Regulation of angiogenesis by hypoxia: role of the HIF system


The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.

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Figure 1: Dual regulation of HIF-α subunits by prolyl and asparaginyl hydroxylation.
Figure 2: Pathways linking angiogenesis to oxygen availability through the regulation of HIF.
Figure 3: Multiple interfaces of hypoxia pathways with the angiogenic growth factor VEGF.
Figure 4
Figure 5: Schematic illustrating the coselection of pathways in cancer.


  1. 1

    Krogh, A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J. Physiol. (London) 52, 409–415 (1919).

  2. 2

    Hudlicka, O., Dodd, L., Renkin, E.M. & Gray, S.D. Early changes in fiber profile and capillary density in long-term stimulated muscles. Am. J. Physiol. 243, H528–H535 (1982).

  3. 3

    Jozsa, L., Balint, J., Reffy, A., Jarvinen, M. & Kvist, M. Capillary density of tenotomized skeletal muscles. II. Observations on human muscles after spontaneous rupture of tendon. Eur. J. Appl. Physiol. Occup. Physiol. 44, 183–188 (1980).

  4. 4

    Ashton, N., Ward, B. & Serpell, G. Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br. J. Ophthalmol. 38, 397–432 (1954).

  5. 5

    Thomlinson, R.H. & Gray, L.H. The histological structure of some human lung cancers and the possible implications for radio-therapy. Br. J. Cancer 9, 539–549 (1955).

  6. 6

    Folkman, J., Merler, E., Abernathy, C. & Williams, G. Isolation of a tumor factor responsible for angiogenesis. J. Exp. Med. 133, 275–288 (1971).

  7. 7

    Knighton, D.R., Silver, I.A. & Hunt, T.K. Regulation of wound-healing angiogenesis - effect of oxygen gradients and inspired oxygen concentration. Surgery 90, 262–270 (1981).

  8. 8

    Knighton, D.R. et al. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 221, 1283–1285 (1983).

  9. 9

    Kourembanas, S., Hannan, R.L. & Faller, D.V. Oxygen tension regulates the expression of the platelet-derived growth factor-β chain gene in human endothelial cells. J. Clin. Invest. 86, 670–674 (1990).

  10. 10

    Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

  11. 11

    Plate, K.H., Breier, G., Weich, H.A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).

  12. 12

    Adair, T.H., Gay, W.J. & Montani, J.-P. Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am. J. Physiol. 259, R393–R404 (1990).

  13. 13

    Jelkmann, W. Erythropoietin: structure, control of production, and function. Physiol. Rev. 72, 449–489 (1992).

  14. 14

    Necas, E. & Thorling, E.B. Unresponsiveness of erythropoietin-producing cells to cyanide. Am. J. Physiol. 222, 1187–1190 (1972).

  15. 15

    Goldwasser, E., Jacobson, L.O., Fried, W. & Plazk, L.F. Studies on erythropoiesis V: the effect of cobalt on the production of erythropoietin. Blood 13, 55–60 (1958).

  16. 16

    Goldberg, M.A. & Schneider, T.J. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269, 4355–4359 (1994).

  17. 17

    Gleadle, J.M., Ebert, B.L., Firth, J.D. & Ratcliffe, P.J. Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am. J. Physiol. 268, C1362–C1368 (1995).

  18. 18

    Liu, Y., Cox, S.R., Morita, T. & Kourembanas, S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Circ. Res. 77, 638–643 (1995).

  19. 19

    Forsythe, J.A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604–4613 (1996).

  20. 20

    Semenza, G.L. & Wang, G.L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12, 5447–5454 (1992).

  21. 21

    Wang, G.L., Jiang, B.-H., Rue, E.A. & Semenza, G.L. 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 (1995).

  22. 22

    Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc. Natl. Acad. Sci. USA 90, 2423–2427 (1993).

  23. 23

    Semenza, G.L. HIF-1 and human disease: one highly involved factor. Genes Dev. 14, 1983–1991 (2000).

  24. 24

    Wenger, R.H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 16, 1151–1162 (2002).

  25. 25

    Tian, H., McKnight, S.L. & Russell, D.W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

  26. 26

    Wiesener, M.S. et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood 92, 2260–2268 (1998).

