Journal of Neuro-Oncology

, Volume 50, Issue 1–2, pp 109–120

VEGF in Brain Tumors

  • Marcia Regina Machein
  • Karl Heinz Plate


Vascular endothelial growth factor (VEGF) is a regulator of angiogenesis, vasculogenesis and vascular permeability. In this contribution, molecular and biological properties of VEGF are described. Furthermore, this article focuses on the evidence that angiogenesis in brain tumors is mediated by VEGF. Among the topics discussed are expression patterns of VEGF and its receptors in different brain tumors, possible regulatory mechanism involved in the VEGF-driven tumor angiogenesis and the involvement of VEGF in the genesis of peritumoral edema. Finally, anti-angiogenesis approaches to target VEGF/VEGF receptors are discussed.

VEGF VEGF receptors angiogenesis brain tumors brain edema 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Folkman J: What is the evidence that tumors are angiogenesis-dependent? J Natl Cancer Inst 82: 4-6, 1990Google Scholar
  2. 2.
    Folkman J: Tumor angiogenesis. In: Mendelsoh H, Howley PM, Israel MA, Liotta LA (eds) The Molecular Basis of Cancer. WB Saunders, Philadelphia, 1995, pp 206-232Google Scholar
  3. 3.
    Risau W: Vasculogenesis, angiogenesis and endothelial cell differentiation during embryonic development. In: Feinberg RN, Sherer KG, Auerbach R (eds) The Development of the Vascular System. S Karger, Basel, 1991, pp 58-68Google Scholar
  4. 4.
    RisauW: What, if anything, is an angiogenic factor? Cancer Metastasis Rev 15: 149-151, 1996Google Scholar
  5. 5.
    Stetler-Stevenson WG: Matrix metalloproteases in angiogenesis: A moving target for therapeutic intervention. J Clin Invest 103: 1237-1241, 1999Google Scholar
  6. 6.
    Hanahan D, Folkamn J: Patterns and emerging mechanisms of angiogenic switch during tumorigenesis. Cell 86: 353-364, 1996Google Scholar
  7. 7.
    Klagsburn M, D'Amore PA: Regulators of angiogenesis. Annu Rev Physiol 53: 217-239, 1991Google Scholar
  8. 8.
    Klagsbrun M, D'Amore PA: Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev 7: 259-270, 1996Google Scholar
  9. 9.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor secrets a vascular permeability factor that promotes accumulation of ascistes fluid Science 219: 983-985, 1983Google Scholar
  10. 10.
    Gospodarowicz D, Abraham JA, Schilling J: Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculostellate cells. Proc Natl Acad Sci USA 86: 7311-7315, 1989Google Scholar
  11. 11.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306-1309, 1989Google Scholar
  12. 12.
    Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT: Vascular endothelial growth factor, an endothelial cell mitogen related to PDGF. Science 246: 1309-1312, 1989Google Scholar
  13. 13.
    Pepper MS, Ferrara N, Orci L, Montesano R: Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181: 902-906, 1991Google Scholar
  14. 14.
    Unemori EN, Ferrara N, Bauer EA, Amento EP: Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153: 557-562, 1992Google Scholar
  15. 15.
    Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM, Dvorak HF: Vascular permeability factor (VPF, VEGF) in tumor biology (Review). Cancer Metastasis Rev 12: 303-324, 1993Google Scholar
  16. 16.
    Brock TA, Dvorak HF, Senger DR: Tumor-secreted vascular permeability factor increases cytosolic Ca+2 and von Willebrand factor release in human endothelial cells. Am J Pathol 138: 213-221, 1991Google Scholar
  17. 17.
    Ku DD, Jaleski JK, Liu S, Brock TA: Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265: H586-H592, 1993Google Scholar
  18. 18.
    Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 10: 1024-1028, 1995Google Scholar
  19. 19.
    Benjamin LE, Keshet E: Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA 94: 8761-8766, 1997Google Scholar
  20. 20.
    Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW: The vascular endothelial growth factor family of polypeptides (Review). J Cell Biochem 47: 211-218, 1991Google Scholar
  21. 21.
    Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC: Vascular endothelial growth factor expression, vascular volume, and capillary permeability in human brain tumors. Neurosurgery 44: 732-740, 1999Google Scholar
  22. 22.
