltration in human tumor angiogenesis. Cancer Chemotherapy and Pharmacology, 43(Suppl), S69–71.PubMedCrossRefGoogle Scholar
  145. 145.
    Jin, D. K., Shido, K., Kopp, H.-G., Petit, I., Shmelkov, S. V., Young, L. M., & Rafii, S. (2006). Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Medicine, 12(5), 557–567.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Mantovani, A., Sozzani, S., Locati, M., Allavena, P., & Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology, 23(11), 549–555.PubMedCrossRefGoogle Scholar
  147. 147.
    De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L., & Lewis, C. E. (2007). Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends in Immunology, 28(12), 519–524.PubMedCrossRefGoogle Scholar
  148. 148.
    Venneri, M. A., De Palma, M., Ponzoni, M., Pucci, F., Scielzo, C., Zonari, E., & Naldini, L. (2007). Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood, 109(12), 5276–5285.PubMedCrossRefGoogle Scholar
  149. 149.
    Ghiringhelli, F., Puig, P. E., Roux, S., Parcellier, A., Schmitt, E., Solary, E., & Zitvogel, L. (2005). Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. The Journal of Experimental Medicine, 202(7), 919–929.PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Nagaraj, S., & Gabrilovich, D. I. (2010). Myeloid-derived suppressor cells in human cancer. Cancer Journal, 16(4), 348–353.CrossRefGoogle Scholar
  151. 151.
    Tazzyman, S., Niaz, H., & Murdoch, C. (2013). Neutrophil-mediated tumour angiogenesis: subversion of immune responses to promote tumour growth. Seminars in Cancer Biology, 23(3), 149–158.PubMedCrossRefGoogle Scholar
  152. 152.
    Looi, L. M. (1987). Tumor-associated tissue eosinophilia in nasopharyngeal carcinoma. A pathologic study of 422 primary and 138 metastatic tumors. Cancer, 59(3), 466–470.PubMedCrossRefGoogle Scholar
  153. 153.
    Reed, J. A., McNutt, N. S., Bogdany, J. K., & Albino, A. P. (1996). Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression. Journal of Cutaneous Pathology, 23(6), 495–505.PubMedCrossRefGoogle Scholar
  154. 154.
    Griffioen, A. W., Damen, C. A., Blijham, G. H., & Groenewegen, G. (1996). Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood, 88(2), 667–673.PubMedGoogle Scholar
  155. 155.
    Griffioen, A. W., Tromp, S. C., & Hillen, H. F. (1998). Angiogenesis modulates the tumour immune response. International Journal of Experimental Pathology, 79(6), 363–368.PubMedCentralPubMedCrossRefGoogle Scholar
  156. 156.
    Tromp, S. C., oude Egbrink, M. G., Dings, R. P., van Velzen, S., Slaaf, D. W., Hillen, H. F., & Griffioen, A. W. ((2000). Tumor angiogenesis factors reduce leukocyte adhesion in vivo. International Immunology, 12(5), 671–676.PubMedCrossRefGoogle Scholar
  157. 157.
    Dirkx, A. E. M., Oude Egbrink, M. G. A., Kuijpers, M. J. E., van der Niet, S. T., Heijnen, V. V. T., Bouma-ter Steege, J. C. A., & Griffioen, A. W. (2003). Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Research, 63(9), 2322–2329.PubMedGoogle Scholar
  158. 158.
    Dirkx, A. E. M., Oude Egbrink, M. G. A., Wagstaff, J., & Griffioen, A. W. (2006). Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. Journal of Leukocyte Biology, 80(6), 1183–1196.PubMedCrossRefGoogle Scholar
  159. 159.
    Jain, R. K., & Booth, M. F. (2003). What brings pericytes to tumor vessels? The Journal of Clinical Investigation, 112(8), 1134–1136.PubMedCentralPubMedCrossRefGoogle Scholar
  160. 160.
    Abramsson, A., Lindblom, P., & Betsholtz, C. (2003). Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. The Journal of Clinical Investigation, 112(8), 1142–1151.PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Koch, A. E., Halloran, M. M., Haskell, C. J., Shah, M. R., & Polverini, P. J. (1995). Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature, 376(6540), 517–519.PubMedCrossRefGoogle Scholar
  162. 162.
