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Role of hypoxia in tumor angiogenesis—molecular and cellular angiogenic crosstalk

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Abstract

The mechanisms by which tumors recruit their vasculature has been subject to intense investigations. The acquisition of a functional blood supply seems to be rate-limiting for the ability of a tumor to grow beyond a certain size and to metastasize to other sites. Accumulating evidence indicates that hypoxia and the key transcriptional system, HIF (hypoxia-inducible factor), are the major triggers for new blood vessel growth in malignant tumors. Although vessel growth and maturation are complex and highly coordinated processes requiring the sequential activation of a multitude of factors, there is a consensus that vascular endothelial growth factor and angiopoietin signaling represent crucial steps in tumor angiogenesis. Recent insights into cellular and molecular crosstalk suggest a model in which hypoxia, HIF, and several HIF target genes participate in the coordinated collaboration between tumor, endothelial, inflammatory/hematopoietic, and circulating endothelial precursor cells to enhance and promote tumor vascularization. A well-integrated understanding of this intricate microenvironment may offer new opportunities for therapeutic intervention.

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References

  • Acker T, Plate KH (2002) A role for hypoxia and hypoxia–inducible transcription factors in tumor physiology. J Mol Med 80:562–575

    Article  CAS  PubMed  Google Scholar 

  • Acker T, Beck H, Plate KH (2001) Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and -2 suggests an important role of astrocytes in cerebellar vascularization. Mech Dev 108:45–57

    CAS  PubMed  Google Scholar 

  • Beck H, Acker T, Wiessner C, Allegrini PR, Plate KH (2000) Expression of angiopoietin-1, angiopoietin-2, and Tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol 157:1473–1483

    CAS  PubMed  Google Scholar 

  • Beck H, Acker T, Puschel AW, Fujisawa H, Carmeliet P, Plate KH (2002) Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. J Neuropathol Exp Neurol 61:339–350

    CAS  PubMed  Google Scholar 

  • Bilton RL, Booker GW (2003) The subtle side to hypoxia inducible factor (HIFalpha) regulation. Eur J Biochem 270:791–798

    Article  CAS  PubMed  Google Scholar 

  • Blagosklonny MV, An WG, Romanova LY, Trepel J, Fojo T, Neckers L (1998) p53 inhibits hypoxia-inducible factor-stimulated transcription. J Biol Chem 273:11995–11998

    CAS  PubMed  Google Scholar 

  • Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL (2000) Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res 60:7106–7113

    CAS  PubMed  Google Scholar 

  • Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 58:1408–1416

    CAS  PubMed  Google Scholar 

  • Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340

    CAS  PubMed  Google Scholar 

  • Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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, Keshet E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  Google Scholar 

  • Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657

    CAS  PubMed  Google Scholar 

  • Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, Harris AL (1997) Targeting gene expression to hypoxic tumor cells. Nat Med 3:515–520

    CAS  PubMed  Google Scholar 

  • Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W, Plate KH (1997) Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res 57:3860–3864

    CAS  PubMed  Google Scholar 

  • Desbaillets I, Diserens AC, Tribolet N de, Hamou MF, Van Meir EG (1999) Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene 18:1447–1456

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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  Google Scholar 

  • Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y (1999) Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J 18:1905–1914

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Eriksson U, Alitalo K (2002) VEGF receptor 1 stimulates stem-cell recruitment and new hope for angiogenesis therapies. Nat Med 8:775–777

    Article  CAS  PubMed  Google Scholar 

  • Favier J, Kempf H, Corvol P, Gasc JM (2001) Coexpression of endothelial PAS protein 1 with essential angiogenic factors suggests its involvement in human vascular development. Dev Dyn 222:377–388

    CAS  PubMed  Google Scholar 

  • Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    CAS  PubMed  Google Scholar 

  • Flamme I, Frohlich T, Reutern M von, 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

