The Situation Is More Complex Than Anticipated

  • Andreas Bikfalvi


Vessels are not uniform tubes but are subdivided into arterial, venous, and lymphatic vessels. Large vessels (arteries, veins, large lymphatic trunks), medium-size vessels (arterioles, venules, medium-sized lymphatics), and capillaries are also distinguished. As we have just seen, the identification of the VEGF family had a considerable impact on both basic and clinical research (see below). Nevertheless, the simple picture that we had following Folkman’s work has become considerably more complicated and many modifications/corrections have been made at the cellular and molecular levels.


  1. 147.
    Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177. Scholar
  2. 148.
    Gerhardt H, Betsholtz C (2005) How do endothelial cells orientate? EXS 94:3–15Google Scholar
  3. 149.
    Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams RH (2012) Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484(7392):110–114. Scholar
  4. 150.
    Zarkada G, Heinolainen K, Makinen T, Kubota Y, Alitalo K (2015) VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proc Natl Acad Sci U S A 112(3):761–766. Scholar
  5. 151.
    Tamariz E, Varela-Echavarria A (2015) The discovery of the growth cone and its influence on the study of axon guidance. Front Neuroanat 9:51. Scholar
  6. 152.
    Pelton JC, Wright CE, Leitges M, Bautch VL (2014) Multiple endothelial cells constitute the tip of developing blood vessels and polarize to promote lumen formation. Development 141(21):4121–4126. Scholar
  7. 153.
    Thomas JL, Baker K, Han J, Calvo C, Nurmi H, Eichmann AC, Alitalo K (2013) Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci 70(10):1779–1792. Scholar
  8. 154.
    Ochsenbein AM, Karaman S, Proulx ST, Berchtold M, Jurisic G, Stoeckli ET, Detmar M (2016) Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells. Development 143(4):589–594. Scholar
  9. 155.
    Teuwen LA, Draoui N, Dubois C, Carmeliet P (2017) Endothelial cell metabolism: an update anno 2017. Curr Opin Hematol.
  10. 156.
    Kur E, Kim J, Tata A, Comin CH, Harrington KI, Costa Lda F, Bentley K, Gu C (2016) Temporal modulation of collective cell behavior controls vascular network topology. eLife 5.
  11. 157.
    Sigurbjornsdottir S, Mathew R, Leptin M (2014) Molecular mechanisms of de novo lumen formation. Nat Rev Mol Cell Biol 15(10):665–676. Scholar
  12. 158.
    Strilic B, Kucera T, Eglinger J, Hughes MR, McNagny KM, Tsukita S, Dejana E, Ferrara N, Lammert E (2009) The molecular basis of vascular lumen formation in the developing mouse aorta. Dev Cell 17(4):505–515. Scholar
  13. 159.
    Kucera T, Strilic B, Regener K, Schubert M, Laudet V, Lammert E (2009) Ancestral vascular lumen formation via basal cell surfaces. PLoS One 4(1):e4132. Scholar
  14. 160.
    Kamei M, Saunders WB, Bayless KJ, Dye L, Davis GE, Weinstein BM (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442(7101):453–456. Scholar
  15. 161.
    Herwig L, Blum Y, Krudewig A, Ellertsdottir E, Lenard A, Belting HG, Affolter M (2011) Distinct cellular mechanisms of blood vessel fusion in the zebrafish embryo. Curr Biol 21(22):1942–1948. Scholar
  16. 162.
    Axnick J, Lammert E (2012) Vascular lumen formation. Curr Opin Hematol 19(3):192–198. Scholar
  17. 163.
    Phng LK, Gebala V, Bentley K, Philippides A, Wacker A, Mathivet T, Sauteur L, Stanchi F, Belting HG, Affolter M, Gerhardt H (2015) Formin-mediated actin polymerization at endothelial junctions is required for vessel lumen formation and stabilization. Dev Cell 32(1):123–132. Scholar
  18. 164.
    Gebala V, Collins R, Geudens I, Phng LK, Gerhardt H (2016) Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo. Nat Cell Biol 18(4):443–450. Scholar
  19. 165.
    Yang Y, Oliver G (2014) Development of the mammalian lymphatic vasculature. J Clin Invest 124(3):888–897. Scholar
  20. 166.
    Sabine A, Agalarov Y, Maby-El Hajjami H, Jaquet M, Hagerling R, Pollmann C, Bebber D, Pfenniger A, Miura N, Dormond O, Calmes JM, Adams RH, Makinen T, Kiefer F, Kwak BR, Petrova TV (2012) Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev Cell 22(2):430–445. Scholar
  21. 167.