    Fukushi, J., Ono, M., Morikawa, W., Iwamoto, Y., & Kuwano, M. (2000). The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13. Journal of Immunology, 165(5), 2818–2823.CrossRefGoogle Scholar
  163. 163.
    Nakao, S., Kuwano, T., Ishibashi, T., Kuwano, M., & Ono, M. (2003). Synergistic effect of TNF-alpha in soluble VCAM-1-induced angiogenesis through alpha 4 integrins. Journal of Immunology, 170(11), 5704–5711.CrossRefGoogle Scholar
  164. 164.
    Calzada, M. J., Zhou, L., Sipes, J. M., Zhang, J., Krutzsch, H. C., Iruela-Arispe, M. L., & Roberts, D. D. (2004). Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo. Circulation Research, 94(4), 462–470.PubMedCrossRefGoogle Scholar
  165. 165.
    Garmy-Susini, B., Jin, H., Zhu, Y., Sung, R.-J., Hwang, R., & Varner, J. (2005). Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. The Journal of Clinical Investigation, 115(6), 1542–1551.PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Banerji, S., Ni, J., Wang, S. X., Clasper, S., Su, J., Tammi, R., & Jackson, D. G. (1999). LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. The Journal of Cell Biology, 144(4), 789–801.PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Wigle, J. T., & Oliver, G. (1999). Prox1 function is required for the development of the murine lymphatic system. Cell, 98(6), 769–778.PubMedCrossRefGoogle Scholar
  168. 168.
    Breiteneder-Geleff, S., Soleiman, A., Kowalski, H., Horvat, R., Amann, G., Kriehuber, E., & Kerjaschki, D. (1999). Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. The American Journal of Pathology, 154(2), 385–394.PubMedCentralPubMedCrossRefGoogle Scholar
  169. 169.
    Baluk, P., & McDonald, D. M. (2008). Markers for microscopic imaging of lymphangiogenesis and angiogenesis. Annals of the New York Academy of Sciences, 1131, 1–12.PubMedCrossRefGoogle Scholar
  170. 170.
    Huang, X. Z., Wu, J. F., Ferrando, R., Lee, J. H., Wang, Y. L., Farese, R. V., Jr., & Sheppard, D. (2000). Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Molecular and Cellular Biology, 20(14), 5208–5215.PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    Mishima, K., Watabe, T., Saito, A., Yoshimatsu, Y., Imaizumi, N., Masui, S., & Miyazono, K. (2007). Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades. Molecular Biology of the Cell, 18(4), 1421–1429.PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Bazigou, E., Xie, S., Chen, C., Weston, A., Miura, N., Sorokin, L., & Makinen, T. (2009). Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Developmental Cell, 17(2), 175–186.PubMedCentralPubMedCrossRefGoogle Scholar
  173. 173.
    Hong, Y.-K., Lange-Asschenfeldt, B., Velasco, P., Hirakawa, S., Kunstfeld, R., Brown, L. F., & Detmar, M. (2004). VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB Journal, 18(10), 1111–1113.PubMedGoogle Scholar
  174. 174.
    Grimaldo, S., Yuen, D., Ecoiffier, T., & Chen, L. (2011). Very late antigen-1 mediates corneal lymphangiogenesis. Investigative Ophthalmology & Visual Science, 52(7), 4808–4812.CrossRefGoogle Scholar
  175. 175.
    Dietrich, T., Onderka, J., Bock, F., Kruse, F. E., Vossmeyer, D., Stragies, R., & Cursiefen, C. (2007). Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. The American Journal of Pathology, 171(1), 361–372.PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    Garmy-Susini, B., Avraamides, C. J., Schmid, M. C., Foubert, P., Ellies, L. G., Barnes, L., & Varner, J. A. (2010). Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Research, 70(8), 3042–3051.PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Garmy-Susini, B., Makale, M., Fuster, M., & Varner, J. A. (2007). Methods to study lymphatic vessel integrins. Methods in Enzymology, 426, 415–438.PubMedCrossRefGoogle Scholar
  178. 178.
