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  • Opinion
  • Published:

Targeting the tumour vasculature: insights from physiological angiogenesis

Abstract

The cardiovascular system ensures the delivery of nutrients, oxygen, and blood and immune cells to all organs and tissues: it is also responsible for the removal of waste metabolites. The vascular system develops and matures through two tightly regulated processes: vasculogenesis and angiogenesis. Angiogenesis is active only under specific physiological conditions in healthy adults but the vasculature can be aberrantly activated to generate new blood vessels during pathological conditions such as cancer and chronic inflammation. In this Opinion article we discuss the parallels and differences in the angiogenic process under either a physiological or a pathological state, especially tumorigenesis.

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Figure 1: A failure to resolve the angiogenesis cascade results in pathological angiogenesis.

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References

  1. Hamilton, W. J., Boyd, J. D. & Mossmann, H. W. Human Embryology (Wiliam & Wilkins, Baltimore, 1962).

    Google Scholar 

  2. de Bold, A. J., de Bold, M. L. & Kraicer, J. Structural relationships between parenchymal and stromal elements in the pars intermedia of the rat adenohypophysis as demonstrated by extracellular space markers. Cell Tissue Res. 207, 347–359 (1980).

    Article  CAS  PubMed  Google Scholar 

  3. Hendrix, M. J., Seftor, E. A., Hess, A. R. & Seftor, R. E. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nature Rev. Cancer 3, 411–421 (2003).

    Article  CAS  Google Scholar 

  4. Semenza, G. L. Oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 336–361 (2009).

    Article  CAS  Google Scholar 

  5. Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nature Rev. Mol. Cell Biol. 9, 285–296 (2008).

    Article  CAS  Google Scholar 

  6. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Tang, N. et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6, 485–495 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687–690 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Park, J. E., Chen, H. H., Winer, J., Houck, K. A. & Ferrara, N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J. Biol. Chem. 269, 25646–25654 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Olofsson, B. et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl Acad. Sci. USA 95, 11709–11714 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alitalo, K., Tammela, T. & Petrova, T. V. Lymphangiogenesis in development and human disease. Nature 438, 946–953 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Shibuya, M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9, 225–230 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 4, 9349–9354 (1998).

    Article  Google Scholar 

  19. Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Wu, Y. et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin. Cancer Res. 12, 6573–6584 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Lichtenberger, B. M. et al. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140, 268–279 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nature Rev. Cancer 8, 579–591 (2008).

    Article  CAS  Google Scholar 

  25. Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hughes, C. C. Endothelial-stromal interactions in angiogenesis. Curr. Opin. Hematol. 15, 204–209 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rhodes, J. M. & Simons, M. The extracellular matrix and blood vessel formation: not just a scaffold. J. Cell. Mol. Med. 11, 176–205 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Davis, G. E. & Senger, D. R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ. Res. 97, 1093–1107 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Iruela-Arispe, M. L. & Davis, G. E. Cellular and molecular mechanisms of vascular lumen formation. Dev. Cell 16, 222–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Whelan, M. C. & Senger, D. R. Collagen I initiates endothelial cell morphogenesis by inducing actin polymerization through suppression of cyclic AMP and protein kinase A. J. Biol. Chem. 278, 327–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Hellstrom, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    Article  PubMed  CAS  Google Scholar 

  33. Folkman, J. & D'Amore, P. A. Blood vessel formation: what is its molecular basis? Cell 87, 1153–1155 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Saunders, W. B. et al. Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. J. Cell Biol. 175, 179–191 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Benjamin, L., Hemo, I. & Keshet, E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591–1598 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Krishnan, L. et al. Effect of mechanical boundary conditions on orientation of angiogenic microvessels. Cardiovasc. Res. 78, 324–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Hellstrom, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sorokin, L. M. et al. Developmental regulation of the laminin α5 chain suggests a role in epithelial and endothelial cell maturation. Dev. Biol. 189, 285–300 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol. 24, 389–399 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Eklund, L. & Olsen, B. R. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp. Cell Res. 312, 630–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev. Mol. Cell Biol. 8, 464–478 (2007).

    Article  CAS  Google Scholar 

  44. Darland, D. C. & D'Amore, P. A. Blood vessel maturation: vascular development comes of age. J. Clin. Invest. 103, 157–158 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Garner, A. in Pathobiology of Ocular Disease (eds Garner, A. & Klintworth, G. K.) 1625–1710 (Marcel Dekker, New York, 1994).

