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Journal of Neuro-Oncology

, Volume 70, Issue 2, pp 229–243 | Cite as

Genetic and hypoxic regulation of angiogenesis in gliomas

  • Balveen Kaur
  • Chalet Tan
  • Daniel J. Brat
  • Erwin G. Van meir
Article

Abstract

Infiltrative astrocytic neoplasms are by far the most common malignant brain tumors in adults. Clinically, they are highly problematic due to their widely invasive nature which makes a complete resection almost impossible. Biologic progression of these tumors is inevitable and adjuvant therapies are only moderately effective in prolonging survival. Glioblastoma multiforme (GBM WHO grade IV), the most malignant form of infiltrating astrocytoma, can evolve from a lower grade precursor tumor (secondary GBM) or can present as high grade lesion from the outset, so-called de novoGBM. Molecular genetic investigations suggest that GBMs are comprised of multiple molecular genetic subsets. Notwithstanding the diversity of genetic alterations leading to the GBM phenotype, the vascular changes that evolve in this disease, presumably favoring further growth, are remarkably similar. Underlying genetic alterations in GBM may tilt the balance in favor of an angiogenic phenotype by upregulation of pro-angiogenic factors and down-regulation of angiogenesis inhibitors. Increased vascularity and endothelial cell proliferation in GBMs are also driven by hypoxia-induced expression of pro-angiogenic cytokines, such vascular endothelial growth factor (VEGF). Understanding the contribution of genetic alterations and hypoxia in angiogenic dysregulation in astrocytic neoplasms will lead to the development of better anti-angiogenic therapies for this disease. This review will summarize the properties of angiogenic dysregulation that lead to the highly vascularized nature of these tumors.

angiogenesis angiopoietin astrocytoma fibroblast growth factor genetics glioblastoma multiforme placenta growth factor vascular endothelial growth factor 

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References

  1. 1.
    Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3): 353–364, 1996Google Scholar
  2. 2.
    Dvorak HF: VPF/VEGF and the angiogenic response. Semin Perinatol 24(1): 75–78, 2000Google Scholar
  3. 3.
    Dvorak HF, Brown LF, Detmar M, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5): 1029–1039, 1995Google Scholar
  4. 4.
    Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, Dvorak AM, Dvorak HF: Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol 158(3): 1145–1160, 2001Google Scholar
  5. 5.
    Dvorak HF, Nagy JA, Feng D, Browrn LF, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237: 97–132, 1999Google Scholar
  6. 6.
    Ferrara N, Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev 18(l): 4–25, 1997Google Scholar
  7. 7.
    Ferrara N, Houck K, Jakeman L, Leung DW: Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13(l): 18–32, 1992Google Scholar
  8. 8.
    Desbaillets I, Diserens AC, de Tribolet N, Hamou MF, Van Meir EG: Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma cells. Oncogene 18(7): 1447–1456, 1999Google Scholar
  9. 9.
    Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B: Tumor induction of VEGF promoter activity in stromal cells. Cell 94(6): 715–725, 1998Google Scholar
  10. 10.
    Fukumura D, Yuan F, Endo M, Jain RK: Role of nitric oxide in tumor microcirculation. Blood flow, vascular permeability, and leukocyte-endothelial interactions. Am J Pathol 150(2): 713–725, 1997Google Scholar
  11. 11.
    Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK: Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol 151(3): 679–688, 1997Google Scholar
  12. 12.
    Van Meir, EG: Cytokines and tumors of the central nervous system. Glia 15(3): 264–288, 1995Google Scholar
  13. 13.
    Salmaggi A, Eoli M, Frigerio S, Silvai A, Gelati M, Corsini E, Broggi G, Boiardi A: Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol 62(3): 297–303, 2003Google Scholar
  14. 14.
    Wesseling P, Ruiter DJ, Burger PC: Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neurooncol 32(3): 253–265, 1997Google Scholar
  15. 15.
    Brat DJ, Van Meir EG: Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am J Pathol 158(3): 789–796, 2001Google Scholar
  16. 16.
    Wesseling P, Schlingmann RO, Reitveld FJ, Link M, Burger PC, Ruiter DJ: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study. J Neuropathol Exp Neurol 54(3): 304–310, 1995Google Scholar
  17. 17.
