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Hypoxia-Dependent Angiogenesis and Lymphangiogenesis in Cancer

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Hypoxia and Cancer Metastasis

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1136))

Abstract

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.

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References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. https://doi.org/10.1056/NEJM197111182852108

    Article  CAS  PubMed  Google Scholar 

  3. Rey S, Schito L, Koritzinsky M, Wouters BG (2017a) Molecular targeting of hypoxia in radiotherapy. Adv Drug Deliv Rev 109:45–62. https://doi.org/10.1016/j.addr.2016.10.002

    Article  CAS  PubMed  Google Scholar 

  4. Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Höckel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276. https://doi.org/10.1093/jnci/93.4.266

    Article  PubMed  Google Scholar 

  6. Vaupel P, Mayer A (2017) Tumor oxygenation status: facts and fallacies. Adv Exp Med Biol 977:91–99. https://doi.org/10.1007/978-3-319-55231-6_13

    Article  CAS  PubMed  Google Scholar 

  7. Schito L, Rey S (2018) Cell-autonomous metabolic reprogramming in hypoxia. Trends Cell Biol 28:128–142. https://doi.org/10.1016/j.tcb.2017.10.006

    Article  CAS  PubMed  Google Scholar 

  8. Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354. https://doi.org/10.1016/S0076-6879(04)81023-1

    Article  CAS  PubMed  Google Scholar 

  9. Schito L, Rey S, Konopleva M (2017) Integration of hypoxic HIF-α signaling in blood cancers. Oncogene 36:5331–5340. https://doi.org/10.1038/onc.2017.119

    Article  CAS  PubMed  Google Scholar 

  10. Vaupel P (2009) Prognostic potential of the pre-therapeutic tumor oxygenation status. Adv Exp Med Biol 645:241–246. https://doi.org/10.1007/978-0-387-85998-9_36

    Article  PubMed  Google Scholar 

  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 92:5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 94:4273–4278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 63:51–60

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.140087397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82

    Article  CAS  PubMed  Google Scholar 

  16. Shen C, Kaelin WG (2013) The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol 23:18–25. https://doi.org/10.1016/j.semcancer.2012.06.001

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/molbev/msr012

    Article  CAS  PubMed  Google Scholar 

  18. Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340. https://doi.org/10.1126/science.1066373

    Article  CAS  PubMed  Google Scholar 

  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 107:43–54

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1059817

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1059796

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/emboj/20.18.5197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1074/jbc.M002740200

    Article  CAS  PubMed  Google Scholar 

  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 95:7987–7992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.190332597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/20459

    Article  CAS  PubMed  Google Scholar 

  27. Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86:236–242. https://doi.org/10.1093/cvr/cvq045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schito L, Rey S (2017) Hypoxic pathobiology of breast cancer metastasis. Biochim Biophys Acta 1868:239–245. https://doi.org/10.1016/j.bbcan.2017.05.004

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1002/cncr.11246

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2559.2005.02045.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0146823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 25:3003–3009

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1214019109

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s10549-006-9190-3

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/jhbp.6

    Article  Google Scholar 

  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 28:1659–1666

    PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.yexmp.2004.11.002

    Article  CAS  PubMed  Google Scholar 

  38. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–30. https://doi.org/10.1038/nm0195-27

    Article  CAS  PubMed  Google Scholar 

  39. Schito L (2018) Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment. Am J Physiol Regul Integr Comp Physiol. https://doi.org/10.1152/ajpregu.00209.2018

    Article  CAS  PubMed  Google Scholar 

  40. Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378–390. https://doi.org/10.1038/nrclinonc.2012.64

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.trecan.2017.05.002

    Article  CAS  PubMed  Google Scholar 

  42. Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–770. https://doi.org/10.1016/j.trecan.2016.10.016

    Article  PubMed  Google Scholar 

  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 161:851–858

    Article  CAS  PubMed  Google Scholar 

  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 246:1309–1312

    Article  CAS  PubMed  Google Scholar 

  45. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    Article  CAS  PubMed  Google Scholar 

  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 255:989–991

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1172/JCI115568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 187:1579–1586

    Article  CAS  PubMed  Google Scholar 

  49. Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127. https://doi.org/10.1111/joim.12019

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0012265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1074/jbc.M211298200

    Article  CAS  PubMed  Google Scholar 

  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 16:4604–4613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 272:23659–23667

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/onc.2012.136

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrc2524

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2353/ajpath.2006.051041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.0908026106

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1209310110

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrc2524

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/jcp.21558

    Article  CAS  PubMed  Google Scholar 

  61. Thomas M, Augustin HG (2009) The role of the angiopoietins in vascular morphogenesis. Angiogenesis 12:125–137. https://doi.org/10.1007/s10456-009-9147-3

    Article  CAS  PubMed  Google Scholar 

  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 284:1994–1998

    Article  CAS  PubMed  Google Scholar 

  63. Schmittnaegel M, De Palma M (2017) Reprogramming tumor blood vessels for enhancing immunotherapy. Trends Cancer 3:809–812. https://doi.org/10.1016/j.trecan.2017.10.002

    Article  PubMed  Google Scholar 

  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 63:3403–3412

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1096/fj.02-1111fje

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nm1075

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature01874

    Article  CAS  PubMed  Google Scholar 

  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 65:465–472

    CAS  PubMed  Google Scholar 

  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 119:629–641

    Article  CAS  PubMed  Google Scholar 

  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 90:1937–1941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 61:5911–5918