    Google Scholar 

  46. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xian, X. et al. Pericytes limit tumor cell metastasis. J. Clin. Invest. 116, 642–651 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ribatti, D. The discovery of endothelial progenitor cells. An historical review. Leuk. Res. 31, 439–444 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Nolan, D. J. et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev. 21, 1546–1558 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Purhonen, S. et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl Acad. Sci. USA 105, 6620–6625 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Coultas, L., Chawengsaksophak, K. & Rossant, J. Endothelial cells and VEGF in vascular development. Nature 438, 937–945 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Red-Horse, K., Crawford, Y., Shojaei, F. & Ferrara, N. Endothelium-microenvironment interactions in the developing embryo and in the adult. Dev. Cell 12, 181–194 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Bailey, J. M., Singh, P. K. & Hollingsworth, M. A. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell. Biochem. 102, 829–839 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Byrd, N. & Grabel, L. Hedgehog signaling in murine vasculogenesis and angiogenesis. Trends Cardiovasc. Med. 14, 308–313 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Wang, Z. et al. Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels. Blood 103, 100–109 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Pepper, M. S. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8, 21–43 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Chambers, R. C., Leoni, P., Kaminski, N., Laurent, G. J. & Heller, R. A. Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am. J. Pathol. 162, 533–546 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 23, 4018–4028 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Zhong, T. P., Childs, S., Leu, J. P. & Fishman, M. C. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Rossant, J. & Howard, L. Signaling pathways in vascular development. Annu. Rev. Cell Dev. Biol. 18, 541–573 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Lawson, N. D. et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675–3683 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Damsky, C. H. & Fisher, S. J. Trophoblast pseudo-vasculogenesis: faking it with endothelial adhesion receptors. Curr. Opin. Cell Biol. 10, 660–666 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Shojaei, F. & Ferrara, N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 68, 5501–5504 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Fischer, C. et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463–475 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Bassett, D. L. The changes in the vascular pattern of the ovary of the albino rat during the estrous cycle. Am. J. Anat. 73, 251–278 (1943).

    Article  Google Scholar 

  72. Phillips, H. S., Hains, J., Leung, D. W. & Ferrara, N. Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology 127, 965–967 (1990).

    Article  CAS  PubMed  Google Scholar 

  73. Ferrara, N. et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nature Medicine 4, 336–340 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Ryan, A. M. et al. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol. Pathol. 27, 78–86 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Hazzard, T. M., Xu, F. & Stouffer, R. L. Injection of soluble vascular endothelial growth factor receptor 1 into the preovulatory follicle disrupts ovulation and subsequent luteal function in rhesus monkeys. Biol. Reprod. 67, 1305–1312 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. LeCouter, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Ferrara, N. et al. Differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries. Am. J. Pathol. 162, 1881–1893 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Clapp, C., Thebault, S., Jeziorski, M. C. & Martinez De La Escalera, G. Peptide hormone regulation of angiogenesis. Physiol. Rev. 89, 1177–1215 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146, 1029–1039 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Mohle, R., Green, D., Moore, M. A., Nachman, R. L. & Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Banks, R. E. et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br. J. Cancer 77, 956–964 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Weller, K., Foitzik, K., Paus, R., Syska, W. & Maurer, M. Mast cells are required for normal healing of skin wounds in mice. FASEB J. 20, 2366–2368 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Nagy, J. A., Chang, S. H., Dvorak, A. M. & Dvorak, H. F. Why are tumour blood vessels abnormal and why is it important to know? Br. J. Cancer 100, 865–869 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jain, R. K. Delivery of molecular medicine to solid tumors. Science 271, 1079–1080 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Hida, K. & Klagsbrun, M. A new perspective on tumor endothelial cells: unexpected chromosome and centrosome abnormalities. Cancer Res. 65, 2507–2510 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Dayan, F., Mazure, N. M., Brahimi-Horn, M. C. & Pouyssegur, J. A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron. 1, 53–68 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Liao, D. & Johnson, R. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26, 281–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084–1091 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kerbel, R. S. Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mercurio, A. M., Bachelder, R. E., Bates, R. C. & Chung, J. Autocrine signaling in carcinoma: VEGF and the α6β4 integrin. Semin. Cancer Biol. 14, 115–122 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Lee, S. et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691–703 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gerber, H.-P. et al. Vascular endothelial growth factor regulates hematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993).

    Article  CAS  PubMed  Google Scholar 

  96. Presta, L. G. et al. Humanization of an anti-VEGF monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593–4599 (1997).

    CAS  PubMed  Google Scholar 

  97. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  Google Scholar 

  98. Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nature Rev. Mol. Cell Biol. 10, 165–177 (2009).