  27. 27

    Makino, Y. et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550–554 (2001).

  28. 28

    Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

  29. 29

    Jaakkola, P. et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

  30. 30

    Yu, F., White, S.B., Zhao, Q. & Lee, F.S. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl. Acad. Sci. USA 98, 9630–9635 (2001).

  31. 31

    Epstein, A.C.R. et al. C. elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).

  32. 32

    Bruick, R.K. & McKnight, S.L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

  33. 33

    Hewitson, K.S. et al. Hypoxia inducible factor (HIF) asparagine hydroxylase is identical to Factor Inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 277, 26351–26355 (2002).

  34. 34

    Masson, N., Willam, C., Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).

  35. 35

    Lando, D., Peet, D.J., Whelan, D.A., Gorman, J.J. & Whitelaw, M.L. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295, 858–861 (2002).

  36. 36

    Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

  37. 37

    Mahon, P.C., Hirota, K. & Semenza, G.L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

  38. 38

    Schofield, C.J. & Zhang, Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr. Opin. Struct. Biol. 9, 722–731 (1999).

  39. 39

    Webster, K.A., Discher, D.J. & Bishopric, N.H. Regulation of fos and jun immediate-early genes by redox or metabolic stress in cardiac myocytes. Circ. Res. 74, 679–686 (1994).

  40. 40

    Koong, A.C., Chen, E.Y. & Giaccia, A.J. Hypoxia causes the activation of nuclear factor κB through the phosphorylation of IκBα on tyrosine residues. Cancer Res. 54, 1425–1430 (1994).

  41. 41

    Graeber, T.G. et al. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol. Cell. Biol. 14, 6264–6277 (1994).

  42. 42

    Alarcon, R., Koumenis, C., Geyer, R.K., Maki, C.G. & Giaccia, A.J. Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. Cancer Res. 59, 6046–6051 (1999).

  43. 43

    Kuznetsova, A.V. et al. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc. Natl. Acad. Sci. USA 100, 2706–2711 (2003).

  44. 44

    Conway, E.M., Collen, D. & Carmeliet, P. Molecular mechanisms of blood vessel growth. Cardiovasc. Res. 49, 507–521 (2001).

  45. 45

    Melillo, G. et al. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J. Exp. Med. 182, 1683–1693 (1995).

  46. 46

    Enholm, B. et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14, 2475–2483 (1997).

  47. 47

    Currie, M.J. et al. Expression of the angiopoietins and their receptor Tie2 in human renal clear cell carcinomas; regulation by the von Hippel-Lindau gene and hypoxia. J. Pathol. 198, 502–510 (2002).

  48. 48

    Tuder, R.M., Flook, B.E. & Voelkel, N.F. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. J. Clin. Invest. 95, 1798–1807 (1995).

  49. 49

    Gerber, H.-P., Condorelli, F., Park, J. & Ferrara, N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. J. Biol. Chem. 272, 23659–23667 (1997).

  50. 50

    Waltenberger, J., Mayr, U., Pentz, S. & Hombach, V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647–1654 (1996).

  51. 51

    Oh, H. et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J. Biol. Chem. 274, 15732–15739 (1999).

  52. 52

    Mandriota, S. et al. Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue ischaemia. Am. J. Pathol. 156, 1–13 (2000).

  53. 53

    Ben-Yosef, Y. et al. Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation. Circ. Res. 90, 784–791 (2002).

  54. 54

    Norman, J.T., Clark, I.M. & Garcia, P.L. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 58, 2351–2366 (2000).

  55. 55

    Takahashi, Y., Takahashi, S., Shiga, Y., Yoshimi, T. & Miura, T. Hypoxic induction of prolyl 4-hydroxylase α(I) in cultured cells. J. Biol. Chem. 275, 14139–14146 (2000).

  56. 56

    Kietzmann, T., Roth, U. & Jungermann, K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 94, 4177–4185 (1999).

  57. 57

    Graham, C.H., Fitzpatrick, T.E. & McCrae, K.R. Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood 91, 3300–3307 (1998).

  58. 58

    Phelan, M.W., Forman, L.W., Perrine, S.P. & Faller, D.V. Hypoxia increases thrombospondin-1 transcript and protein in cultured endothelial cells. J. Lab. Clin. Med. 132, 519–529 (1998).