    Zhou, F., Chang, Z., Zhang, L., Hong, Y.-K., Shen, B., Wang, B., & He, Y. (2010). Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development. The American Journal of Pathology, 177(4), 2124–2133.PubMedCentralPubMedCrossRefGoogle Scholar
  179. 179.
    Garmy-Susini, B., Avraamides, C. J., Desgrosellier, J. S., Schmid, M. C., Foubert, P., Ellies, L. G., & Varner, J. (2013). PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes. Proceedings of the National Academy of Sciences of the United States of America, 110(22), 9042–9047.PubMedCentralPubMedCrossRefGoogle Scholar
  180. 180.
    Testaz, S., & Duband, J. L. (2001). Central role of the alpha4beta1 integrin in the coordination of avian truncal neural crest cell adhesion, migration, and survival. Developmental Dynamics, 222(2), 127–140.PubMedCrossRefGoogle Scholar
  181. 181.
    Alvarez-Dolado, M. (2007). Cell fusion: biological perspectives and potential for regenerative medicine. Frontiers in Bioscience: a Journal and Virtual Library, 12, 1–12.CrossRefGoogle Scholar
  182. 182.
    Nygren, J. M., Liuba, K., Breitbach, M., Stott, S., Thorén, L., Roell, W., & Jacobsen, S. E. W. (2008). Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nature Cell Biology, 10(5), 584–592.PubMedCrossRefGoogle Scholar
  183. 183.
    Nygren, J. M., Jovinge, S., Breitbach, M., Säwén, P., Röll, W., Hescheler, J., & Jacobsen, S. E. W. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature Medicine, 10(5), 494–501.PubMedCrossRefGoogle Scholar
  184. 184.
    Singec, I., & Snyder, E. Y. (2008). Inflammation as a matchmaker: revisiting cell fusion. Nature Cell Biology, 10(5), 503–505.PubMedCrossRefGoogle Scholar
  185. 185.
    Mortensen, K., Lichtenberg, J., Thomsen, P. D., & Larsson, L.-I. (2004). Spontaneous fusion between cancer cells and endothelial cells. Cellular and Molecular life Sciences: CMLS, 61(16), 2125–2131.PubMedCrossRefGoogle Scholar
  186. 186.
    Song, K., Zhu, F., Zhang, H., & Shang, Z. (2012). Tumor necrosis factor-α enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway. Experimental Cell Research, 318(14), 1707–1715.PubMedCrossRefGoogle Scholar
  187. 187.
    Durand, R. E., & Sutherland, R. M. (1972). Effects of intercellular contact on repair of radiation damage. Experimental Cell Research, 71(1), 75–80.PubMedCrossRefGoogle Scholar
  188. 188.
    Fridman, R., Giaccone, G., Kanemoto, T., Martin, G. R., Gazdar, A. F., & Mulshine, J. L. (1990). Reconstituted basement membrane (Matrigel) and laminin can enhance the tumorigenicity and the drug resistance of small cell lung cancer cell lines. Proceedings of the National Academy of Sciences of the United States of America, 87(17), 6698–6702.PubMedCentralPubMedCrossRefGoogle Scholar
  189. 189.
    Meredith, J. E., Jr., Fazeli, B., & Schwartz, M. A. (1993). The extracellular matrix as a cell survival factor. Molecular Biology of the Cell, 4(9), 953–961.PubMedCentralPubMedCrossRefGoogle Scholar
  190. 190.
    Schuetz, J. D., & Schuetz, E. G. (1993). Extracellular matrix regulation of multidrug resistance in primary monolayer cultures of adult rat hepatocytes. Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research, 4(1), 31–40.Google Scholar
  191. 191.
    Bates, R. C., Buret, A., van Helden, D. F., Horton, M. A., & Burns, G. F. (1994). Apoptosis induced by inhibition of intercellular contact. The Journal of Cell Biology, 125(2), 403–415.PubMedCrossRefGoogle Scholar
  192. 192.