    Rojiani AM, Dorovini-Zis K: Glomeruloid vascular structures in glioblastoma multiforme: an immunohistochemical and ultrastructural study. J Neurosurg 85(6): 1078–1084, 1996Google Scholar
  18. 18.
    Tanaka F, Oyanagi H, Takenaka K, Ishikawa S, Yanagihara K, Miyahara R, Kawano Y, Li M, Otake Y, Wada H: Glomeruloid microvascular proliferation is superior to intratumoral microvessel density as a prognostic marker in non-small cell lung cancer. Cancer Res 63(20): 6791–6794, 2003Google Scholar
  19. 19.
    Straume O, Chappuis PO, Salvesan HB, Halvorsen OJ, Haukaas SA, Goffin JR, Begin LR, Foukes WD, Akslen LA: Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62(23): 6808–6811, 2002Google Scholar
  20. 20.
    Plate, KH: Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58(4): 313–320, 1999Google Scholar
  21. 21.
    Barker FG, 2nd, Davis RL, Chang SM, Prados MD: Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 77(6): 1161–1166, 1996Google Scholar
  22. 22.
    Kleihues P, BP, Collins VP: Glioblastoma. In: Pathology and Genetics of Tumors of the Nervous System Intl Agency for Research cancer, Editor: Lyon, 2000Google Scholar
  23. 23.
    Evans SM, Hahn SM, Magarelli DP, Koch CJ: Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation. Am J Clin Oncol 24(5): 467–472, 2001Google Scholar
  24. 24.
    Holland EC: Glioblastoma multiforme: the terminator. Proc Natl Acad Sci USA 97(12): 6242–6244, 2000Google Scholar
  25. 25.
    Brat DS, Van Meir EG: Vaso-Occlusive and prothrombotic mechanisims associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84(4): 397–405, 2004Google Scholar
  26. 26.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ: Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422): 1994–1998, 1999Google Scholar
  27. 27.
    Zagzag D, Amirnovin R, Greco MA, Yee H, Holash J, Wiegand SJ, Zabski S, Yancopoulos GD, Grumet M: Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80(6): 837–849, 2000Google Scholar
  28. 28.
    Semenza G: Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64(5–6): 993–998, 2002Google Scholar
  29. 29.
    Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW: Regulation and destabilization of HIF-1 alpha by ARD1-mediated acetylation. Cell 111(5): 709–720, 2002Google Scholar
  30. 30.
    Mahon PC, Hirota K, Semenza GL: FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15(20): 2675–2686, 2001Google Scholar
  31. 31.
    Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG: Frequent co-alterations of TP53, p16/ CDKN2A, p14ARF and PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9(3): 469–479, 1999Google Scholar
  32. 32.
    Holland EC, Hively WP, DePinho RA, Varmus HE: A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12(23): 3675–3685, 1998Google Scholar
  33. 33.
    Zundel W, Schindler C, Hass-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ: Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14(4): 391–396, 2000Google Scholar
  34. 34.
    Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G: The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4(2): 133–146, 2003Google Scholar
  35. 35.
    Ferrara N, Henzel WJ: Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161(2): 851–858, 1989Google Scholar
  36. 36.
    Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K: Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60(2): 203–212, 2000Google Scholar
  37. 37.
    Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573): 435–439, 1996Google Scholar
  38. 38.
    Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573): 439–442, 1996Google Scholar
  39. 39.
    Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI: Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci USA 93(5): 1988–1992, 1996Google Scholar
  40. 40.
    Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 15(7): 290–298, 1996Google Scholar
  41. 41.
    Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, AJitalo K: Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282(5390): 946–949, 1998Google Scholar
  42. 42.
    Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD: Neuropilin is a semaphorin III receptor. Cell 90(4): 753–762, 1997Google Scholar
  43. 43.
    Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H: A requirement for neuropilin-1 in embryonic vessel formation. Development 126(21): 4895–4902, 1999Google Scholar
  44. 44.
    Kitsukawa T, Shimizu M, Sanbo M, Hirata T, Taniguchi M, Bekku Y, Yagi T, Fujisawa H: Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19(5): 995–1005, 1997Google Scholar
  45. 45.
    Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki Ji J, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M: Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 99(6): 3657–3662, 2002Google Scholar
  46. 46.
    Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M: Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its blb2 domain. J Biol Chem 277(27): 24818–24825, 2002Google Scholar
  47. 47.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M: Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92(6): 735–745, 1998Google Scholar
  48. 48.
    Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G: Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 275(24): 18040–18045, 2000Google Scholar
  49. 49.
    Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M: VEGF 165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 85(2): 357–368, 2002Google Scholar
  50. 50.
    Whitaker GB, Limberg BJ, Rosenbaum JS: Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121). J Biol Chem 276(27): 25520–25531, 2001Google Scholar
  51. 51.
    Oh H, Takagi H, Otani A, Koyama S, Kemmochi S, Uemura A, Honda Y: Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis. Proc Natl Acad Sci USA 99(1): 383–388, 2002Google Scholar
  52. 52.
    Miao HQ, Lee P, Lin H, Soker S, Klagsbrurn M: Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. Faseb J 14(15): 2532–2539, 2000Google Scholar
  53. 53.
    Brat DJ, Kaur B, Van Meir EG: Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors. Front Biosci 8: D100–l16, 2003Google Scholar
  54. 54.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC: Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376(6535): 62–66, 1995Google Scholar
  55. 55.
    Fong GH, Rossant J, Gertsenstein M, Breitman ML: Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535): 66–70, 1995Google Scholar
  56. 56.
    Plate KH, Breier G, Weich HA, Mennel HD, Risau W: Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59(4): 520–529, 1994Google Scholar
  57. 57.
    Kanno S, Oda N, Abe M, Terai Y, Ito M, Shitara K, Tabayashi K, Shibuya M, Sato Y: Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. Oncogene 19(17): 2138–2146, 2000Google Scholar
  58. 58.
    Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM: Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6(12): 1335–1340, 2000Google Scholar
  59. 59.
    Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359(6398): 843–845, 1992Google Scholar
  60. 60.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733): 271–275, 1999Google Scholar
  61. 61.
    Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W, Plate KH: Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res 57(17): 3860–3864, 1997Google Scholar
  62. 62.
    Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S, Nose T: Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56(9): 2185–2190, 1996Google Scholar
  63. 63.
    Zeng H, Dvorak HF, Mukhopadhyay D: Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) peceptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 276(29): 26969–26979, 2001Google Scholar
  64. 64.
    Zeng H, Zhao D, Mukhopadhyay D: Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. J Biol Chem 277(6): 4003–4009, 2002Google Scholar
  65. 65.
    Gollmer JC, Ladoux A, Gioanni J, Paquis P, Dubreuil A, Chatel M, Frelin C: Expression of vascular endothelial growth factor-b in human astrocytoma. Neuro-oncol 2(2): 80–86, 2000Google Scholar
  66. 66.
    Maity A, Pore N, Lee J, Solomon D, O'Rourke DM: Epidermal growth factor receptor transcriptionally upregulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3¢-kinase and distinct from that induced by hypoxia. Cancer Res 60(20): 5879–5886, 2000Google Scholar
  67. 67.
    Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG: Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88(20): 9267–9271, 1991Google Scholar
  68. 68.
    Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269(41): 25646–25654, 1994Google Scholar
  69. 69.
    Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Shibuya M, Collen D, Conway EM, Carmeliet P: Role of PlGF in the intraand intermolecular cross talk between the VEGF receptors Flt1 andFlk1. Nat Med 9(7): 936–943, 2003Google Scholar
  70. 70.
    Autiero M, Luttun A, Tjwa M, Carmeliet P: Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1(7): 1356–1370, 2003Google Scholar
  71. 71.
    Nomura M, Yamagishi S, Harada S, Yamashima T, Yamashita J, Yamamoto H: Placenta growth factor (PIGF) mRNA expression in brain tumors. J Neurooncol 40(2): 123–130, 1998Google Scholar
  72. 72.
    Ziegler SF, Bird TA, Schneringer JA, Schooley KA, Baum PR: Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogene 8(3): 663–670, 1993Google Scholar
  73. 73.
    Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD: Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87(7): 1161–1169, 1996Google Scholar
  74. 74.
    Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM: Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286(5449): 2511–2514, 1999Google Scholar
  75. 75.
    Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD: Increased vascularization in mice overexpressing angiopoietin-1. Science 282(5388): 468–471, 1998Google Scholar
  76. 76.
    Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ, Kim KW: SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med 9(7): 900–906, 2003Google Scholar
  77. 77.
    Kim I, Kim JH, Ryu YS, Jung SH, Nah JJ, Koh GY: Characterization and expression of a novel alternatively spliced human angiopoietin-2. J Biol Chem 275(24): 18550–18556, 2000Google Scholar
  78. 78.
    Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD, Grumet M: In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159(2): 391–400, 1999Google Scholar
  79. 79.
    Tse V, Xu L, Yung YC, Santarelli JG, Juan D, Fabel K, Silverberg G, Harsh Gt: The temporal-spatial expression of VEGF, angiopoietins-1 and 2, and Tie-2 during tumor angiogenesis and their functional correlation with tumor neovascular architecture. Neurol Res 25(7): 729–738, 2003Google Scholar
  80. 80.
    Stratmann A, Risau W, Plate KH: Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153(5): 1459–1466, 1998Google Scholar
  81. 81.
    Hu B, Guo P, Fang Q, Tao HQ, Wang D, Nagane M, Huang HJ, Gunji Y, Nishikawa R, Alitalo K, Cavenee WK, Cheng SY: Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc Natl Acad Sci USA 100(15): 8904–8909, 2003Google Scholar
  82. 82.
    Zadeh G, Qian B, Okhowat A, Sabha N, Kontos CD, Guha A: Targeting the tie2/tek receptor in astrocytomas. Am J Pathol 164(2): 467–476, 2004Google Scholar
  83. 83.
    Yamashita T, Yoshioka M, Itoh N: Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277(2): 494–498, 2000Google Scholar
  84. 84.
    Nakatake Y, Hoshikawa M, Asaki T, Kassai Y, Itoh N: Identification of a novel fibroblast growth factor, FGF-22, preferentially expressed in the inner root sheath of the hair follicle. Biochem Biophys Acta 1517(3): 460–463, 2001Google Scholar
  85. 85.
    Naski MC, Ornitz DM: FGF signaling in skeletal development. Front Biosci 3: D781–794, 1998Google Scholar
  86. 86.
    Eckenstein FP: Fibroblast growth factors in the nervous system. J Neurobiol 25(11): 1467–1480, 1994Google Scholar
  87. 87.
    Eckenstein FP, Kuzis K, Nishi R, Woodward WR, Meshul C, Sherman L, Ciment G: Cellular distribution, subcellular localization and possible functions of basic and acidic fibroblast growth factors. Biochem Pharmacol 47(1): 103–110, 1994Google Scholar
  88. 88.
    Munoz-Sanjuan I, Smallwood PM, Nathans J: Isoform diversity among fibroblast growth factor homologous factors is generated by alternative promoter usage and differential splicing. J Biol Chem 275(4): 2589–2597, 2000Google Scholar
  89. 89.
    Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J, Lax I: Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell 79(6): 1015–1024, 1994Google Scholar
  90. 90.
    Plotnikov AN, Hubbard SR, Schlessinger J, Mohammadi M: Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity. Cell 101(4): 413–424, 2000Google Scholar
  91. 91.
    Plotnikov AN, Schlessinger J, Hubbard SR, Mohammadi M: Structural basis for FGF receptor dimerization and activation. Cell 98(5): 641–650, 1999Google Scholar
  92. 92.
    Qiao D, Meyer K, Mundhenke C, Drew SA, Friedl A: Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis. J Biol Chem 278(18): 16045–16053, 2003Google Scholar
  93. 93.
    Bikfalvi A, Klein S, Pintucci G, Rifkin DB: Biological roles of fibroblast growth factor-2. Endocr Rev 18(1): 26–45, 1997Google Scholar
  94. 94.
    Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM, Lamszus K: Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84(1): 10–18, 1999Google Scholar
  95. 95.
    Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA: Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301(5629): 94–96, 2003Google Scholar
  96. 96.
    Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA: Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis. J Cell Biol 162(5): 933–943, 2003Google Scholar
  97. 97.
