Hypoxia-Dependent Angiogenesis and Lymphangiogenesis in Cancer

  • Luana SchitoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1136)


Hypoxia (low O2) is a ubiquitous feature of solid cancers, arising as a mismatch between cellular O2 supply and consumption. Hypoxia is associated to metastatic disease and mortality owing to its ability to stimulate the formation of blood (angiogenesis) and lymphatic vessels (lymphangiogenesis), thereby allowing cancer cells to escape the unfavorable tumor microenvironment and disseminate into secondary sites. This review outlines molecular mechanisms by which intratumoral hypoxia regulates the expression of motogenic and mitogenic factors that induce angiogenesis and lymphangiogenesis, whilst discussing their implications for metastatic cancers.


Angiogenesis HIF Hypoxia Lymphangiogenesis Metastasis 


  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. Scholar
  2. 2.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. Scholar
  3. 3.
    Rey S, Schito L, Koritzinsky M, Wouters BG (2017a) Molecular targeting of hypoxia in radiotherapy. Adv Drug Deliv Rev 109:45–62. Scholar
  4. 4.
    Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549CrossRefGoogle Scholar
  5. 5.
    Höckel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276. Scholar
  6. 6.
    Vaupel P, Mayer A (2017) Tumor oxygenation status: facts and fallacies. Adv Exp Med Biol 977:91–99. Scholar
  7. 7.
    Schito L, Rey S (2018) Cell-autonomous metabolic reprogramming in hypoxia. Trends Cell Biol 28:128–142. Scholar
  8. 8.
    Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354. Scholar
  9. 9.
    Schito L, Rey S, Konopleva M (2017) Integration of hypoxic HIF-α signaling in blood cancers. Oncogene 36:5331–5340. Scholar
  10. 10.
    Vaupel P (2009) Prognostic potential of the pre-therapeutic tumor oxygenation status. Adv Exp Med Biol 645:241–246. Scholar
  11. 11.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514CrossRefGoogle Scholar
  12. 12.
    Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94:4273–4278CrossRefGoogle Scholar
  13. 13.
    Flamme I, Fröhlich T, von Reutern M, Kappel A, Damert A, Risau W (1997) HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev 63:51–60CrossRefGoogle Scholar
  14. 14.
    Peng J, Zhang L, Drysdale L, Fong GH (2000) The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci USA 97:8386–8391. Scholar
  15. 15.
    Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82CrossRefGoogle Scholar
  16. 16.
    Shen C, Kaelin WG (2013) The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol 23:18–25. Scholar
  17. 17.
    Rytkönen KT, Williams TA, Renshaw GM, Primmer CR, Nikinmaa M (2011) Molecular evolution of the metazoan PHD-HIF oxygen-sensing system. Mol Biol Evol 28:1913–1926. Scholar
  18. 18.
    Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340. Scholar
  19. 19.
    Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54CrossRefGoogle Scholar
  20. 20.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468. Scholar
  21. 21.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472. Scholar
  22. 22.
    Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206. Scholar
  23. 23.
    Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733–25741. Scholar
  24. 24.
    Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992CrossRefGoogle Scholar
  25. 25.
    Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW (2000) Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 97:10430–10435. Scholar
  26. 26.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275. Scholar
  27. 27.
    Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86:236–242. Scholar
  28. 28.
    Schito L, Rey S (2017) Hypoxic pathobiology of breast cancer metastasis. Biochim Biophys Acta 1868:239–245. Scholar
  29. 29.
    Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97:1573–1581. Scholar
  30. 30.
    Bos R, van Diest PJ, de Jong JS, van der Groep P, van der Valk P, van der Wall E (2005) Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 46:31–36. Scholar
  31. 31.
    Nalwoga H, Ahmed L, Arnes JB, Wabinga H, Akslen LA (2016) Strong expression of hypoxia-inducible factor-1α (HIF-1α) is associated with Axl expression and features of aggressive tumors in African breast Cancer. PLoS One 11:e0146823. Scholar
  32. 32.
    Okada K, Osaki M, Araki K, Ishiguro K, Ito H, Ohgi S (2005) Expression of hypoxia-inducible factor (HIF-1alpha), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas. Anticancer Res 25:3003–3009PubMedGoogle Scholar
  33. 33.
    Schito L, Rey S, Tafani M, Zhang H, Wong CC-L, Russo A, Russo MA, Semenza GL (2012) Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA 109:E2707–E2716. Scholar
  34. 34.