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/bbrc.1998.9078

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/71517

    Article  PubMed  Google Scholar 

  74. Sargiannidou I, Zhou J, Tuszynski GP (2001) The role of thrombospondin-1 in tumor progression. Exp Biol Med (Maywood) 226:726–733

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/s41388-018-0256-6

    Article  CAS  PubMed  Google Scholar 

  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 3:347–361

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0002-9440(10)63905-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-08-2007

    Article  CAS  PubMed  Google Scholar 

  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–L219

    CAS  Google Scholar 

  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. https://doi.org/10.1172/JCI20806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1161/01.ATV.20.3.659

    Article  CAS  PubMed  Google Scholar 

  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 80:845–852

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nm1730

    Article  CAS  PubMed  Google Scholar 

  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 275:964–967

    Article  CAS  PubMed  Google Scholar 

  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 107:1164–1169

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.0911921106

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.ccr.2008.01.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.0812801106

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/cam4.105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1093/jnci/djv155

  91. Naresh KN, Nerurkar AY, Borges AM (2001) Angiogenesis is redundant for tumour growth in lymph node metastases. Histopathology 38:466–470

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/path.4845

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nm.4197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1093/jnci/djw030

    Article  PubMed Central  Google Scholar 

  95. Gould CM, Courtneidge SA (2014) Regulation of invadopodia by the tumor microenvironment. Cell Adhes Migr 8:226–235

    Article  Google Scholar 

  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. https://doi.org/10.1016/j.ajpath.2012.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.CCR-11-3237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.biopha.2016.03.010

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.bbrc.2011.04.089

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.canlet.2006.08.016

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/labinvest.2009.20

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-05-2468

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/path.5152

    Article  CAS  PubMed  Google Scholar 

  104. Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17:1371–1380. https://doi.org/10.1038/nm.2545

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1152/ajpheart.00913.2003

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1089/lrb.2007.5303

    Article  PubMed  Google Scholar 

  107. Karaman S, Leppänen V-M, Alitalo K (2018) Vascular endothelial growth factor signaling in development and disease. Dev Camb Engl 145. https://doi.org/10.1242/dev.151019

    Article  PubMed  Google Scholar 

  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 144:789–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S0002-9440(10)65285-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 58:1599–1604

    CAS  PubMed  Google Scholar 

  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 92:3566–3570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.febslet.2013.01.053

    Article  CAS  PubMed  Google Scholar 

  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 95:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-04-4576

    Article  CAS  PubMed  Google Scholar 

  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 15:290–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 122:3829–3837

    CAS  Google Scholar 

  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. https://doi.org/10.1002/ijc.22937

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrc3677

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-06-1392

    Article  CAS  PubMed  Google Scholar 

  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 60:4324–4327

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1071420

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ccr.2011.12.026

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1136/jcp.2003.015644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.bbamcr.2007.03.001

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ajpath.2017.04.007

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.celrep.2013.12.011

    Article  CAS  PubMed  Google Scholar 

  128. Farnsworth RH, Achen MG, Stacker SA (2018) The evolving role of lymphatics in cancer metastasis. Curr Opin Immunol 53:64–73. https://doi.org/10.1016/j.coi.2018.04.008

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0002-9440(10)64255-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 282:946–949

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature07083

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-06-3567

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ccr.2008.04.022

    Article  CAS  PubMed  Google Scholar 

  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 276:1423–1425

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/dbio.1997.8639

    Article  CAS  PubMed  Google Scholar 

  136. He Y, Karpanen T, Alitalo K (2004) Role of lymphangiogenic factors in tumor metastasis. Biochim Biophys Acta 1654:3–12. https://doi.org/10.1016/j.bbcan.2003.07.003

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1182/blood-2006-05-021758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 61:1786–1790

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2353/ajpath.2007.060835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/ijc.22900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S0002-9440(10)64328-3

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1093/emboj/20.4.672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 98:946–951

    Article  CAS  PubMed  Google Scholar 

  144. Podgrabinska S, Skobe M (2014) Role of lymphatic vasculature in regional and distant metastases. Microvasc Res 95:46–52. https://doi.org/10.1016/j.mvr.2014.07.004

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/84643

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/84635

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2353/ajpath.2007.060761

    Article  PubMed  PubMed Central  Google Scholar 

  148. Hirakawa S (2009) From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci 100:983–989. https://doi.org/10.1111/j.1349-7006.2009.01142.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1084/jem.20041896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.0507865102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-04-2345

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2141.2005.05695.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-06-1488

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ccr.2004.08.034

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1349-7006.2010.01639.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1161/01.RES.0000102937.50486.1B

    Article  CAS  PubMed  Google Scholar 

  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 19:233–245

    Article  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-08-1879

    Article  CAS  PubMed  Google Scholar 

  159. Grimshaw MJ (2007) Endothelins and hypoxia-inducible factor in cancer. Endocr Relat Cancer 14:233–244. https://doi.org/10.1677/ERC-07-0057

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s004240100679

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ccr.2007.04.020

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-06-1222

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1078-0432.CCR-12-0708

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.18632/oncotarget.15861

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada

    Luana Schito

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  1. Luana Schito
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Correspondence to Luana Schito .

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  1. Breast and Ovarian Cancer Program, Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniele M. Gilkes

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Schito, L. (2019). Hypoxia-Dependent Angiogenesis and Lymphangiogenesis in Cancer. In: Gilkes, D. (eds) Hypoxia and Cancer Metastasis. Advances in Experimental Medicine and Biology, vol 1136. Springer, Cham. https://doi.org/10.1007/978-3-030-12734-3_5

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