    Scott, G., Cassidy, L., & Busacco, A. (1997). Fibronectin suppresses apoptosis in normal human melanocytes through an integrin-dependent mechanism. The Journal of Investigative Dermatology, 108(2), 147–153.PubMedCrossRefGoogle Scholar
  193. 193.
    Bradstock, K. F., & Gottlieb, D. J. (1995). Interaction of acute leukemia cells with the bone marrow microenvironment: implications for control of minimal residual disease. Leukemia & Lymphoma, 18(1–2), 1–16.CrossRefGoogle Scholar
  194. 194.
    St Croix, B., & Kerbel, R. S. (1997). Cell adhesion and drug resistance in cancer. Current Opinion in Oncology, 9(6), 549–556.PubMedCrossRefGoogle Scholar
  195. 195.
    Matsunaga, T., Takemoto, N., Sato, T., Takimoto, R., Tanaka, I., Fujimi, A., & Niitsu, Y. (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.PubMedCrossRefGoogle Scholar
  196. 196.
    Damiano, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A., & Dalton, W. S. (1999). Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood, 93(5), 1658–1667.PubMedGoogle Scholar
  197. 197.
    Mori, Y., Shimizu, N., Dallas, M., Niewolna, M., Story, B., Williams, P. J., & Yoneda, T. (2004). Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood, 104(7), 2149–2154.PubMedCrossRefGoogle Scholar
  198. 198.
    Park, C. C., Zhang, H., Pallavicini, M., Gray, J. W., Baehner, F., Park, C. J., & Bissell, M. J. (2006). Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Research, 66(3), 1526–1535.PubMedCentralPubMedCrossRefGoogle Scholar
  199. 199.
    Meads, M. B., Gatenby, R. A., & Dalton, W. S. (2009). Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Reviews Cancer, 9(9), 665–674.PubMedCrossRefGoogle Scholar
  200. 200.
    Chen, Y.-X., Wang, Y., Fu, C.-C., Diao, F., Song, L.-N., Li, Z.-B., & Lu, J. (2010). Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells. Endocrine-Related Cancer, 17(1), 39–50.PubMedCrossRefGoogle Scholar
  201. 201.
    Scalici, J. M., Harrer, C., Allen, A., Jazaeri, A., Atkins, K. A., McLachlan, K. R., & Slack-Davis, J. K. (2014). Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin. Gynecologic Oncology, 132(2), 455–461.PubMedCentralPubMedCrossRefGoogle Scholar
  202. 202.
    Weekes, C. D., Pirruccello, S. J., Vose, J. M., Kuszynski, C., & Sharp, J. G. (1998). Lymphoma cells associated with bone marrow stromal cells in culture exhibit altered growth and survival. Leukemia & Lymphoma, 31(1–2), 151–165.CrossRefGoogle Scholar
  203. 203.
    Weekes, C. D., Kuszynski, C. A., & Sharp, J. G. (2001). VLA-4 mediated adhesion to bone marrow stromal cells confers chemoresistance to adherent lymphoma cells. Leukemia & Lymphoma, 40(5–6), 631–645.CrossRefGoogle Scholar
  204. 204.
    St Croix, B., Flørenes, V. A., Rak, J. W., Flanagan, M., Bhattacharya, N., Slingerland, J. M., & Kerbel, R. S. (1996). Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nature Medicine, 2(11), 1204–1210.PubMedCrossRefGoogle Scholar
  205. 205.
    Fukai, F., Mashimo, M., Akiyama, K., Goto, T., Tanuma, S., & Katayama, T. (1998). Modulation of apoptotic cell death by extracellular matrix proteins and a fibronectin-derived antiadhesive peptide. Experimental Cell Research, 242(1), 92–99.PubMedCrossRefGoogle Scholar
  206. 206.
    Ilić, D., Almeida, E. A., Schlaepfer, D. D., Dazin, P., Aizawa, S., & Damsky, C. H. (1998). Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. The Journal of Cell Biology, 143(2), 547–560.PubMedCentralPubMedCrossRefGoogle Scholar
  207. 207.