    Article  CAS  Google Scholar 

  99. Broxterman, H. J., Lankelma, J. & Hoekman, K. Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences. Drug Resist. Updat. 6, 111–127 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, P. et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc. Natl Acad. Sci. USA 95, 8829–8834 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L. & Lewis, C. E. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol. 28, 519–524 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Murdoch, C., Tazzyman, S., Webster, S. & Lewis, C. E. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J. Immunol. 178, 7405–7411 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. De Palma, M. & Naldini, L. Tie2-expressing monocytes (TEMs): novel targets and vehicles of anticancer therapy? Biochim. Biophys. Acta 1796, 5–10 (2009).

    CAS  PubMed  Google Scholar 

  105. Oliner, J. et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6, 507–516 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Brown, J. L. et al. A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models. Mol. Cancer Ther. 9, 145–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. De Palma, M. et al. Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 14, 299–311 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P. & Persico, M. G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc. Natl Acad. Sci. USA 88, 9267–9271 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hiratsuka, S. et al. Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res. 61, 1207–1213 (2001).

    CAS  PubMed  Google Scholar 

  113. Xu, L. et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res. 66, 3971–3977 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007).

    Article  CAS  Google Scholar 

  115. Bais, C. et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141, 166–177 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Van de Viere, S. et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141, 178–690 (2010).

    Article  CAS  Google Scholar 

  117. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  118. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006).

    Article  CAS  Google Scholar 

  119. Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hlatky, L., Tsionou, C., Hahnfeldt, P. & Coleman, C. N. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54, 6083–6086 (1994).

    CAS  PubMed  Google Scholar 

  121. Dong, J. et al. VEGF-null cells require PDGFRα signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 23, 2800–2810 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pietras, K., Pahler, J., Bergers, G. & Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 5, e19 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Crawford, Y. et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15, 21–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Tejada, M. L. et al. Tumor-driven paracrine platelet-derived growth factor receptor alpha signaling is a key determinant of stromal cell recruitment in a model of human lung carcinoma. Clin. Cancer Res. 12, 2676–2688 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Anderberg, C. et al. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 69, 369–378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lokker, N. A., Sullivan, C. M., Hollenbach, S. J., Israel, M. A. & Giese, N. A. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 62, 3729–3735 (2002).

    CAS  PubMed  Google Scholar 

  128. di Tomaso, E. et al. PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment. PLoS ONE 4, e5123 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Pollard, J. W. Trophic macrophages in development and disease. Nature Rev. Immunol. 9, 259–270 (2009).

    Article  CAS  Google Scholar 

  130. Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nature Med. 14, 518–527 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Solinas, G., Germano, G., Mantovani, A. & Allavena, P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol. 86, 1065–1073 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Murdoch, C., Giannoudis, A. & Lewis, C. E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104, 2224–2234 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nature Rev. Cancer 8, 618–631 (2008).

    Article  CAS  Google Scholar 

  136. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Giraudo, E., Inoue, M. & Hanahan, D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 114, 623–633 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jodele, S. et al. The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent. Cancer Res. 65, 3200–3208 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Ahn, G. O. & Brown, J. M. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13, 193–205 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Nyberg, P., Xie, L. & Kalluri, R. Endogenous inhibitors of angiogenesis. Cancer Res. 65, 3967–3979 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Crivellato, E., Nico, B. & Ribatti, D. Mast cells and tumour angiogenesis: New insight from experimental carcinogenesis. Cancer Lett. 269, 1–6 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Shchors, K. & Evan, G. Tumor angiogenesis: cause or consequence of cancer? Cancer Res. 67, 7059–7061 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  149. Pan, P.-Y. et al. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111, 219–228 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ferrara, N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 21, 21–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Shojaei, F. et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc. Natl Acad. Sci. USA 106, 6742–6747 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. LeCouter, J. et al. The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: localization of Bv8 receptors to endothelial cells. Proc. Natl Acad. Sci. USA 100, 2685–2690 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. LeCouter, J., Zlot, C., Tejada, M., Peale, F. & Ferrara, N. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc. Natl Acad. Sci. USA 101, 16813–16818 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mueller, M. D., Lebovic, D. I., Garrett, E. & Taylor, R. N. Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis. Fertil. Steril. 74, 107–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Lin, Y. J., Lai, M. D., Lei, H. Y. & Wing, L. Y. Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology 147, 1278–1286 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Pahler, J. C. et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10, 329–340 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Grothey, A. et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J. Clin. Oncol. 26, 5326–5334 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Strilic, B. et al. The molecular basis of vascular lumen formation in the developing mouse aorta. Dev. Cell 17, 505–515 (2009).

    Article  CAS  PubMed  Google Scholar 

  160. Rubenstein, J. L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2, 306–314 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Chung, A., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10, 505–514 (2010). https://doi.org/10.1038/nrc2868

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