    Morrison RS, Gross JL, Herblin WF, Reilly TM, LaSala PA, Alterman RL, Moskal JR, Kornblith PL, Dexter DL: Basic fibroblast growth factor-like activity and receptors are expressed in a human glioma cell line. Cancer Res 50(8): 2524–2529, 1990Google Scholar
  98. 98.
    Paulus W, Grothe C, Sensenbrener M, Janet T, Baur I, Graf M, Roggendorf W: Localization of basic fibroblast growth factor, a mitogen and angiogenic factor, in human brain tumors. Acta Neuropathol (Berl) 79(4): 418–423, 1990Google Scholar
  99. 99.
    Shim JW, Koh YC, Ahn HK, Park YE, Hwang DY, Chi JG: Expression of bFGF and VEGF in brain astrocytoma. J Korean Med Sci 11(2): 149–157, 1996Google Scholar
  100. 100.
    Li VW, Folkerth RD, Watanabe H, Yu C, Rupnick M, Barnes P, Scott RM, Black PM, Sallan SE, Folkman J: Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344(8915): 82–86, 1994Google Scholar
  101. 101.
    Folkman J, Watson K, Ingber D, Hanahan D: Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339(6219): 58–61, 1989Google Scholar
  102. 102.
    Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J, 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(10): 4606–4610, 1995Google Scholar
  103. 103.
    Gately S, Soff GA, Brem S: The potential role of basic fibroblast growth factor in the transformation of cultured primary human fetal astrocytes and the proliferation of human glioma (U-87) cells. Neurosurgery 37(4): 723–730; discussion 730–722, 1995Google Scholar
  104. 104.
    Gately S, Tsanaclis AM, Takano S, Klagsbrun M, Brem S: Cells transfected with the basic fibroblast growth factor gene fused to a signal sequence are invasive in vitro and in situ in the brain. Neurosurgery 36(4): 780–788, 1995Google Scholar
  105. 105.
    Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, Di Santo JP, Bikfalvi A: Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and-independent mechanisms. Cancer Res 61(4): 1717–1726, 2001Google Scholar
  106. 106.
    C.W. Kleihuis P; 2000; Diffusely infiltrating astrocytomas. In: Cavenee WK, FF, Nagane M (eds) Pathology and Genetics of Tumors of the Nervous System, 2nd edn. Lyon: Intl Agency for ResearchGoogle Scholar
  107. 107.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308): 1943–1947, 1997Google Scholar
  108. 108.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMACl, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15(4): 356–362, 1997Google Scholar
  109. 109.
    Maehama T, Dixon JE: The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273(22): 13375–13378, 1998Google Scholar
  110. 110.
    Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK: The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci USA 95(25): 14950–14955, 1998Google Scholar
  111. 111.
    Mazure NM, Chen EY, Laderoute KR, Giaccia AJ: Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/ Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90(9): 3322–3331, 1997Google Scholar
  112. 112.
    Hsu SC, Volpert OV, Steck PA, Mikkelsen T, Polverini PJ, Rao S, Chou P, Bouck NP: Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction ofthrombospondin-L Cancer Res 56(24): 5684–5691, 1996Google Scholar
  113. 113.
    Tenan M, Fulci G, Albertoni M, Diserens AC, Hamou MF, El Atifi-Borel M, Feige JJ, Pepper MS, Van Meir EG: Thrombospondin-1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. J Exp Med 191(10): 1789–1798, 2000Google Scholar
  114. 114.
    Wen S, Stolarov J, Myers MP, Su JD, Wigler MH, Tonks NK, Durden DL: PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci USA 98(8): 4622–4627, 2001Google Scholar
  115. 115.
    Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Coillins VP: Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51(8): 2164–2172, 1991Google Scholar
  116. 116.
    Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B: Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84(19): 6899–6903, 1987Google Scholar
  117. 117.
    Frederick L, Wang XY, Eley G, James CD: Diversity and frequency epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60(5): 1383–1387, 2000Google Scholar
  118. 118.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B: Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89(7): 2965–2969, 1992Google Scholar
  119. 119.
    Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY: Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4(1): 121–133, 1993Google Scholar
  120. 120.