    CAS  PubMed  Google Scholar 

  • Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18

    Article  CAS  Google Scholar 

  • Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61

    CAS  PubMed  Google Scholar 

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza G L (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    CAS  PubMed  Google Scholar 

  • Fox SB (1997) Tumour angiogenesis and prognosis. Histopathology 30:294–301

    CAS  PubMed  Google Scholar 

  • Fukumura D, Xavier R, Sugiura T, Chen Y, Park E C, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Goldberg I, Furneaux H, Levy AP (2002) A 40 bp RNA element that mediates stabilization of VEGF mRNA by HuR. J Biol Chem 100:10–20

    Google Scholar 

  • Green CJ, Lichtlen P, Huynh NT, Yanovsky M, Laderoute KR, Schaffner W, Murphy BJ (2001) Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1. Cancer Res 61:2696–2703

    CAS  PubMed  Google Scholar 

  • Griffiths L, Binley K, Iqball S, Kan O, Maxwell P, Ratcliffe P, Lewis C, Harris A, Kingsman S, Naylor S (2000) The macrophage—a novel system to deliver gene therapy to pathological hypoxia. Gene Ther 7:255–262

    CAS  PubMed  Google Scholar 

  • Grimshaw MJ, Balkwill F R (2001) Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation––a potential mechanism. Eur J Immunol 31:480–489

    CAS  PubMed  Google Scholar 

  • Grunstein J, Masbad JJ, Hickey R, Giordano F, Johnson RS (2000) Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature. Mol Cell Biol 20:7282–7291

    Article  CAS  PubMed  Google Scholar 

  • Gu J, Milligan J, Huang LE (2001) Molecular mechanism of hypoxia-inducible factor 1alpha-p300 interaction. A leucine-rich interface regulated by a single cysteine. J Biol Chem 276:3550–3554

    CAS  PubMed  Google Scholar 

  • Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA (1998) Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 7:205–213

    CAS  PubMed  Google Scholar 

  • Hanahan D (1997) Signaling vascular morphogenesis and maintenance. Science 277:48–50

    CAS  PubMed  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    PubMed  Google Scholar 

  • Hansen-Algenstaedt N, Stoll BR, Padera TP, Dolmans DE, Hicklin DJ, Fukumura D, Jain RK (2000) Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Res 60:4556–4560

    CAS  PubMed  Google Scholar 

  • Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Helmlinger G, Endo M, Ferrara N, Hlatky L, Jain RK (2000) Formation of endothelial cell networks. Nature 405:139–141

    Article  CAS  Google Scholar 

  • Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95:9349–9354

    CAS  PubMed  Google Scholar 

  • Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213

    CAS  PubMed  Google Scholar 

  • Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (1997) Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 272:8581–8593

    CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Ikeda E, Achen MG, Breier G, Risau W (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270:19761–19766

    CAS  PubMed  Google Scholar 

  • Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D (2002) VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1:193–202

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    CAS  PubMed  Google Scholar 

  • Jain RK, Munn LL (2000) Leaky vessels? Call Ang1! Nat Med 6:131–132

    Google Scholar 

  • Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW (2002) Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111:709–720

    CAS  PubMed  Google Scholar 

  • Jiang BH, Zheng JZ, Leung SW, Roe R, Semenza GL (1997) Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha modulation of transcriptional activity by oxygen tension. J Biol Chem 272:19253–19260

    CAS  PubMed  Google Scholar 

  • Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L (1999) Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem 274:6519–6525

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Kappel A, Ronicke V, Damert A, Flamme I, Risau W, Breier G (1999) Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice. Blood 93:4284–4292

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    CAS  PubMed  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443

    PubMed  Google Scholar 

  • Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, Hong K, Dewhirst MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56:5522–5528

    CAS  PubMed  Google Scholar 

  • Kremer C, Breier G, Risau W, Plate KH (1997) Up-regulation of flk-1/vascular endothelial growth factor receptor 2 by its ligand in a cerebral slice culture system. Cancer Res 57:3852–3859