    Damiano, J. S., & Dalton, W. S. (2000). Integrin-mediated drug resistance in multiple myeloma. Leukemia & Lymphoma, 38(1–2), 71–81.Google Scholar
  208. 208.
    Higashimoto, I., Chihara, J., Kakazu, T., Kawabata, M., Nakajima, S., & Osame, M. (1996). Regulation of eosinophil cell death by adhesion to fibronectin. International Archives of Allergy and Immunology, 111(Suppl 1), 66–69.PubMedCrossRefGoogle Scholar
  209. 209.
    De la Fuente, M. T., Casanova, B., Garcia-Gila, M., Silva, A., & Garcia-Pardo, A. (1999). Fibronectin interaction with alpha4beta1 integrin prevents apoptosis in B cell chronic lymphocytic leukemia: correlation with Bcl-2 and Bax. Leukemia, 13(2), 266–274.PubMedCrossRefGoogle Scholar
  210. 210.
    Konopleva, M., Konoplev, S., Hu, W., Zaritskey, A. Y., Afanasiev, B. V., & Andreeff, M. (2002). Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia, 16(9), 1713–1724.PubMedCrossRefGoogle Scholar
  211. 211.
    Liu, C.-C., Leclair, P., Yap, S. Q., & Lim, C. J. (2013). The membrane-proximal KXGFFKR motif of α-integrin mediates chemoresistance. Molecular and Cellular Biology, 33(21), 4334–4345.PubMedCentralPubMedCrossRefGoogle Scholar
  212. 212.
    Layani-Bazar, A., Skornik, I., Berrebi, A., Pauker, M. H., Noy, E., Silberman, A., & Sredni, B. (2014). Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state. Cancer Research. doi: 10.1158/0008-5472.CAN-13-2159.PubMedGoogle Scholar
  213. 213.
    Jacamo, R., Chen, Y., Wang, Z., Ma, W., Zhang, M., Spaeth, E. L., & Andreeff, M. (2014). Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood, 123(17), 2691–2702.PubMedCentralPubMedCrossRefGoogle Scholar
  214. 214.
    Brachtl, G., Piñón Hofbauer, J., Greil, R., & Hartmann, T. N. (2014). The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia. Annals of Hematology, 93(3), 361–374.PubMedCentralPubMedCrossRefGoogle Scholar
  215. 215.
    Gattei, V., Bulian, P., Del Principe, M. I., Zucchetto, A., Maurillo, L., Buccisano, F., & Del Poeta, G. (2008). Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood, 111(2), 865–873.PubMedCrossRefGoogle Scholar
  216. 216.
    Nückel, H., Switala, M., Collins, C. H., Sellmann, L., Grosse-Wilde, H., Dührsen, U., & Rebmann, V. (2009). High CD49d protein and mRNA expression predicts poor outcome in chronic lymphocytic leukemia. Clinical Immunology, 131(3), 472–480.PubMedCrossRefGoogle Scholar
  217. 217.
    Balcer, L. J., Galetta, S. L., Calabresi, P. A., Confavreux, C., Giovannoni, G., Havrdova, E., & Panzara, M. A. (2007). Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology, 68(16), 1299–1304.PubMedCrossRefGoogle Scholar
  218. 218.
    Havrdova, E., Galetta, S., Hutchinson, M., Stefoski, D., Bates, D., Polman, C. H., & Hyde, R. (2009). Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. The Lancet. Neurology, 8(3), 254–260.PubMedCrossRefGoogle Scholar
  219. 219.
    Armuzzi, A., & Felice, C. (2013). Natalizumab in Crohn’s disease: past and future areas of applicability. Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology, 26(3), 189–190.Google Scholar
  220. 220.
    Lanzarotto, F., Carpani, M., Chaudhary, R., & Ghosh, S. (2006). Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin. Drugs, 66(9), 1179–1189.PubMedCrossRefGoogle Scholar
  221. 221.
    Polman, C. H., O’Connor, P. W., Havrdova, E., Hutchinson, M., Kappos, L., Miller, D. H., & Investigators, A. F. F. I. R. M. (2006). A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. The New England Journal of Medicine, 354(9), 899–910.PubMedCrossRefGoogle Scholar
  222. 222.