    Trani M, Dejana E (2015) New insights in the control of vascular permeability: vascular endothelial-cadherin and other players. Curr Opin Hematol.
  22. 168.
    Le Guelte A, Dwyer J, Gavard J (2011) Jumping the barrier: VE-cadherin, VEGF and other angiogenic modifiers in cancer. Biol Cell 103(12):593–605. Scholar
  23. 169.
    Azzi S, Hebda JK, Gavard J (2013) Vascular permeability and drug delivery in cancers. Front Oncol 3:211. Scholar
  24. 170.
    Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15(7):1751PubMedPubMedCentralGoogle Scholar
  25. 171.
    Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM (2003) The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 111(11):1723–1732. Scholar
  26. 172.
    Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463–475. Scholar
  27. 173.
    Dewerchin M, Carmeliet P (2014) Placental growth factor in cancer. Expert Opin Ther Targets 18(11):1339–1354. Scholar
  28. 174.
    Eriksson A, Cao R, Pawliuk R, Berg SM, Tsang M, Zhou D, Fleet C, Tritsaris K, Dissing S, Leboulch P, Cao Y (2002) Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell 1(1):99–108CrossRefPubMedGoogle Scholar
  29. 175.
    Yang X, Zhang Y, Yang Y, Lim S, Cao Z, Rak J, Cao Y (2013) Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc Natl Acad Sci U S A 110(34):13932–13937. Scholar
  30. 176.
    Davis S, Yancopoulos GD (1999) The angiopoietins: Yin and Yang in angiogenesis. Curr Top Microbiol Immunol 237:173–185PubMedGoogle Scholar
  31. 177.
    Koh GY (2013) Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med 19(1):31–39. Scholar
  32. 178.
    Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, Di Santo JP, Bikfalvi A (2001) Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms. Cancer Res 61(4):1717–1726PubMedGoogle Scholar
  33. 179.
    Larrieu-Lahargue F, Welm AL, Bouchecareilh M, Alitalo K, Li DY, Bikfalvi A, Auguste P (2012) Blocking Fibroblast Growth Factor receptor signaling inhibits tumor growth, lymphangiogenesis, and metastasis. PLoS One 7(6):e39540. Scholar
  34. 180.
    Shin JW, Min M, Larrieu-Lahargue F, Canron X, Kunstfeld R, Nguyen L, Henderson JE, Bikfalvi A, Detmar M, Hong YK (2006) Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 17(2):576–584. Scholar
  35. 181.
    Rousseau B, Larrieu-Lahargue F, Javerzat S, Guilhem-Ducleon F, Beermann F, Bikfalvi A (2004) The tyrp1-Tag/tyrp1-FGFR1-DN bigenic mouse: a model for selective inhibition of tumor development, angiogenesis, and invasion into the neural tissue by blockade of fibroblast growth factor receptor activity. Cancer Res 64(7):2490–2495CrossRefPubMedGoogle Scholar
  36. 182.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4):299–309. Scholar
  37. 183.
    Murakami M, Nguyen LT, Zhuang ZW, Moodie KL, Carmeliet P, Stan RV, Simons M (2008) The FGF system has a key role in regulating vascular integrity. J Clin Invest 118(10):3355–3366. Scholar
  38. 184.
    De Smet F, Tembuyser B, Lenard A, Claes F, Zhang J, Michielsen C, Van Schepdael A, Herbert JM, Bono F, Affolter M, Dewerchin M, Carmeliet P (2014) Fibroblast growth factor signaling affects vascular outgrowth and is required for the maintenance of blood vessel integrity. Chem Biol 21(10):1310–1317. Scholar
  39. 185.
    Yu P, Wilhelm K, Dubrac A, Tung JK, Alves TC, Fang JS, Xie Y, Zhu J, Chen Z, De Smet F, Zhang J, Jin SW, Sun L, Sun H, Kibbey RG, Hirschi KK, Hay N, Carmeliet P, Chittenden TW, Eichmann A, Potente M, Simons M (2017) FGF-dependent metabolic control of vascular development. Nature 545(7653):224–228. Scholar
  40. 186.
    Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23. Scholar
  41. 187.
    Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G, Dejana E, Ostman A, Lindahl P, Betsholtz C (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17(15):1835–1840. Scholar
  42. 188.
    Gaengel K, Genove G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29(5):630–638. Scholar
  43. 189.