  59. 59

    Kuwubara, K. et al. Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc. Natl. Acad. Sci. USA 92, 4606–4610 (1995).

  60. 60

    Negus, R.P., Turner, L., Burke, F. & Balkwill, F.R. Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors. J. Leukoc. Biol. 63, 758–765 (1998).

  61. 61

    Wykoff, C.C., Pugh, C.W., Maxwell, P.H., Harris, A.L. & Ratcliffe, P.J. Identification of novel hypoxia-dependent and independent target genes of the von Hippel-Lindau (VHL) tumor suppressor by mRNA differential expression profiling. Oncogene 19, 6297–6305 (2000).

  62. 62

    Sakuda, H., Nakashima, Y., Kuriyama, S. & Sueishi, K. Media conditioned by smooth muscle cells cultured in a variety of hypoxic environments stimulates in vitro angiogenesis. A relationship to transforming growth factor-β1. Am. J. Pathol. 141, 1507–1516 (1992).

  63. 63

    Phillips, P.G., Birnby, L.M. & Narendran, A. Hypoxia induces capillary network formation in cultured bovine pulmonary microvessel endothelial cells. Am. J. Physiol. 268, L789–L800 (1995).

  64. 64

    Krishnamachary, B. et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63, 1138–1143 (2003).

  65. 65

    Meininger, C.J., Schelling, M.E. & Granger, H.J. Adenosine and hypoxia stimulate proliferation and migration of endothelial cells. Am. J. Physiol. 255, H554–H562 (1988).

  66. 66

    Shreeniwas, R. et al. Macrovascular and microvascular endothelium during long-term hypoxia: alterations in cell growth, monolayer permeability, and cell surface coagulant properties. J. Cell. Physiol. 146, 8–17 (1991).

  67. 67

    Tucci, M. et al. Distinct effect of hypoxia on endothelial cell proliferation and cycling. Am. J. Physiol. 272, C1700–C1708 (1997).

  68. 68

    Iyer, N.V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1997).

  69. 69

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

  70. 70

    Ryan, H.E., Lo, J. & Johnson, R.S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

  71. 71

    Levy, N.S., Chung, S., Furneaux, H. & Levy, A.P. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J. Biol. Chem. 273, 6417–6423 (1998).

  72. 72

    Stein, I. et al. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol. Cell. Biol. 18, 3112–3119 (1998).

  73. 73

    Barleon, B. et al. Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells. Cancer Res. 57, 5421–5425 (1997).

  74. 74

    Kotch, L.E., Iyer, N.V., Laughner, E. & Semenza, G.L. Defective vascularization of HIF-1α-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev. Biol. 209, 254–267 (1999).

  75. 75

    Maltepe, E., Schmidt, J.V., Baunoch, D., Bradfield, C.A. & Simon, M.C. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386, 403–407 (1997).

  76. 76

    Peng, J., Zhang, L., Drysdale, L. & Fong, G.H. The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc. Natl. Acad. Sci. USA 97, 8386–8391 (2000).

  77. 77

    Tian, H., Hammer, R.E., Matsumoto, A.M., Russell, D.W. & McKnight, S.L. The hypoxia responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

  78. 78

    Compernolle, V. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat. Med. 8, 702–710 (2002).

  79. 79

    Lee, Y.M. et al. Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev. Dyn. 220, 175–186 (2001).

  80. 80

    Morita, M. et al. HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22, 1134–1146 (2003).

  81. 81

    Grimm, C. et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat. Med. 8, 718–724 (2002).

  82. 82

    Rosenberger, C. et al. Expression of hypoxia-inducible factor-1α and -2α in hypoxic and ischemic rat kidneys. J. Am. Soc. Nephrol. 13, 1721–1732 (2002).

  83. 83

    Lee, S.H. et al. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N. Engl. J. Med. 342, 626–633 (2000).

  84. 84

    Stroka, D.M. et al. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J. 15, 2445–2453 (2001).

  85. 85

    Wiesener, M.S. et al. Widespread, hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2002).