    CAS  PubMed  Google Scholar 

  • Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM (2000) Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6:1335–1340

    CAS  PubMed  Google Scholar 

  • Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567

    CAS  PubMed  Google Scholar 

  • Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861

    CAS  PubMed  Google Scholar 

  • Lando D, Gorman JJ, Whitelaw ML, Peet DJ (2003) Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem 270:781–790

    Article  CAS  PubMed  Google Scholar 

  • Lauren J, Gunji Y, Alitalo K (1998) Is angiopoietin-2 necessary for the initiation of tumor angiogenesis? Am J Pathol 153:1333–1339

    Google Scholar 

  • Lee C G, Heijn M, Tomaso E di, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565–5570

    CAS  PubMed  Google Scholar 

  • Levy AP, Levy NS, Goldberg MA (1996a) Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J Biol Chem 271:25492–25497

    CAS  PubMed  Google Scholar 

  • Levy AP, Levy NS,Goldberg MA (1996b) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271:2746–2753

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Li J, Post M, Volk R, Gao Y, Li M, Metais C, Sato K, Tsai J, Aird W, Rosenberg RD, Hampton TG, Sellke F, Carmeliet P, Simons M (2000) PR39, a peptide regulator of angiogenesis. Nat Med 6:49–55

    CAS  PubMed  Google Scholar 

  • Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740

    Article  CAS  PubMed  Google Scholar 

  • Lin P, Polverini P, Dewhirst M, Shan S, Rao PS, Peters K (1997) Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J Clin Invest 100:2072–2078

    CAS  PubMed  Google Scholar 

  • Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M, Krek W (1999) The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev 13:1822–1833

    CAS  PubMed  Google Scholar 

  • Liu Y, Cox SR, Morita T, Kourembanas S (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells Identification of a 5' enhancer. Circ Res 77:638–643

    CAS  PubMed  Google Scholar 

  • Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840

    CAS  PubMed  Google Scholar 

  • Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  CAS  PubMed  Google Scholar 

  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    PubMed  Google Scholar 

  • Matsumoto K, Yoshitomi H, Rossant J, Zaret KS (2001) Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294:559–563

    CAS  PubMed  Google Scholar 

  • Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ (1997) 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11:293–299

    CAS  PubMed  Google Scholar 

  • Michiels C, Arnould T, Remacle J (2000) Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 1497:1–10

    CAS  Google Scholar 

  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579

    CAS  PubMed  Google Scholar 

  • Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H (1998) Placenta growth factor (PlGF) mRNA expression in brain tumors. J Neurooncol 40:123–130

    Article  CAS  PubMed  Google Scholar 

  • Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hutter J, Schramm M, Flamme I (2002) Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun 296:343–349

    Article  CAS  PubMed  Google Scholar 

  • Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y (1999) Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 274:15732–15739

    CAS  PubMed  Google Scholar 

  • Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427

    CAS  PubMed  Google Scholar 

  • Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138

    CAS  PubMed  Google Scholar 

  • O'Rourke JF, Tian YM, Ratcliffe PJ, Pugh CW (1999) Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha. J Biol Chem 274:2060–2071

    CAS  PubMed  Google Scholar 

  • Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T (2000) Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Wound Biol 100:10-20

    Google Scholar 

  • Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320

    CAS  PubMed  Google Scholar 

  • Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848

    CAS  PubMed  Google Scholar 

  • Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ (1997) Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem 272:11205–11214

    CAS  PubMed  Google Scholar 

  • Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti–angiogenesis therapy? Nat Rev Cancer 2:826–835

    Google Scholar 

  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44

    CAS  PubMed  Google Scholar 

  • Roberts WG, Palade GE (1997) Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 57:765–772

    CAS  PubMed  Google Scholar 

  • Ruoslahti E (2000) Targeting tumor vasculature with homing peptides from phage display. Semin Cancer Biol 10:435–442