    Ferrara N (2010) Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis. Curr Opin Hematol 17(3):219–224. Scholar
  44. 190.
    Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, Ouyang W, Ferrara N (2013) An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19(9):1114–1123. Scholar
  45. 191.
    Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA (2005) WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437(7057):417–421. Scholar
  46. 192.
    Stefater JA III, Lewkowich I, Rao S, Mariggi G, Carpenter AC, Burr AR, Fan J, Ajima R, Molkentin JD, Williams BO, Wills-Karp M, Pollard JW, Yamaguchi T, Ferrara N, Gerhardt H, Lang RA (2011) Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474(7352):511–515. Scholar
  47. 193.
    Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455. Scholar
  48. 194.
    Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM (2014) Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17(1):109–118. Scholar
  49. 195.
    Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551. Scholar
  50. 196.
    Rymo SF, Gerhardt H, Wolfhagen Sand F, Lang R, Uv A, Betsholtz C (2011) A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLoS One 6(1):e15846. Scholar
  51. 197.
    Zhang F, Li Y, Tang Z, Kumar A, Lee C, Zhang L, Zhu C, Klotzsche-von Ameln A, Wang B, Gao Z, Zhang S, Langer HF, Hou X, Jensen L, Ma W, Wong W, Chavakis T, Liu Y, Cao Y, Li X (2012) Proliferative and survival effects of PUMA promote angiogenesis. Cell Rep 2(5):1272–1285. Scholar
  52. 198.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364CrossRefPubMedGoogle Scholar
  53. 199.
    Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33(4):207–214. Scholar
  54. 200.
    Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402. Scholar
  55. 201.
    Berra E, Pages G, Pouyssegur J (2000) MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev 19(1–2):139–145CrossRefPubMedGoogle Scholar
  56. 202.
    Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38(9):1060–1065. Scholar
  57. 203.
    Shibuya M (2013) VEGFR and type-V RTK activation and signaling. Cold Spring Harb Perspect Biol 5(10):a009092. Scholar
  58. 204.
    Lampropoulou A, Ruhrberg C (2014) Neuropilin regulation of angiogenesis. Biochem Soc Trans 42(6):1623–1628. Scholar
  59. 205.
    Murakami M, Simons M (2008) Fibroblast growth factor regulation of neovascularization. Curr Opin Hematol 15(3):215–220. Scholar
  60. 206.
    Hawinkels LJ, Garcia de Vinuesa A, Ten Dijke P (2013) Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy. Expert Opin Investig Drugs 22(11):1371–1383. Scholar
  61. 207.
    Freitas C, Larrivee B, Eichmann A (2008) Netrins and UNC5 receptors in angiogenesis. Angiogenesis 11(1):23–29. Scholar
  62. 208.
    Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314CrossRefGoogle Scholar
  63. 209.
    Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270PubMedGoogle Scholar
  64. 210.
    Verdegem D, Moens S, Stapor P, Carmeliet P (2014) Endothelial cell metabolism: parallels and divergences with cancer cell metabolism. Cancer Metab 2:19. Scholar
  65. 211.
    Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, Heggermont W, Godde L, Vinckier S, Van Veldhoven PP, Eelen G, Schoonjans L, Gerhardt H, Dewerchin M, Baes M, De Bock K, Ghesquiere B, Lunt SY, Fendt SM, Carmeliet P (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520(7546):192–197. Scholar
  66. 212.
    Lazarus A, Del-Moral PM, Ilovich O, Mishani E, Warburton D, Keshet E (2011) A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways. Development 138(11):2359–2368. Scholar
  67. 213.
    Magenheim J, Ilovich O, Lazarus A, Klochendler A, Ziv O, Werman R, Hija A, Cleaver O, Mishani E, Keshet E, Dor Y (2011) Blood vessels restrain pancreas branching, differentiation and growth. Development 138(21):4743–4752. Scholar
  68. 214.
    Lammert E, Cleaver O, Melton D (2003) Role of endothelial cells in early pancreas and liver development. Mech Dev 120(1):59–64CrossRefPubMedGoogle Scholar
  69. 215.
    Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh LC, Gerber HP, Ferrara N, Melton DA (2003) Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 13(12):1070–1074CrossRefPubMedGoogle Scholar
  70. 216.
    Rafii S, Butler JM, Ding BS (2016) Angiocrine functions of organ-specific endothelial cells. Nature 529(7586):316–325. Scholar
  71. 217.
    Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ (2013) An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med 19(1):74–82. Scholar
  72. 218.