    Cheng SY, Nagane M, Huang HS, Cavence WK: Intracerebral tumor-associated hemorrhage caused by overexpression of vascular endothelial growth factor proforms VEGF121 and VEGF165 but not VEGF189. Proc Natl Acad Sci USA 94(22): 12081-12087, 1997Google Scholar
  23. 23.
    Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M: Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to fms family. Oncogene 5: 519-524, 1990Google Scholar
  24. 24.
    De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255: 989-991, 1992Google Scholar
  25. 25.
    Terman BC, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Boehlen P: Identification of the KDR tyrosine kinase receptor as a receptor for vascular endothelial growth factor. Biochem Biophys Res Comm 187: 1579-1586, 1992Google Scholar
  26. 26.
    Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A: High affinity VEGF binding and development expression suggest flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72: 835-846, 1993Google Scholar
  27. 27.
    Breier G, Clauss M, Risau W: Coordinate expression of VEGF-receptor 1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development. Dev Dyn 204: 228-239, 1995Google Scholar
  28. 28.
    Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt-1, two receptors for vascular endothelial growth factor. J Biol Chem 269: 26988-26995, 1994Google Scholar
  29. 29.
    Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M: Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95: 9349-9354, 1998Google Scholar
  30. 30.
    Matthews W, Jordan CT, Gavin M, Jenkins NA, Copeland NG, Lemischka IR: A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoetic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci USA 88: 9026-9030, 1991Google Scholar
  31. 31.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu X-F, Breitman ML, Schuh AC: Failure of blood-island formation and vasculogenesis in flk-1-deficient mice. Nature 376: 62-66, 1995Google Scholar
  32. 32.
    Fong G-H, Rossant J, Gertsenstein M, Breitman ML: Role of the flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376: 66-70, 1995Google Scholar
  33. 33.
    Carmeliet P, Ferreira V, Breier G, Pllefeyet S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq, 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: 435-439, 1996Google Scholar
  34. 34.
    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 80: 439-442, 1996Google Scholar
  35. 35.
    Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG: Isolation of human placental cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88: 9267-9271, 1991Google Scholar
  36. 36.
    Olofsson B, Pajusola K, Kaipanen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U: Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93: 2576-2581, 1996Google Scholar
  37. 37.
    Jaukov V, Pasujola K, Kaipanen A, Chilvo D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 15: 290-298, 1996Google Scholar
  38. 38.
    Grimmond S, Lagercrantz J, Drinkwater C, Sums G, Townson S, Pollock P, Gotley D, Carson E, Rakar S, Nordenskjold M, Ward I, Hayward N, Weber G: Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res 6: 124-131, 1996Google Scholar
  39. 39.
    Yamada Y, Nezu J, Shimane M, Hirata Y: Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 15: 483-488, 1997Google Scholar
  40. 40.
    Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M, Lanz C, Buttner M, Rziha HJ, Dehio C: A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. Embo J 15: 363-374, 1999Google Scholar
  41. 41.
    Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K: VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122: 3829-3837, 1996Google Scholar
  42. 42.
    Li J, Perrella MA, Tsai JC, Yet SF, Hsich CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME: Induction of vascular endothelial growth factor gene expression by interleukin-1β in rat aortic smooth muscle cells. J Biol Chem 270: 308-312, 1995Google Scholar
  43. 43.
    Pertovaara L, Kaipainen A, Musttonen T, Orpana A, Ferrara N, Saksela O, Alitalo K: Vascular endothelial growth factor is induced in response to transforming growth factor-β in fibroblastic and epithelial cells. J Biol Chem 269: 6271-6274, 1994Google Scholar
  44. 44.
    Goldman CK, Kim J, Wong W-L, 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: 121-133, 1993Google Scholar
  45. 45.
    Tsai J-C, Goldman CK, Gillespie Y: Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB and bFGF. J Neurosurg 82: 864-873, 1995Google Scholar
  46. 46.
    Stavri GT, Hong Y, Zachary IC, Breier G, Baskerville PA, Yla-Herttualla S, Risau W, Martin JF, Erusalimsky JD: Hypoxia and platelet-derived growth factor-BB synergistically upregulate the expression of vascular endothelial growth factor in vascular smooth muscle cells. FEBS Lett 358: 311-315, 1995Google Scholar
  47. 47.
    Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ: Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271: 736-741, 1996Google Scholar
  48. 48.