    Rudick, R. A., Stuart, W. H., Calabresi, P. A., Confavreux, C., Galetta, S. L., Radue, E.-W., & Investigators, S. E. N. T. I. N. E. L. (2006). Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. The New England Journal of Medicine, 354(9), 911–923.PubMedCrossRefGoogle Scholar
  223. 223.
    Berger, J. R., & Houff, S. (2006). Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab. Neurological Research, 28(3), 299–305.PubMedCrossRefGoogle Scholar
  224. 224.
    Tur, C., & Montalban, X. (2014). Natalizumab: risk stratification of individual patients with multiple sclerosis. CNS Drugs, 28(7), 641–648.PubMedCrossRefGoogle Scholar
  225. 225.
    Cutter, G. R., & Stüve, O. (2014). Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? Multiple Sclerosis, 20(10), 1304–1305.PubMedCrossRefGoogle Scholar
  226. 226.
    Vavricka, B. M. P., Baumberger, P., Russmann, S., & Kullak-Ublick, G. A. (2011). Diagnosis of melanoma under concomitant natalizumab therapy. Multiple Sclerosis, 17(2), 255–256.PubMedCrossRefGoogle Scholar
  227. 227.
    Mullen, J. T., Vartanian, T. K., & Atkins, M. B. (2008). Melanoma complicating treatment with natalizumab for multiple sclerosis. The New England Journal of Medicine, 358(6), 647–648.PubMedCrossRefGoogle Scholar
  228. 228.
    Olson, D. L., Burkly, L. C., Leone, D. R., Dolinski, B. M., & Lobb, R. R. (2005). Anti-alpha4 integrin monoclonal antibody inhibits multiple myeloma growth in a murine model. Molecular Cancer Therapeutics, 4(1), 91–99.PubMedGoogle Scholar
  229. 229.
    Podar, K., Zimmerhackl, A., Fulciniti, M., Tonon, G., Hainz, U., Tai, Y.-T., & Anderson, K. C. (2011). The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. British Journal of Haematology, 155(4), 438–448.PubMedCrossRefGoogle Scholar
  230. 230.
    Study of Natalizumab in Relapsed/Refractory Multiple Myeloma - (n.d.). Retrieved August 28, 2014, from
  231. 231.
    Ramirez, P., Rettig, M. P., Uy, G. L., Deych, E., Holt, M. S., Ritchey, J. K., & DiPersio, J. F. (2009). BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood, 114(7), 1340–1343.PubMedCentralPubMedCrossRefGoogle Scholar
  232. 232.
    Rettig, M. P., Ansstas, G., & DiPersio, J. F. (2012). Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4. Leukemia, 26(1), 34–53.PubMedCentralPubMedCrossRefGoogle Scholar
  233. 233.
    Davenport, R. J., & Munday, J. R. (2007). Alpha4-integrin antagonism—an effective approach for the treatment of inflammatory diseases? Drug Discovery Today, 12(13–14), 569–576.PubMedCrossRefGoogle Scholar
  234. 234.
    Davenport, R. J., & Munday, J. R. (2008). Blocking alpha4-integrins—a small molecule approach to treatment of multiple sclerosis. Journal of the Neurological Sciences, 274(1–2), 27–30.PubMedCrossRefGoogle Scholar
  235. 235.
    Schmid, M. C., Avraamides, C. J., Foubert, P., Shaked, Y., Kang, S. W., Kerbel, R. S., & Varner, J. A. (2011). Combined blockade of integrin-α4β1 plus cytokines SDF-1α or IL-1β potently inhibits tumor inflammation and growth. Cancer Research, 71(22), 6965–6975.PubMedCentralPubMedCrossRefGoogle Scholar
  236. 236.
    Schlesinger, M., Roblek, M., Ortmann, K., Naggi, A., Torri, G., Borsig, L., & Bendas, G. (2014). The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin. Thrombosis Research, 133(5), 855–862.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of PharmacyRheinische Friedrich-Wilhelms-University BonnBonnGermany

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