    Schoppmann SF, Fenzl A, Schindl M, Bachleitner-Hofmann T, Nagy K, Gnant M, Horvat R, Jakesz R, Birner P (2006) Hypoxia inducible factor-1alpha correlates with VEGF-C expression and lymphangiogenesis in breast cancer. Breast Cancer Res Treat 99:135–141. Scholar
  35. 35.
    Matsuo Y, Ding Q, Desaki R, Maemura K, Mataki Y, Shinchi H, Natsugoe S, Takao S (2014) Hypoxia inducible factor-1 alpha plays a pivotal role in hepatic metastasis of pancreatic cancer: an immunohistochemical study. J Hepato-Biliary-Pancreat Sci 21:105–112. Scholar
  36. 36.
    Liang X, Yang D, Hu J, Hao X, Gao J, Mao Z (2008) Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma. Anticancer Res 28:1659–1666PubMedGoogle Scholar
  37. 37.
    Katsuta M, Miyashita M, Makino H, Nomura T, Shinji S, Yamashita K, Tajiri T, Kudo M, Ishiwata T, Naito Z (2005) Correlation of hypoxia inducible factor-1alpha with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol 78:123–130. Scholar
  38. 38.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–30. Scholar
  39. 39.
    Schito L (2018) Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment. Am J Physiol Regul Integr Comp Physiol. Scholar
  40. 40.
    Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378–390. Scholar
  41. 41.
    Rey S, Schito L, Wouters BG, Eliasof S, Kerbel RS (2017b) Targeting hypoxia-inducible factors for antiangiogenic Cancer therapy. Trends Cancer 3:529–541. Scholar
  42. 42.
    Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–770. Scholar
  43. 43.
    Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–858CrossRefGoogle Scholar
  44. 44.
    Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312CrossRefGoogle Scholar
  45. 45.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309CrossRefGoogle Scholar
  46. 46.
    de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991CrossRefGoogle Scholar
  47. 47.
    Jakeman LB, Winer J, Bennett GL, Altar CA, Ferrara N (1992) Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest 89:244–253. Scholar
  48. 48.
    Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586CrossRefGoogle Scholar
  49. 49.
    Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127. Scholar
  50. 50.
    Bougatef F, Menashi S, Khayati F, Naïmi B, Porcher R, Podgorniak M-P, Millot G, Janin A, Calvo F, Lebbé C, Mourah S (2010) EMMPRIN promotes melanoma cells malignant properties through a HIF-2alpha mediated up-regulation of VEGF-receptor-2. PLoS One 5:e12265. Scholar
  51. 51.
    Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate K, Sieweke M, Breier G, Flamme I (2003) Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha ) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J Biol Chem 278:7520–7530. Scholar
  52. 52.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613CrossRefGoogle Scholar
  53. 53.
    Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667CrossRefGoogle Scholar
  54. 54.
    Pullamsetti SS, Banat GA, Schmall A, Szibor M, Pomagruk D, Hänze J, Kolosionek E, Wilhelm J, Braun T, Grimminger F, Seeger W, Schermuly RT, Savai R (2013) Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF. Oncogene 32:1121–1134. Scholar
  55. 55.
    Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008a) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956. Scholar
  56. 56.
    Marcellini M, De Luca N, Riccioni T, Ciucci A, Orecchia A, Lacal PM, Ruffini F, Pesce M, Cianfarani F, Zambruno G, Orlandi A, Failla CM (2006) Increased melanoma growth and metastasis spreading in mice overexpressing placenta growth factor. Am J Pathol 169:643–654. Scholar
  57. 57.
    Hedlund E-M, Hosaka K, Zhong Z, Cao R, Cao Y (2009) Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature. Proc Natl Acad Sci USA 106:17505–17510. Scholar
  58. 58.
    Hedlund E-ME, Yang X, Zhang Y, Yang Y, Shibuya M, Zhong W, Sun B, Liu Y, Hosaka K, Cao Y (2013) Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs. Proc Natl Acad Sci USA 110:654–659. Scholar
  59. 59.
    Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008b) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956. Scholar
  60. 60.
    Simon M-P, Tournaire R, Pouyssegur J (2008) The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol 217:809–818. Scholar
  61. 61.
    Thomas M, Augustin HG (2009) The role of the angiopoietins in vascular morphogenesis. Angiogenesis 12:125–137. Scholar
  62. 62.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998CrossRefGoogle Scholar
  63. 63.