  86. 86

    Rajakumar, A., Doty, K., Daftary, A., Harger, G. & Conrad, K.P. Impaired oxygen-dependent reduction of HIF-1α and -2α proteins in pre-eclamptic placentae. Placenta 24, 199–208 (2003).

  87. 87

    Hollander, A.P., Corke, K.P., Freemont, A.J. & Lewis, C.E. Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum. 44, 1540–1544 (2001).

  88. 88

    Ozaki, H. et al. Hypoxia inducible factor-1α is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 40, 182–189 (1999).

  89. 89

    Elson, D.A., Ryan, H.E., Snow, J.W., Johnson, R. & Arbeit, J.M. Coordinate up-regulation of hypoxia inducible factor (HIF)-1α and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing. Cancer Res. 60, 6189–6195 (2000).

  90. 90

    Elson, D.A. et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α. Genes Dev. 15, 2520–2532 (2001).

  91. 91

    Vincent, K.A. et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation 102, 2255–2261 (2000).

  92. 92

    Shyu, K.G. et al. Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc. Res. 54, 576–583 (2002).

  93. 93

    Li, J. et al. PR39, a peptide regulator of angiogenesis. Nat. Med. 6, 49–55 (2000).

  94. 94

    Willam, C. et al. Peptide blockade of HIFα degradation modulates cellular metabolism and angiogenesis. Proc. Natl. Acad. Sci. USA 99, 10423–10428 (2002).

  95. 95

    Nwogu, N.I. et al. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104, 2216–2221 (2001).

  96. 96

    Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl. Acad. Sci. USA 99, 13459–13464 (2002).

  97. 97

    Aravind, L. & Koonin, E.V. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol. 2, 0007.1–0007.8 (2001).

  98. 98

    Elkins, J.M. et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α. J. Biol. Chem. 278, 1802–1806 (2003).

  99. 99

    Semenza, G.L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol. Biol. 35, 71–103 (2000).

  100. 100

    Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293–299 (2001).

  101. 101

    Richard, D.E., Berra, E., Gothie, E., Roux, D. & Pouysségur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 (1999).

  102. 102

    Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

  103. 103

    Chan, D.A., Sutphin, P.D., Denko, N.C. & Giaccia, A.J. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α. J. Biol. Chem. 277, 40112–40117 (2002).

  104. 104

    Knowles, H.J., Raval, R.R., Harris, A.L. & Ratcliffe, P.J. Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res. 63, 1764–1768 (2003).

  105. 105

    Le, N.T.V. & Richardson, D.R. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim. Biophys. Acta 1603, 31–46 (2002).

  106. 106

    Maxwell, P.H. et al. Hypoxia inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. USA 94, 8104–8109 (1997).

  107. 107

    Kung, A.L., Wang, S., Klco, J.M., Kaelin, W.G. & Livingston, D.M. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat. Med. 6, 1335–1340 (2000).

  108. 108

    Hopfl, G. et al. Rescue of hypoxia-inducible factor-1α-deficient tumor growth by wild-type cells is independent of vascular endothelial growth factor. Cancer Res. 62, 2962–2970 (2002).

  109. 109

    Ryan, H.E. et al. Hypoxia-inducible factor-lα is a positive factor in solid tumor growth. Cancer Res. 60, 4010–4015 (2000).

  110. 110

    Kaelin, W.G. Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer 2, 673–682 (2002).

  111. 111

    Maxwell, P.H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

  112. 112

    Iliopoulos, O., Kibel, A., Gray, S. & Kaelin, W.G., Jr. Tumour supression by the human von Hippel-Lindau gene product. Nat. Med. 1, 822–826 (1995).

  113. 113

    Kondo, K., Kico, J., Nakamura, E., Lechpammer, M. & Kaelin, W.G.J. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1, 237–246 (2002).

  114. 114

    Maranchie, J.K. et al. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1, 247–255 (2002).

  115. 115

    Vaux, E.C. et al. Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor. J. Biol. Chem. 276, 44323–44330 (2001).

  116. 116

    Mack, F.A. et al. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3, 75–88 (2003).

  117. 117

    Knudson, A.G. Chasing the cancer demon. Annu. Rev. Genet. 34, 1–19 (2000).

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C.W.P. and P.J.R. are scientific cofounders of ReOx, Ltd.

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

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