    CAS  PubMed  Google Scholar 

  • Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2:83–90

    Article  PubMed  Google Scholar 

  • Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015

    CAS  PubMed  Google Scholar 

  • Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Shih SC, Claffey KP (1999) Regulation of human vascular endothelial growth factor mRNA stability in hypoxia by heterogeneous nuclear ribonucleoprotein L. J Biol Chem 274:1359–1365

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Srinivas V, Zhang LP, Zhu XH, Caro J (1999) Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun 260:557–561

    CAS  PubMed  Google Scholar 

  • St. Croix B, Rago C, Velculescu V, Traverso G, Romans K E, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, Kinzler KW (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202

    Google Scholar 

  • Stebbins CE, Kaelin WG Jr, Pavletich NP (1999) Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284:455–461

    CAS  PubMed  Google Scholar 

  • Stein I, Neeman M, Shweiki D, Itin A, Keshet E (1995) Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia–induced genes. Mol Cell Biol 15:5363–5368

    CAS  PubMed  Google Scholar 

  • Stein I, Itin A, Einat P, Skaliter R, Grossman Z, Keshet E (1998) Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol Cell Biol 18:3112–3119

    CAS  PubMed  Google Scholar 

  • Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466

    CAS  PubMed  Google Scholar 

  • Stratmann A, Acker T, Burger A M, Amann K, Risau W, Plate KH (2001) Differential inhibition of tumor angiogenesis by Tie2 and vascular endothelial growth factor receptor-2 dominant-negative receptor mutants. Int J Cancer 91:273–282

    CAS  PubMed  Google Scholar 

  • Strawn LM, McMahon G, App H, Schreck R, Kuchler W R, Longhi M P, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996) Flk-1 as a target for tumor growth inhibition. Cancer Res 56:3540–3545

    CAS  PubMed  Google Scholar 

  • Sutter CH, Laughner E, Semenza GL (2000) Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci USA 97:4748–4753

    CAS  PubMed  Google Scholar 

  • Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, Satake M, Suda T (2000) A role for hematopoietic stem cells in promoting angiogenesis. Cell 102:199–209

    CAS  PubMed  Google Scholar 

  • Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421

    CAS  PubMed  Google Scholar 

  • Tanimoto K, Makino Y, Pereira T, Poellinger L (2000) Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 19:4298–4309

    CAS  PubMed  Google Scholar 

  • Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  • Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Wartenberg M, Donmez F, Ling FC, Acker H, Hescheler J, Sauer H (2001) Tumor-induced angiogenesis studied in confrontation cultures of multicellular tumor spheroids and embryoid bodies grown from pluripotent embryonic stem cells. FASEB J 15:995–1005

    CAS  PubMed  Google Scholar 

  • Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW, Ratcliffe PJ, Maxwell PH (1998) Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood 92:2260–2268

    CAS  PubMed  Google Scholar 

  • Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2000) Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19:6297–6305

    CAS  PubMed  Google Scholar 

  • Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    CAS  PubMed  Google Scholar 

  • Yu F, White SB, Zhao Q, Lee FS (2001) Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein. Cancer Res 61:4136–4142

    CAS  PubMed  Google Scholar 

  • Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL (2000) Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 88:2606–2618

    CAS  PubMed  Google Scholar 

  • Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    CAS  PubMed  Google Scholar 

  • Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835

    CAS  PubMed  Google Scholar 

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Correspondence to Till Acker.

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The authors acknowledge grants from the Deutsche Krebshilfe (Dr. Mildred-Scheel Stiftung), the Bundesministerium für Bildung und Forschung (01KV0102), and the Deutsche Forschungsgemeinschaft (PL158/3–1, PL158/4–1 and PL158/4–2)

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Acker, T., Plate, K.H. Role of hypoxia in tumor angiogenesis—molecular and cellular angiogenic crosstalk. Cell Tissue Res 314, 145–155 (2003). https://doi.org/10.1007/s00441-003-0763-8

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