    Yang P, Read C, Kuc RE, Buonincontri G, Southwood M, Torella R, Upton PD, Crosby A, Sawiak SJ, Carpenter TA, Glen RC, Morrell NW, Maguire JJ, Davenport AP (2017) Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension. Circulation 135(12):1160–1173. Scholar
  73. 219.
    de Jesus Perez V, Yuan K, Alastalo TP, Spiekerkoetter E, Rabinovitch M (2014) Targeting the Wnt signaling pathways in pulmonary arterial hypertension. Drug Discov Today 19(8):1270–1276. Scholar
  74. 220.
    Fan Y, Potdar AA, Gong Y, Eswarappa SM, Donnola S, Lathia JD, Hambardzumyan D, Rich JN, Fox PL (2014) Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1alpha accumulation. Nat Cell Biol 16(5):445–456. Scholar
  75. 221.
    Cao Z, Ding BS, Guo P, Lee SB, Butler JM, Casey SC, Simons M, Tam W, Felsher DW, Shido K, Rafii A, Scandura JM, Rafii S (2014) Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25(3):350–365. Scholar
  76. 222.
    Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6(6):553–563. Scholar
  77. 223.
    Watkins S, Robel S, Kimbrough IF, Robert SM, Ellis-Davies G, Sontheimer H (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196. Scholar
  78. 224.
    Cuddapah VA, Robel S, Watkins S, Sontheimer H (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15(7):455–465. Scholar
  79. 225.
    Bikfalvi A, Moenner M, Javerzat S, North S, Hagedorn M (2011) Inhibition of angiogenesis and the angiogenesis/invasion shift. Biochem Soc Trans 39(6):1560–1564. Scholar
  80. 226.
    Scherer HJ (1938) Structural development in gliomas. Am J Cancer 34:333–351Google Scholar
  81. 227.
    Talasila KM, Soentgerath A, Euskirchen P, Rosland GV, Wang J, Huszthy PC, Prestegarden L, Skaftnesmo KO, Sakariassen PO, Eskilsson E, Stieber D, Keunen O, Brekka N, Moen I, Nigro JM, Vintermyr OK, Lund-Johansen M, Niclou S, Mork SJ, Enger PO, Bjerkvig R, Miletic H (2013) EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis. Acta Neuropathol 125(5):683–698. Scholar
  82. 228.
    Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22(1):21–35. Scholar
  83. 229.
    Auf G, Jabouille A, Guerit S, Pineau R, Delugin M, Bouchecareilh M, Magnin N, Favereaux A, Maitre M, Gaiser T, von Deimling A, Czabanka M, Vajkoczy P, Chevet E, Bikfalvi A, Moenner M (2010) Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci U S A 107(35):15553–15558. Scholar
  84. 230.
    Boye K, Pujol N, D Alves I, Chen YP, Daubon T, Lee YZ, Dedieu S, Constantin M, Bello L, Rossi M, Bjerkvig R, Sue SC, Bikfalvi A, Billottet C (2017) The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors. Nat Commun 8(1):1571. Scholar
  85. 231.
    Montana V, Sontheimer H (2011) Bradykinin promotes the chemotactic invasion of primary brain tumors. J Neurosci 31(13):4858–4867. Scholar
  86. 239.
    Javerzat SGV, Bikfalvi A (2013) Balancing risks and benefits of anti-angiogenic drugs for malignant glioma. Future Neurol 8(2):159–174CrossRefGoogle Scholar
  87. 232.
    Moussion C, Girard JP (2011) Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature 479(7374):542–546. Scholar
  88. 233.
    Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP (2011) Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71(17):5678–5687. Scholar
  89. 234.
    Yao L, Sgadari C, Furuke K, Bloom ET, Teruya-Feldstein J, Tosato G (1999) Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood 93(5):1612–1621PubMedGoogle Scholar
  90. 235.
    Martinet L, Garrido I, Girard JP (2012) Tumor high endothelial venules (HEVs) predict lymphocyte infiltration and favorable prognosis in breast cancer. Oncoimmunology 1(5):789–790. Scholar
  91. 236.
    Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, Feyen K, Tawney J, Hanahan D, Michael IP, Bergers G (2017) Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 9(385).
  92. 237.
    Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989. Scholar
  93. 238.
    Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9(6):685–693. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Andreas Bikfalvi
    • 1
  1. 1.Angiogenesis and Tumor Microenvironment LaboratoryUniversity of Bordeaux and National Institute of Health and Medical ResearchPessacFrance

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