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  • Review Article
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Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way

Nature Reviews Clinical Oncology volume 6, pages 315–326 (2009)Cite this article

Abstract

From the original concepts that tumors require a vascular supply to grow and that blocking angiogenesis could suppress tumor growth, the oncology field has witnessed clinical successes of VEGF-targeted antiangiogenic medicine. The field is now facing the challenge of overcoming resistance to VEGF-targeted therapy, and therefore additional angiogenesis inhibitors are being developed. Studies on how endothelial 'tip, stalk and phalanx cells' form sprouts have identified promising candidate targets with complementary mechanisms to VEGF. This Review provides a conceptual framework in which molecular discoveries and principles are discussed in light of clinical opportunities to develop new antiangiogenic agents.

Key Points

  • Tumors require a vascular supply to grow, and blocking angiogenesis can suppress tumor growth; however, the oncology field is now facing the challenge of overcoming resistance to VEGF-targeted therapy

  • A vessel branching morphogenesis model postulates that an endothelial 'tip cell' leads the nascent vessel sprouts at the forefront, while a trailing endothelial 'stalk cell' elongates the stalk of this sprout

  • By stimulating excess formation of tip cells, inhibition of delta-like ligand 4/Notch signaling causes nonproductive angiogenesis of hypoperfused tumor vessels, and inhibits tumor growth, alone and in combination with VEGF inhibitors

  • Antiangiogenic agents (for example, antagonists of VEGFR3, placental growth factor, neuropilin-1 and neuropilin-2) enhance the anticancer effect of VEGF inhibitors via complementary mechanisms, including inhibition of angiogenesis, lymphangiogenesis, inflammation or via stimulation of vessel maturation

  • Traditional antiangiogenic agents cause hypoperfused vessels and induce hypoxia, which promotes tumor invasiveness and metastasis

  • Inhibition of the oxygen sensor, prolyl hydroxylase domain 2 protein, in endothelial cells normalizes tumor vessels by forming a phalanx of streamlined quiescent endothelial cells, improving tumor perfusion, oxygenation, and reducing metastasis

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Figure 1: Formation of novel vessel branches.
Figure 2: Inhibition of VEGF pathway induces therapeutic effects and adverse effects.
Figure 3: Role of PHD2 in endothelial normalization.
Figure 4: Tip-cell selection occurs via lateral inhibition by Notch.
Figure 5: Nrarp coordinates Notch and Wnt signaling in endothelial cells.
Figure 6: Role of VEGFR1 and its ligand PlGF in vessel branching.

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References

  1. Affolter, M. & Caussinus, E. Tracheal branching morphogenesis in Drosophila: new insights into cell behavior and organ architecture. Development 135, 2055–2064 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. 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 

  4. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jain, R. K. Normalization of tumor vasculature: an emerging concept in anti-angiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Crawford, Y. & Ferrara, N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res. 335, 261–269 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Stalmans, I. et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327–336 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Baluk, P., Hashizume, H. & McDonald, D. M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15, 102–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Potenta, S., Zeisberg, E. & Kalluri, R. The role of endothelial-to-mesenchymal transition in cancer progression. Br. J. Cancer 99, 1375–1379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Loges, S., Mazzone, M., Hohensinner, P. & Carmeliet, P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15, 167–170 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Paez-Ribes, M. et al. Anti-angiogenic 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 

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

    Article  CAS  PubMed  Google Scholar 

  19. Ridgway, J. et al. Inhibition of Dll4 signaling inhibits tumor growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Dufraine, J., Funahashi, Y. & Kitajewski, J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27, 5132–5137 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Funahashi, Y. et al. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 68, 4727–4735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. D'Souza, B., Miyamoto, A. & Weinmaster, G. The many facets of Notch ligands. Oncogene 27, 5148–5167 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hofmann, J. J. & Iruela-Arispe, M. L. Notch signaling in blood vessels: who is talking to whom about what? Circ. Res. 100, 1556–1568 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Phng, L. K. et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev. Cell 16, 70–82 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hellström, M. et al. Dll4 signaling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    Article  PubMed  CAS  Google Scholar 