    Cullinan-Bove K, Koos RD: Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus rapid stimulation by estrogen correlates with estrogen-induced increases in uterine permeability and growth. Endocrinology 133: 829-837, 1993Google Scholar
  49. 49.
    Kieser A, Weich HA, Brandner G, Marmé D, Kölch W: Mutatant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9: 963-969, 1994Google Scholar
  50. 50.
    Siemeister G, Weindel HA, Mohrs K, Barleon B, Martiny-Baron G, Marme D: Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel Lindau tumor suppressor protein. Cancer Res 56: 2299-2301, 1996Google Scholar
  51. 51.
    Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sazuki T, Kerbel RS: Mutant ras Oncogene upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575-4580, 1995Google Scholar
  52. 52.
    Grugel S, Finkenzeller G, Weindel K, Barleon B, Marmé D: Both v-Ha Ras and v-Raf stimulate expression of vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 270: 25915-25919, 1995Google Scholar
  53. 53.
    Mukhopadhyay D, Tsiokas L, Sukhatme VP: Wild-type p53 and v-src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55: 6161-6165, 1995Google Scholar
  54. 54.
    Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA: The human gene for vascular endothelial growth factor. J Biol Chem 266: 11947-11954, 1991Google Scholar
  55. 55.
    Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia initiated angiogenesis. Nature 359: 843-845, 1992Google Scholar
  56. 56.
    Ikeda E, Achen MG, Breier G, Risau W: Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270: 19761-19766, 1995Google Scholar
  57. 57.
    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: 3860-3864, 1997Google Scholar
  58. 58.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor-1. Mol Cell Biol 16: 4604-4613, 1996Google Scholar
  59. 59.
    Levy AP, Levy NS, Goldberg MA: Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271: 2746-2753, 1996Google Scholar
  60. 60.
    Stein I, Neeman D, Shweiki A, Itin A, Keshet E: Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol 15: 5363-5368, 1995Google Scholar
  61. 61.
    Zagzag D, Miller DC, Sato Y, Rifkin DB, Burstein DE: Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res 50: 7393-7398, 1990Google Scholar
  62. 62.
    Ekstrand AJ, James JC, Cavenee WK, Selinger B, Petterson RF, Collins VP: Genes for epidermal growth factor receptor, transforming growth factor and epidermal growth factor and their expression in humans gliomas in vivo. Cancer Res 51: 2164-2172, 1991Google Scholar
  63. 63.
    Plate KH, Breier G, Farrel CL, Risau W: Platelet-derived growth factor receptor-β is induced during tumor progression in endothelial cells in human gliomas. Lab Invest 67: 529-534, 1992Google Scholar
  64. 64.
    Hermanson M, Funa K, Hartman M, Claesson-Wassh L, Heldin C-H, Westermark B, Nister M: Platelet-derived growth factor and its receptor in human glioma tissue: expression of messager RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52: 3213-3219, 1992Google Scholar
  65. 65.
    Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845-847, 1992Google Scholar
  66. 66.
    Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali UI, Oldfield EH: Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91: 153-159, 1993Google Scholar
  67. 67.
    Pietsch T, Valter MM, Wolf HK, von Deimling A, Huang HJ, Cavenee WK, Wiestler OD: Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol 93: 109-117, 1997Google Scholar
  68. 68.
    Nishikawa R, Cheng SY, Nagashima R, Huang HJ, Cavenee WK, Matsutani M: Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 96: 453-462, 1998Google Scholar
  69. 69.
    Strugar J, Rothbart D, Harrington W, Criscuolo GR: Vascular permeability factor in brain metastasis: Correlation with vasogenic brain edema and tumor angiogenesis. J Neurosurg 81: 560-566, 1994Google Scholar
  70. 70.
    Meister B, Grunebach F, Bautz F, Brugger W, Fink FM, Kanz L, Mohle R: Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma. Eur J Cancer 35: 445-449, 1999Google Scholar
  71. 71.
    Gold EB: Epidemiology of brain tumors. In: Lilenfeld AM (ed) Rewiews in Cancer Epidemiology, vol 1, the Netherlands Elsevier, North Holland, 1980, pp 245-292Google Scholar
  72. 72.
    Russel DS, Rubinstein LJ: Pathology of tumors of the nervous system. Edward Arnold, London, 1989Google Scholar
  73. 73.
    Burger PC, Scheithauer BW, Vogel FS: Surgical Pathology of the Nervous System and its Coverings. Ed 3. Churchill Livingstone, New York, 199, pp 65-70Google Scholar
  74. 74.
