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Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells

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Abstract

An ancestral function of vessels is to conduct blood flow and supply oxygen (O2). In hypoxia, cells secrete angiogenic factors to initiate vessel sprouting. Angiogenic factors are balanced off by inhibitors, ensuring that vessels form optimally and supply sufficient oxygen (O2). By contrast, in tumors, excessive production of angiogenic factors induces vessels and their endothelial cell (EC) layer to become highly abnormal, thereby impairing tumor perfusion and oxygenation. In such pathological conditions, angiogenic factors act as “abnormalization factors” and promote the vessel “abnormalization switch.” Recent genetic data indicate that ECs sense an imbalance in oxygen levels, by using the oxygen-sensing prolyl hydroxylase PHD2. In conditions of O2 shortage, a decrease in PHD2 activity in ECs initiates a feedback that restores their shape, not their numbers. This induces ECs to align in a streamlined “phalanx” of tightly apposed, regularly ordered cobblestone ECs, which improves perfusion and oxygenation. As a result, EC normalization in PHD2 haplodeficient tumor vessels improves oxygenation and renders tumor cells less invasive and metastatic. This review discusses the role of PHD2 in the regulation of vessel (ab)normalization and the therapeutic potential of PHD2 inhibition for tumor invasiveness and metastasis.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Gasparini F, Longo F, Manni L, Burighel P, Zaniolo G (2007) Tubular sprouting as a mode of vascular formation in a colonial ascidian (Tunicata). Dev Dyn 236:719–731

    Article  PubMed  CAS  Google Scholar 

  3. 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 161:1163–1177

    Article  PubMed  CAS  Google Scholar 

  4. Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian Y-M, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, AragonÈs JN, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839–851

    Article  PubMed  CAS  Google Scholar 

  5. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  6. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  7. Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St. Croix B (2007) Genes that Distinguish Physiological and Pathological Angiogenesis. Cancer cell 11:539–554

    Article  PubMed  CAS  Google Scholar 

  8. Grange C, Bussolati B, Bruno S, Fonsato V, Sapino A, Camussi G (2006) Isolation and characterization of human breast tumor-derived endothelial cells. Oncol Rep 15:381–386

    PubMed  CAS  Google Scholar 

  9. Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE (2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci U S A 105:11305–11310

    Article  PubMed  CAS  Google Scholar 

  10. Helmlinger G, Yuan F, Dellian M, Jain RK (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3:177–182

    Article  PubMed  CAS  Google Scholar 

  11. Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis. Cancer Cell 15:232–239

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  PubMed  CAS  Google Scholar 

  14. 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 6:553–563

    PubMed  CAS  Google Scholar 

  15. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hagedorn NL, McCarville MB, Stewart CF, Davidoff AM (2007) Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 13:3942–3950

    Article  PubMed  CAS  Google Scholar 

  16. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, de Bruijn EA, van Oosterom AT (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979–1986

    Article  PubMed  CAS  Google Scholar 

  17. Ward JP (2008) Oxygen sensors in context. Biochim Biophys Acta 1777:1–14

    Article  PubMed  CAS  Google Scholar 

  18. Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402

    Article  PubMed  CAS  Google Scholar 

  19. Fong GH, Takeda K (2008) Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ 15:635–641

    Article  PubMed  CAS  Google Scholar 

  20. Fraisl P, Aragones J, Carmeliet P (2009) Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 8:139–152

    Article  PubMed  CAS  Google Scholar 

  21. Fong GH (2009) Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med. doi: 10.1007/s00109-009-0458-z

  22. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686

    Article  PubMed  CAS  Google Scholar 

  23. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  PubMed  CAS  Google Scholar 

  24. Gordan JD, Simon MC (2007) Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 17:71–77

    Article  PubMed  CAS  Google Scholar 

  25. Semenza GL (2009) Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Seminars in Cancer Biology 19:12–16

    Article  PubMed  CAS  Google Scholar 

  26. Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC (2007) Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A 104:2301–2306

    Article  PubMed  CAS  Google Scholar 

  27. Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, Labosky PA, Simon MC, Keith B (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20:557–570