  26. Suchting, S. et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl Acad. Sci. USA 104, 3225–3230 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Siekmann, A. F. & Lawson, N. D. Notch signaling limits angiogenic cell behavior in developing zebrafish arteries. Nature 445, 781–784 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Scehnet, J. S. et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109, 4753–4760 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Poellinger, L. & Lendahl, U. Modulating Notch signaling by pathway-intrinsic and pathway-extrinsic mechanisms. Curr. Opin. Genet. Dev. 18, 449–454 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Hayward, P., Kalmar, T. & Arias, A. M. Wnt/Notch signaling and information processing during development. Development 135, 411–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Dou, G. R. et al. RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J. 22, 1606–1617 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Li, J. L. et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 67, 11244–11253 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Hu, X. B. et al. Blockade of Notch signaling in tumor-bearing mice may lead to tumor regression, progression, or metastasis, depending on tumor cell types. Neoplasia 11, 32–38 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koch, U. & Radtke, F. Notch and cancer: a double-edged sword. Cell. Mol. Life Sci. 64, 2746–2762 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. High, F. A. et al. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc. Natl Acad. Sci. USA 105, 1955–1959 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zeng, Q. et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8, 13–23 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Karpanen, T. & Alitalo, K. Molecular biology and pathology of lymphangiogenesis. Annu. Rev. Pathol. 3, 367–397 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Ny, A. et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat. Med. 11, 998–1004 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. He, Y. et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl Cancer Inst. 94, 819–825 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Dumont, D. J. et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946–949 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Shawber, C. J. et al. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J. Clin. Invest. 117, 3369–3382 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Haiko, P. et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol. Cell. Biol. 28, 4843–4850 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Caunt, M. et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13, 331–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Padera, T. P. et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Ther. 7, 2272–2279 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Neufeld, G. & Kessler, O. The semaphorins: versatile regulators of tumor progression and tumor angiogenesis. Nat. Rev. Cancer 8, 632–645 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Bielenberg, D. R., Pettaway, C. A., Takashima, S. & Klagsbrun, M. Neuropilins in neoplasms: expression, regulation, and function. Exp. Cell. Res. 312, 584–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Vieira, J. M., Schwarz, Q. & Ruhrberg, C. Selective requirements for NRP1 ligands during neurovascular patterning. Development 134, 1833–1843 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Wang, L. et al. Neuropilin-1 modulates p53/caspases axis to promote endothelial cell survival. PLoS ONE 2, e1161 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Chittenden, T. W. et al. Selective regulation of arterial branching morphogenesis by synectin. Dev. Cell 10, 783–795 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Eichmann, A., Le Noble, F., Autiero, M. & Carmeliet, P. Guidance of vascular and neural network formation. Curr. Opin. Neurobiol. 15, 108–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Staton, C. A., Kumar, I., Reed, M. W. & Brown, N. J. Neuropilins in physiological and pathological angiogenesis. J. Pathol. 212, 237–248 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. 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 

  56. Pan, Q. et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11, 53–67 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Gerhardt, H. et al. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system. Dev. Dyn. 231, 503–509 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Miao, H. Q. et al. Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J. Cell Biol. 146, 233–242 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McLennan, R. & Kulesa, P. M. In vivo analysis reveals a critical role for neuropilin-1 in cranial neural crest cell migration in chick. Dev. Biol. 301, 227–239 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Siekmann, A. F., Covassin, L. & Lawson, N. D. Modulation of VEGF signaling output by the Notch pathway. Bioessays 30, 303–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Stella, M. C., Trusolino, L., Pennacchietti, S. & Comoglio, P. M. Negative feedback regulation of Met-dependent invasive growth by Notch. Mol. Cell Biol. 25, 3982–3996 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Harrington, L. S. et al. Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvasc. Res. 75, 144–154 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Matthies, A. M., Low, Q. E., Lingen, M. W. & DiPietro, L. A. Neuropilin-1 participates in wound angiogenesis. Am. J. Pathol. 160, 289–296 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Shen, J. et al. Deficiency of neuropilin 2 suppresses VEGF-induced retinal neovascularization. Mol. Med. 10, 12–18 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dallas, N. A. et al. Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma. Clin. Cancer Res. 14, 8052–8060 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Autiero, M. et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat. Med. 9, 936–943 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat. Rev. Cancer 8, 942–956 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Kappas, N. C. et al. The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. J. Cell Biol. 181, 847–858 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Boulton, M. E., Cai, J. & Grant, M. B. gamma-Secretase: a multifaceted regulator of angiogenesis. J. Cell. Mol. Med. 12, 781–795 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Kaplan, R. N. et al. VEGFR1-positive hematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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 

  75. Taylor, A. P., Rodriguez, M., Adams, K., Goldenberg, D. M. & Blumenthal, R. D. Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int. J. Cancer 105, 158–164 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Kaelin, W. G., Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Carmeliet, P. et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Wu, S. et al. Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene. Mol. Ther. 16, 1227–1234 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Nangaku, M. et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler. Thromb. Vasc. Biol. 27, 2548–2554 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Dor, Y. et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 21, 1939–1947 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Nasarre, P. et al. Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res. 69, 1324–1333 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kashiwagi, S. et al. Perivascular nitric oxide gradients normalize tumor vasculature. Nat. Med. 14, 255–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Jones, C. A. et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat. Med. 14, 448–453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumors promotes immune destruction. Nature 453, 410–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chen, J. X. & Stinnett, A. Ang-1 gene therapy inhibits hypoxia-inducible factor-1alpha (HIF-1alpha)-prolyl-4-hydroxylase-2, stabilizes HIF-1alpha expression, and normalizes immature vasculature in db/db mice. Diabetes 57, 3335–3343 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  PubMed  Google Scholar 

  88. Kerbel, R. S. Anti-angiogenic therapy: a universal chemosensitization strategy for cancer? Science 312, 1171–1175 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Sullivan, C. J., Doetschman, T. & Hoying, J. B. Targeted disruption of the Fgf2 gene does not affect vascular growth in the mouse ischemic hindlimb. J. Appl. Physiol. 93, 2009–2017 (2002).

    Article  CAS  PubMed  Google Scholar 

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  1. Vesalius Research Center, VIB, Leuven, Belgium

    Peter Carmeliet, Frederik De Smet, Sonja Loges & Massimiliano Mazzone

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Correspondence to Peter Carmeliet.

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P. Carmeliet receives research support and is a patent holder and stock holder for ThromboGenics. P. Carmeliet declares to be named as an inventor on patents, claiming subject matter that is partially based on the results described in this review article. The aforementioned patents are licensed or submitted, which may result in a royalty payment to P. Carmeliet. The other authors declare no competing interests.

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Carmeliet, P., De Smet, F., Loges, S. et al. Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way. Nat Rev Clin Oncol 6, 315–326 (2009). https://doi.org/10.1038/nrclinonc.2009.64

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