    Schmittnaegel M, De Palma M (2017) Reprogramming tumor blood vessels for enhancing immunotherapy. Trends Cancer 3:809–812. Scholar
  64. 64.
    Zhang L, Yang N, Park J-W, Katsaros D, Fracchioli S, Cao G, O’Brien-Jenkins A, Randall TC, Rubin SC, Coukos G (2003a) Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63:3403–3412PubMedGoogle Scholar
  65. 65.
    Zhang SXL, Gozal D, Sachleben LR, Rane M, Klein JB, Gozal E (2003b) Hypoxia induces an autocrine-paracrine survival pathway via platelet-derived growth factor (PDGF)-B/PDGF-beta receptor/phosphatidylinositol 3-kinase/Akt signaling in RN46A neuronal cells. FASEB J 17:1709–1711. Scholar
  66. 66.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. Scholar
  67. 67.
    Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W (2003) Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425:307–311. Scholar
  68. 68.
    Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M, Moons L, Wei S, Zou L, Machelon V, Emilie D, Terrassa M, Lackner A, Curiel TJ, Carmeliet P, Zou W (2005) CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 65:465–472PubMedGoogle Scholar
  69. 69.
    Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641CrossRefGoogle Scholar
  70. 70.
    Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P, Rosen EM (1993) Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci USA 90:1937–1941CrossRefGoogle Scholar
  71. 71.
    Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C (2001) Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res 61:5911–5918PubMedGoogle Scholar
  72. 72.
    Moriyama T, Kataoka H, Hamasuna R, Yokogami K, Uehara H, Kawano H, Goya T, Tsubouchi H, Koono M, Wakisaka S (1998) Up-regulation of vascular endothelial growth factor induced by hepatocyte growth factor/scatter factor stimulation in human glioma cells. Biochem Biophys Res Commun 249:73–77. Scholar
  73. 73.
    Jiménez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6:41–48. Scholar
  74. 74.
    Sargiannidou I, Zhou J, Tuszynski GP (2001) The role of thrombospondin-1 in tumor progression. Exp Biol Med (Maywood) 226:726–733CrossRefGoogle Scholar
  75. 75.
    Glück AA, Orlando E, Leiser D, Poliaková M, Nisa L, Quintin A, Gavini J, Stroka DM, Berezowska S, Bubendorf L, Blaukat A, Aebersold DM, Medová M, Zimmer Y (2018) Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia. Oncogene 37:4181–4196. Scholar
  76. 76.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361CrossRefGoogle Scholar
  77. 77.
    Guo P, Hu B, Gu W, Xu L, Wang D, Huang H-JS, Cavenee WK, Cheng S-Y (2003) Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol 162:1083–1093. Scholar
  78. 78.
    Song N, Huang Y, Shi H, Yuan S, Ding Y, Song X, Fu Y, Luo Y (2009) Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis. Cancer Res 69:6057–6064. Scholar
  79. 79.
    Palmer LA, Semenza GL, Stoler MH, Johns RA (1998) Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Phys 274:L212–L219Google Scholar
  80. 80.
    Ward ME, Toporsian M, Scott JA, Teoh H, Govindaraju V, Quan A, Wener AD, Wang G, Bevan SC, Newton DC, Marsden PA (2005) Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest 115:3128–3139. Scholar
  81. 81.
    Dulak J, Józkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wójtowicz A, Szuba A, Cooke JP (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20:659–666. Scholar
  82. 82.
    Ziche M, Parenti A, Ledda F, Dell’Era P, Granger HJ, Maggi CA, Presta M (1997) Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res 80:845–852CrossRefGoogle Scholar
  83. 83.
    Kashiwagi S, Tsukada K, Xu L, Miyazaki J, Kozin SV, Tyrrell JA, Sessa WC, Gerweck LE, Jain RK, Fukumura D (2008) Perivascular nitric oxide gradients normalize tumor vasculature. Nat Med 14:255–257. Scholar
  84. 84.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967CrossRefGoogle Scholar
  85. 85.
    Rehman J, Li J, Orschell CM, March KL (2003) Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107:1164–1169CrossRefGoogle Scholar
  86. 86.
    Rey S, Lee K, Wang CJ, Gupta K, Chen S, McMillan A, Bhise N, Levchenko A, Semenza GL (2009) Synergistic effect of HIF-1alpha gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia. Proc Natl Acad Sci USA 106:20399–20404. Scholar
  87. 87.
    Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220. Scholar
  88. 88.
    Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A 106:2353–2358. Scholar
  89. 89.
    Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, Gatter KC, Pezzella F (2013) Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med 2:427–436. Scholar
  90. 90.
    Jeong H-S, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, Willett CG, Jain RK, Padera TP (2015) Investigation of the lack of angiogenesis in the formation of lymph node metastases. J Natl Cancer Inst 107.
  91. 91.
    Naresh KN, Nerurkar AY, Borges AM (2001) Angiogenesis is redundant for tumour growth in lymph node metastases. Histopathology 38:466–470CrossRefGoogle Scholar
  92. 92.
    Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, Hegedus B, Hoetzenecker K, Renyi-Vamos F, Kuczynski EA, Vasudev NS, Larkin J, Gore M, Dvorak HF, Paku S, Kerbel RS, Dome B, Reynolds AR (2016) Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol. n/a-n/a. Scholar
  93. 93.
    Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan MR, Wotherspoon A, Gao Z, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, van Rheenen J, Khashper A, Brown G, Nyström H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22:1294–1302. Scholar
  94. 94.
    Kuczynski EA, Yin M, Bar-Zion A, Lee CR, Butz H, Man S, Daley F, Vermeulen PB, Yousef GM, Foster FS, Reynolds AR, Kerbel RS (2016) Co-option of liver vessels and not sprouting angiogenesis drives acquired Sorafenib resistance in hepatocellular carcinoma. J Natl Cancer Inst 108. Scholar
  95. 95.
    Gould CM, Courtneidge SA (2014) Regulation of invadopodia by the tumor microenvironment. Cell Adhes Migr 8:226–235CrossRefGoogle Scholar
  96. 96.
    Seftor REB, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, Hendrix MJC (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181:1115–1125. Scholar
  97. 97.
    Kirschmann DA, Seftor EA, Hardy KM, Seftor REB, Hendrix MJC (2012) Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res 18:2726–2732. Scholar
  98. 98.
    Li S, Meng W, Guan Z, Guo Y, Han X (2016) The hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatment. Biomed Pharmacother 80:127–135. Scholar
  99. 99.
    Ma J, Han S, Zhu Q, Zhao J, Zhang D, Wang L, Lv Y (2011) Role of Twist in vasculogenic mimicry formation in hypoxic hepatocellular carcinoma cells in vitro. Biochem Biophys Res Commun 408:686–691. Scholar
  100. 100.
    Sun B, Zhang D, Zhang S, Zhang W, Guo H, Zhao X (2007) Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett 249:188–197. Scholar
  101. 101.
    Zhang S, Li M, Zhang D, Xu S, Wang X, Liu Z, Zhao X, Sun B (2009) Hypoxia influences linearly patterned programmed cell necrosis and tumor blood supply patterns formation in melanoma. Lab Investig J Tech Methods Pathol 89:575–586. Scholar
  102. 102.
    van der Schaft DWJ, Hillen F, Pauwels P, Kirschmann DA, Castermans K, Egbrink MGAO, Tran MGB, Sciot R, Hauben E, Hogendoorn PCW, Delattre O, Maxwell PH, Hendrix MJC, Griffioen AW (2005) Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res 65:11520–11528. Scholar
  103. 103.
    Thijssen VL, Paulis YW, Nowak-Sliwinska P, Deumelandt KL, Hosaka K, Soetekouw PM, Cimpean AM, Raica M, Pauwels P, van den Oord JJ, Tjan-Heijnen VC, Hendrix MJ, Heldin C-H, Cao Y, Griffioen AW (2018) Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth. J Pathol. Scholar
  104. 104.
    Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17:1371–1380. Scholar
  105. 105.
    Hangai-Hoger N, Cabrales P, Briceño JC, Tsai AG, Intaglietta M (2004) Microlymphatic and tissue oxygen tension in the rat mesentery. Am J Physiol Heart Circ Physiol 286:H878–H883. Scholar
  106. 106.
    Hangai-Hoger N, Tsai AG, Cabrales P, Intaglietta M (2007) Terminal lymphatics: the potential “lethal corner” in the distribution of tissue pO2. Lymphat Res Biol 5:159–168. Scholar
  107. 107.
    Karaman S, Leppänen V-M, Alitalo K (2018) Vascular endothelial growth factor signaling in development and disease. Dev Camb Engl 145. Scholar
  108. 108.
    Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801CrossRefGoogle Scholar
  109. 109.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394. Scholar
  110. 110.
    Jussila L, Valtola R, Partanen TA, Salven P, Heikkilä P, Matikainen MT, Renkonen R, Kaipainen A, Detmar M, Tschachler E, Alitalo R, Alitalo K (1998) Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res 58:1599–1604PubMedGoogle Scholar
  111. 111.
    Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92:3566–3570CrossRefGoogle Scholar
  112. 112.
    Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778CrossRefGoogle Scholar
  113. 113.
    Zhou B, Si W, Su Z, Deng W, Tu X, Wang Q (2013) Transcriptional activation of the Prox1 gene by HIF-1α and HIF-2α in response to hypoxia. FEBS Lett 587:724–731. Scholar
  114. 114.
    Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 95:548–553CrossRefGoogle Scholar
  115. 115.
    He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K (2005) Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65:4739–4746. Scholar
  116. 116.
    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 15:290–298CrossRefGoogle Scholar
  117. 117.
    Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Dev Camb Engl 122:3829–3837Google Scholar
  118. 118.
    Whitehurst B, Flister MJ, Bagaitkar J, Volk L, Bivens CM, Pickett B, Castro-Rivera E, Brekken RA, Gerard RD, Ran S (2007) Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int J Cancer 121:2181–2191. Scholar
  119. 119.
    Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG (2014) Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14:159–172. Scholar
  120. 120.
    Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen Y-L, Pytowski B, Fukumura D, Padera TP, Jain RK (2006) Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66:8065–8075. Scholar
  121. 121.
    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–4327PubMedGoogle Scholar
  122. 122.
    Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886. Scholar
  123. 123.
    Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TWT, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA (2012) VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 21:181–195. Scholar
  124. 124.
    Currie MJ, Hanrahan V, Gunningham SP, Morrin HR, Frampton C, Han C, Robinson BA, Fox SB (2004) Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1alpha) and the HIF-1alpha target gene DEC1, but not lymph node metastasis in primary human breast carcinomas. J Clin Pathol 57:829–834. Scholar
  125. 125.
    Irigoyen M, Ansó E, Martínez E, Garayoa M, Martínez-Irujo JJ, Rouzaut A (2007) Hypoxia alters the adhesive properties of lymphatic endothelial cells. A transcriptional and functional study. Biochim Biophys Acta 1773:880–890. Scholar
  126. 126.
    Guo Y-C, Zhang M, Wang F-X, Pei G-C, Sun F, Zhang Y, He X, Wang Y, Song J, Zhu F-M, Pandupuspitasari NS, Liu J, Huang K, Yang P, Xiong F, Zhang S, Yu Q, Yao Y, Wang C-Y (2017) Macrophages regulate unilateral ureteral obstruction-induced renal Lymphangiogenesis through C-C motif chemokine receptor 2-dependent phosphatidylinositol 3-kinase-AKT-mechanistic target of rapamycin signaling and hypoxia-inducible factor-1α/vascular endothelial growth factor-C expression. Am J Pathol 187:1736–1749. Scholar
  127. 127.
    Morfoisse F, Kuchnio A, Frainay C, Gomez-Brouchet A, Delisle M-B, Marzi S, Helfer A-C, Hantelys F, Pujol F, Guillermet-Guibert J, Bousquet C, Dewerchin M, Pyronnet S, Prats A-C, Carmeliet P, Garmy-Susini B (2014) Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1α-independent translation-mediated mechanism. Cell Rep 6:155–167. Scholar
  128. 128.
    Farnsworth RH, Achen MG, Stacker SA (2018) The evolving role of lymphatics in cancer metastasis. Curr Opin Immunol 53:64–73. Scholar
  129. 129.
    Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956. Scholar
  130. 130.
    Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949CrossRefGoogle Scholar
  131. 131.
    Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660. Scholar
  132. 132.
    Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K (2007) Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67:593–599. Scholar
  133. 133.
    Petrova TV, Bono P, Holnthoner W, Chesnes J, Pytowski B, Sihto H, Laakkonen P, Heikkilä P, Joensuu H, Alitalo K (2008) VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell 13:554–556. Scholar
  134. 134.
    Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425CrossRefGoogle Scholar
  135. 135.
    Oh SJ, Jeltsch MM, Birkenhäger R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96–109. Scholar
  136. 136.
    He Y, Karpanen T, Alitalo K (2004) Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta 1654:3–12. Scholar
  137. 137.
    Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109:1010–1017. Scholar
  138. 138.
    Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Ylä-Herttuala S, Jäättelä M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790PubMedGoogle Scholar
  139. 139.
    Kopfstein L, Veikkola T, Djonov VG, Baeriswyl V, Schomber T, Strittmatter K, Stacker SA, Achen MG, Alitalo K, Christofori G (2007) Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol 170:1348–1361. Scholar
  140. 140.
    Brakenhielm E, Burton JB, Johnson M, Chavarria N, Morizono K, Chen I, Alitalo K, Wu L (2007) Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer 121:2153–2161. Scholar
  141. 141.
    Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960. Scholar
  142. 142.
    Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682. Scholar
  143. 143.
    Mattila MM-T, Ruohola JK, Karpanen T, Jackson DG, Alitalo K, Härkönen PL (2002) VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int J Cancer 98:946–951CrossRefGoogle Scholar
  144. 144.
    Podgrabinska S, Skobe M (2014) Role of lymphatic vasculature in regional and distant metastases. Microvasc Res 95:46–52. Scholar
  145. 145.
    Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198. Scholar
  146. 146.
    Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191. Scholar
  147. 147.
    Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786. Scholar
  148. 148.
    Hirakawa S (2009) From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci 100:983–989. Scholar
  149. 149.
    Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099. Scholar
  150. 150.
    Björndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005a) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 102:15593–15598. Scholar
  151. 151.
    Björndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y (2005b) Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 65:9261–9268. Scholar
  152. 152.
    Kadowaki I, Ichinohasama R, Harigae H, Ishizawa K, Okitsu Y, Kameoka J, Sasaki T (2005) Accelerated lymphangiogenesis in malignant lymphoma: possible role of VEGF-A and VEGF-C. Br J Haematol 130:869–877. Scholar
  153. 153.
    Zeng Y, Opeskin K, Goad J, Williams ED (2006) Tumor-induced activation of lymphatic endothelial cells via vascular endothelial growth factor receptor-2 is critical for prostate cancer lymphatic metastasis. Cancer Res 66:9566–9575. Scholar
  154. 154.
    Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6:333–345. Scholar
  155. 155.
    Kodama M, Kitadai Y, Sumida T, Ohnishi M, Ohara E, Tanaka M, Shinagawa K, Tanaka S, Yasui W, Chayama K (2010) Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor β is associated with lymphatic metastasis in human gastric carcinoma. Cancer Sci 101:1984–1989. Scholar
  156. 156.
    Kelly BD, Hackett SF, Hirota K, Oshima Y, Cai Z, Berg-Dixon S, Rowan A, Yan Z, Campochiaro PA, Semenza GL (2003) Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ Res 93:1074–1081. Scholar
  157. 157.
    Ullerås E, Wilcock A, Miller SJ, Franklin GC (2001) The sequential activation and repression of the human PDGF-B gene during chronic hypoxia reveals antagonistic roles for the depletion of oxygen and glucose. Growth Factors Chur Switz 19:233–245CrossRefGoogle Scholar
  158. 158.
    Spinella F, Garrafa E, Di Castro V, Rosanò L, Nicotra MR, Caruso A, Natali PG, Bagnato A (2009) Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. Cancer Res 69:2669–2676. Scholar
  159. 159.
    Grimshaw MJ (2007) Endothelins and hypoxia-inducible factor in cancer. Endocr Relat Cancer 14:233–244. Scholar
  160. 160.
    Camenisch G, Stroka DM, Gassmann M, Wenger RH (2001) Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch 443:240–249. Scholar
  161. 161.
    Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA (2007) Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11:526–538. Scholar
  162. 162.
    Wilson JL, Burchell J, Grimshaw MJ (2006) Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor a and hypoxia-inducible factor-1. Cancer Res 66:11802–11807. Scholar
  163. 163.
    Zhuo W, Jia L, Song N, Lu X-A, Ding Y, Wang X, Song X, Fu Y, Luo Y (2012) The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis. Clin Cancer Res 18:5387–5398. Scholar
  164. 164.
    Tudisco L, Orlandi A, Tarallo V, De Falco S (2017) Hypoxia activates placental growth factor expression in lymphatic endothelial cells. Oncotarget 8:32873–32883. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Biological Sciences Platform, Sunnybrook Research InstituteUniversity of TorontoTorontoCanada

Personalised recommendations