    Article  PubMed  CAS  Google Scholar 

  28. Gordan JD, Thompson CB, Simon MC (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12:108–113

    Article  PubMed  CAS  Google Scholar 

  29. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684

    Article  PubMed  CAS  Google Scholar 

  30. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6:485–495

    Article  PubMed  CAS  Google Scholar 

  31. Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL (2003) Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63:6130–6134

    PubMed  CAS  Google Scholar 

  32. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

    Article  PubMed  CAS  Google Scholar 

  33. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162

    Article  PubMed  CAS  Google Scholar 

  34. Vincent KA, Shyu KG, Luo Y, Magner M, Tio RA, Jiang C, Goldberg MA, Akita GY, Gregory RJ, Isner JM (2000) Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation 102:2255–2261

    PubMed  CAS  Google Scholar 

  35. Duan LJ, Zhang-Benoit Y, Fong GH (2005) Endothelium-intrinsic requirement for Hif-2alpha during vascular development. Circulation 111:2227–2232

    Article  PubMed  CAS  Google Scholar 

  36. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P (2002) Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702–710

    PubMed  CAS  Google Scholar 

  37. Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA (2003) Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet 35:331–340

    Article  PubMed  CAS  Google Scholar 

  38. 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  PubMed  CAS  Google Scholar 

  39. Yamashita T, Ohneda K, Nagano M, Miyoshi C, Kaneko N, Miwa Y, Yamamoto M, Ohneda O, Fujii-Kuriyama Y (2008) HIF-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. J Biol Chem: 283(27):18926–18936

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Nasarre P, Thomas M, Kruse K, Helfrich I, Wolter V, Deppermann C, Schadendorf D, Thurston G, Fiedler U, Augustin HG (2009) Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res 69:1324–1333

    Article  PubMed  CAS  Google Scholar 

  42. Helfrich I, Edler L, Sucker A, Thomas M, Christian S, Schadendorf D, Augustin HG (2009) Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 15:1384–1392

    Article  PubMed  CAS  Google Scholar 

  43. Nakamura Y, Patrushev N, Inomata H, Mehta D, Urao N, Kim HW, Razvi M, Kini V, Mahadev K, Goldstein BJ, McKinney R, Fukai T, Ushio-Fukai M (2008) Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. Circ Res 102:1182–1191

    Article  PubMed  CAS  Google Scholar 

  44. Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oosthuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    Article  PubMed  CAS  Google Scholar 

  45. Kearney JB, Kappas NC, Ellerstrom C, DiPaola FW, Bautch VL (2004) The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 103:4527–4535

    Article  PubMed  CAS  Google Scholar 

  46. Le Bras A, Lionneton F, Mattot V, Lelievre E, Caetano B, Spruyt N, Soncin F (2007) HIF-2alpha specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites. Oncogene 26:7480–7489

    Article  PubMed  Google Scholar 

  47. van Hinsbergh VWM, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78:203–212

    Article  PubMed  Google Scholar 

  48. Jones CA, London NR, Chen H, Park KW, Sauvaget D, Stockton RA, Wythe JD, Suh W, Larrieu-Lahargue F, Mukouyama YS, Lindblom P, Seth P, Frias A, Nishiya N, Ginsberg MH, Gerhardt H, Zhang K, Li DY (2008) Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med 14:448–453

    Article  PubMed  CAS  Google Scholar 

  49. Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813

    Article  PubMed  CAS  Google Scholar 

  50. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R (2008) Vascular normalization in Rgs5- deficient tumours promotes immune destruction. Nature 453:410–414

    Article  PubMed  CAS  Google Scholar 

  51. 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

    Article  PubMed  CAS  Google Scholar 

  52. Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH (2006) Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol 26:8336–8346

    Article  PubMed  CAS  Google Scholar 

  53. Takeda K, Cowan A, Fong GH (2007) Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation 116:774–781

    Article  PubMed  CAS  Google Scholar 

  54. Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan L-J, Takeda H, Lee FS, Fong G-H (2008) Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111:3229–3235

    Article  PubMed  CAS  Google Scholar 

  55. Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG Jr (2008) Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111:3236–3244

    Article  PubMed  CAS  Google Scholar 

  56. Takeda K, Fong GH (2007) Prolyl hydroxylase domain 2 protein suppresses hypoxia-induced endothelial cell proliferation. Hypertension 49:178–184