    Clarke K, Smith K, Gullick WJ, Harris AL: Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulinlike growth factor-1 via a PI3 kinase dependent pathway. Br J Cancer 84(10): 1322–1329, 2001Google Scholar
  121. 121.
    Lang FF, Miller DC, Koslow M, Newcomb EW: Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors. J Neurosurg 81(3): 427–436, 1994Google Scholar
  122. 122.
    Fulci G, Ishii N, Van Meir EG: p53 and brain tumors: from gene mutations to gene therapy. Brain Pathol 8(4): 599–613, 1998Google Scholar
  123. 123.
    Van Meir EG, Kikuchi T, Tada M, Li H, Diserens AC, Wojcik BE, Huang HJ, Friedmann T, de Tribolet N, Cavenee WK: Analyses of the p53 gene and its expression in human glioblastoma cells. Cancer Res 54(3): 649–652, 1994Google Scholar
  124. 124.
    Albertoni M, Daub DM, Arden KC, Viars CS, Powell C, Van Meir EG: Genetic instability leads to loss of both p53 alleles in a human glioblastoma. Oncogene 16(3): 321–326, 1998Google Scholar
  125. 125.
    Van Meir EG, Roemer K, Diserens AC, Kikuchi T, Rempel SA, Haas M, Huang HJ, Friedmann T, de Tribolet N, Cavenee WK: Single cell monitoring of growth arrest and morphological changes induced by wild-type p53 alleles in glioblastoma cells. Proc Natl Acad Sci USA 92(4): 1008–1012, 1995Google Scholar
  126. 126.
    Ueba T, Nosaka T, Takahashi JA, Shibata F, Florkiewicz RZ, Vogelstein B, Oda Y, Kikuchi H, Hatanaka M: Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc Natl Acad Sci USA 91(19): 9009–9013, 1994Google Scholar
  127. 127.
    Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M: Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc Natl Acad Sci USA 87(15): 5710–5714, 1990Google Scholar
  128. 128.
    de Fraipont F, Nicholson AC, Feige JJ, Van Meir EG: Thrombospondins and tumor angiogenesis. Trends Mol Med 7(9): 401–407, 2001Google Scholar
  129. 129.
    Dameron KM, Volpert OV, Tainsky MA, Bouck N: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265(5178): 1582–1584, 1994Google Scholar
  130. 130.
    Van Meir EG, Polverini PJ, Chazin VR, Huang HS, de Tribolet N, Cavenee WK: Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8(2): 171–176, 1994Google Scholar
  131. 131.
    Grossfeld GD, Ginsberg DA, Stein JP, Bochner BH, Esrig D, Groshen S, Dunn M, Nichols PW, Taylor CR, Skinner DG, Cote RJ: Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89(3): 219–227, 1997Google Scholar
  132. 132.
    Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, Fang B, Lee JJ, Roth JA: Adenovirusmediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res 58(11): 2288–2292, 1998Google Scholar
  133. 133.
    Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1 alpha. Genes Dev 14(1): 34–44, 2000Google Scholar
  134. 134.
    Nishimori H, Shiratsuchi T, Urano T, Kimura Y, Kiyono K, Tatsumi K, Yoshida S, Ono M, Kuwano M, Nakamura Y, Tokino T: A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 15(18): 2145–2150, 1997Google Scholar
  135. 135.
    Kaur B, Brat DJ, Calkins CC, Van Meir EG: Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 162(1): 19–27, 2003Google Scholar
  136. 136.
    Sato Y, Kanno S, Oda N, Abe M, Ito M, Shitara K, Shibuya M: Properties of two VEGF receptors, Flt-1 and KDR, in signal transduction. Ann N Y Acad Sci 902: 201–205; discussion 205–207, 2000Google Scholar
  137. 137.
    Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. Embo J 18(4): 882–892, 1999Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Balveen Kaur
    • 1
  • Chalet Tan
    • 1
  • Daniel J. Brat
    • 1
    • 2
  • Erwin G. Van meir
    • 1
  1. 1.Laboratory of Molecular Neuro-Oncology, Department of Neuro-surgery and Hematology/OncologyWinship Cancer InstituteAtlanta
  2. 2.Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlanta

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