    Brem S, Cotran R, Folkamn J: Tumor angiogenesis: A quantitative method for histologic grading. J Natl Cancer Inst 48: 347-356, 1972Google Scholar
  75. 75.
    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: 520-529, 1994Google Scholar
  76. 76.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ: Hypoxia-mediated selection of cells with diminished apopotic potential in solid tumors. Nature 379: 88-91, 1996Google Scholar
  77. 77.
    Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ: Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res 56: 3436-3440, 1996Google Scholar
  78. 78.
    Plate KH, Breier G, Millauer B, Ullrich A, Risau W: Upregulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumour angiogenesis. Cancer Res 53: 5822-5827, 1993Google Scholar
  79. 79.
    Hatva E, Kaipanen A, Mentula P, Jaaskelainen J, Paetau A, Haltia M, Alitalo K: Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146: 368-378, 1995Google Scholar
  80. 80.
    Kremer C, Breier G, Risau W, Plate KH: Upregulation of flk-1/VEGF receptor-2 by its ligand in a cerebral slice culture system. Cancer Res 57: 3852-3859, 1997Google Scholar
  81. 81.
    Shen BQ, Lee DY, Gerber HP, Keyt BA, Ferrara N, Zioncheck TF: Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitro. J Biol Chem 273: 29979-29985, 1998Google Scholar
  82. 82.
    Samoto K, Kiyonobu I, Mayumi O, Tadhisa S, Kimitoshi K, Kuwano M, Fukui M: Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 55: 1189-1193, 1995Google Scholar
  83. 83.
    Strugar JG, Criscuolo GR, Rothbart D, Harrington WN: Vascular endothelial growth/permeability factor expression in human glioma specimens: Correlation with vasogenic brain edema and tumor-associated cysts. J Neurosurg 83: 682-689, 1995Google Scholar
  84. 84.
    Leung SY, Chan AS, Wong MP, Yuen ST, Cheung N, Chung LP: Expression of vascular endothelial growth factor and its receptors in pilocytic astrocytoma. Am J Surg Pathol 21: 941-950, 1997Google Scholar
  85. 85.
    Pietsch T, Wiestler OD: Molecular neuropathology of astrocytic tumors. J Neuro-Oncol 35: 211-222, 1997Google Scholar
  86. 86.
    Abdulrauf SI, Edvardsen K, Ho KL, Yang XY, Rock JP, Rosenblum ML: Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma. J Neurosurg 3: 513-520, 1998Google Scholar
  87. 87.
    Christov C, Adle-Biassette H, Guerinel C, Natchev S, Gherardi RK: Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the vasculature of oligodendrogliomas. Neuropathol Appl Neurobiol 24: 29-35, 1998Google Scholar
  88. 88.
    Spence AM, Rubinstein LJ: Cerebellar capillary hemangioblastomas: its histogenesis studied by organ culture and electron microscopy. Cancer (Phila) 35: 326-341, 1975Google Scholar
  89. 89.
    Wizigmann-Voss S, Breier G, Risau W, Plate KH: Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 55: 1358-1364, 1995Google Scholar
  90. 90.
    Morii K, Tanaka R, Washiyama K, Kumanishi T, Kuwano R: Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem Biophys Res Commun 194: 749-755, 1993Google Scholar
  91. 91.
    Bohling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M: Expression of growth factors and growth factor receptors in capillary hemangioblastomas. J Neuropathol Exp Neurol 55: 522-527, 1996Google Scholar
  92. 92.
    Krieg M, Marti HH, Plate KH: Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood 92: 3388-3393, 1998Google Scholar
  93. 93.
    Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T, Yao M: Somatic mutations of von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54: 4845-4847, 1994Google Scholar
  94. 94.
    Oberstrass J, Reifenberger G, Reifenberger J, Wechsler W, Collins VP: Mutation of von Hippel-Lindau tumor suppressor gene in capillary hemangioblastomas of the central nervous system. J Pathol 179: 151-156, 1996Google Scholar
  95. 95.
    Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG Jr: Binding of the von Hippel-Lindau tumor suppressor gene to Elongin B and C. Science 269: 1444-1446, 1995Google Scholar
  96. 96.