    Article  PubMed  CAS  Google Scholar 

  57. Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B (2008) Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci U S A 105:19898–19903

    Article  PubMed  CAS  Google Scholar 

  58. Chan DA, Sutphin PD, Denko NC, Giaccia AJ (2002) Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. J Biol Chem 277:40112–40117

    Article  PubMed  CAS  Google Scholar 

  59. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153

    Article  PubMed  CAS  Google Scholar 

  60. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85

    Article  PubMed  CAS  Google Scholar 

  61. Aprelikova O, Pandolfi S, Tackett S, Ferreira M, Salnikow K, Ward Y, Risinger JI, Barrett JC, Niederhuber J (2009) Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response. Cancer Res 69:616–624

    Article  PubMed  CAS  Google Scholar 

  62. Lee KA, Lynd JD, O’Reilly S, Kiupel M, McCormick JJ, LaPres JJ (2008) The biphasic role of the hypoxia-inducible factor prolyl-4-hydroxylase, PHD2, in modulating tumor-forming potential. Mol Cancer Res 6:829–842

    Article  CAS  Google Scholar 

  63. Ozer A, Wu LC, Bruick RK (2005) The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A 102:7481–7486

    Article  PubMed  CAS  Google Scholar 

  64. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032–1037

    Article  PubMed  CAS  Google Scholar 

  65. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, Singh M, Chien M, Tan C, Hongo JA, de Sauvage F, Plowman G, Yan M (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083–1087

    Article  PubMed  CAS  Google Scholar 

  66. Scehnet JS, Jiang W, Ram Kumar S, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, Gill PS (2007) Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109:4753–4760

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  68. Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23:14–25

    Article  PubMed  Google Scholar 

  69. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776–780

    Article  PubMed  Google Scholar 

  70. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478

    Article  PubMed  CAS  Google Scholar 

  71. Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos AK, Breier G, Gessler M (2007) Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 313:1–9

    Article  PubMed  CAS  Google Scholar 

  72. Patel NS, Li J-L, Generali D, Poulsom R, Cranston DW, Harris AL (2005) Up- regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65:8690–8697

    Article  PubMed  CAS  Google Scholar 

  73. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628

    Article  PubMed  CAS  Google Scholar 

  74. Coleman ML, McDonough MA, Hewitson KS, Coles C, Mecinovic J, Edelmann M, Cook KM, Cockman ME, Lancaster DE, Kessler BM, Oldham NJ, Ratcliffe PJ, Schofield CJ (2007) Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J Biol Chem 282:24027–24038

    Article  PubMed  CAS  Google Scholar 

  75. Zheng X, Linke S, Dias JM, Zheng X, Gradin K, Wallis TP, Hamilton BR, Gustafsson M, Ruas JL, Wilkins S, Bilton RL, Brismar K, Whitelaw ML, Pereira T, Gorman JJ, Ericson J, Peet DJ, Lendahl U, Poellinger L (2008) Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc Natl Acad Sci U S A 105:3368–3373

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

P.C. is supported by long-term structural funding (Methusalem funding by the Flemish Government), Interuniversity attraction pole (Grant P60/30, funded by Belgian Government, BELSPO), FWO G.0692.09 (Flemish Government), research grant by the Belgian “Foundation against Cancer,” GAO 2006/11-K.U. Leuven. R.L.d.O. is recipient of a FWO PhD-fellowship. K.A. is recipient of an IWT PhD-fellowship.

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  1. Vesalius Research Center (VRC), K.U. Leuven, Leuven, 3000, Belgium

    Katrien De Bock, Frederik De Smet, Rodrigo Leite De Oliveira, Kristof Anthonis & Peter Carmeliet

  2. Vesalius Research Center, Flanders Institute for Biotechnology (VIB), Leuven, 3000, Belgium

    Katrien De Bock, Frederik De Smet, Rodrigo Leite De Oliveira, Kristof Anthonis & Peter Carmeliet

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De Bock, K., De Smet, F., Leite De Oliveira, R. et al. Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells. J Mol Med 87, 561–569 (2009). https://doi.org/10.1007/s00109-009-0482-z

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