    Duan DR, Pause A, Burgess WH, Aso T, Chen DY, Garret KP, Conaway RC, Conaway JW, Linehan WM, Kausner RD: Inhibition of transcription by VHL tumor suppressor protein. Science 269: 1402-1406, 1995Google Scholar
  97. 97.
    Iliopoulos O, Levy AP, Jiang C, Kaelin Jr WG, Goldberg MA: Negative regulation of hypoxia-inducible genes by von Hippel-Lindau protein. Proc Natl Acad Sci USA 93: 10595-10599, 1996Google Scholar
  98. 98.
    Flamme I, Krieg M, Plate KH: Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of transcription factor HRF/HIF-2 alpha. Am J Pathol 153: 25-29, 1998Google Scholar
  99. 99.
    Christov C, Lechapt-Zalcman E, Adle-Biassette H, Nachev S, Gherardi RK: Vascular permeability factor/ vascular endothelial growth factor (VPF/VEGF) and its receptor flt-1 in microcystic meningiomas. Acta Neuropathol 98: 414-420, 1999Google Scholar
  100. 100.
    Provias J, Claffey K, DelAguila L, Nelson L, Feldkamp M, Guha A: Meningiomas: Role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40: 1016-1026, 1997Google Scholar
  101. 101.
    Black PMcL: Meningiomas. Neurosurgery 32: 643-657, 1993Google Scholar
  102. 102.
    Smith D, Cahill D: The biology of meningiomas. Neurosurg Clin North Am 5: 201-215, 1994Google Scholar
  103. 103.
    Weisman AS, Raguet SS, Kelly PA: Characterization of epidermal growth factor receptor in human meningiomas. Cancer Res 47: 2172-2176, 1987Google Scholar
  104. 104.
    Maxwell M, Galanopoulos T, Hedley-Whyte ET, J Black PM, Antoniades HN: Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their products. Int J Cancer 46: 16-21, 1990Google Scholar
  105. 105.
    Speirs V, Boyle-Walsh E, Fraser WD: Constitutive co-expression of estrogen and progesterone receptor mRNA in human meningiomas by RT-PCR and response of in vitro cell cultures to steroid hormones. Int J Cancer 72: 714-719, 1997Google Scholar
  106. 106.
    Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN: Expression of androgen and progesterone receptors in primary human meningiomas. J Neurosurg 71: 347-351, 1993Google Scholar
  107. 107.
    Shweiki D, Ahuva I, Neufeld G, Gitay-Goren H, Keshet E: Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 91: 2235-2243, 1993Google Scholar
  108. 108.
    Donnini S, Machein MR, Plate KH, Weich HA: Expression and localization of placenta growth factor and PIGF receptors in human meningiomas. J Pathol 189: 66-71, 1999Google Scholar
  109. 109.
    Weindel K, Moringlane JR, Marmé D, Weich HA: Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid. Neurosurgery 35: 439-449, 1994Google Scholar
  110. 110.
    Enholm B, Paavonen K, Ristimäke A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K: Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14: 2475-2483, 1997Google Scholar
  111. 111.
    Hirano A, Kawanami T, Llena JF: Electron microscopy of the blood-brain barrier in disease (Review). Microsc Res Tech 27: 543-556, 1994Google Scholar
  112. 112.
    Connolly DT: Vascular permeability factor: A unique regulator of blood vessel function. J Cell Biochem 47: 219-223, 1991Google Scholar
  113. 113.
    Criscuolo GR: The genesis of peritumoral vasogenic brain edema and tumor cysts, a hypothetical role for tumor-derived vascular permeability factor (Review). Yale J Biol Med 66: 277-314, 1993Google Scholar
  114. 114.
    Kalkanis SN, Carroll RS, Zhang J, Zamani AA, Black PM: Correlation of vascular endothelial growth factor messenger RNA expression with peritumoral vasogenic edema in meningiomas.Google Scholar
  115. 115.
    Goldman CK, Bharar S, Plamer Ca, Vitek J, Tsai JC, Weiss HL, Gillespie GY: Brain edema in meningiomas is associated with increased vascular endothelial growth factor expression. Neurosurgery 40: 1269-1277, 1997Google Scholar
  116. 116.
    Roberts WG, Palade GE: Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Science 108: 2369-2379, 1995Google Scholar
  117. 117.
    Roberts WG, Palade GE: Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res 57: 765-772, 1997Google Scholar
  118. 118.
    Monacci WT, Merrill MJ, Oldfield EH: Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264: C995-C1002, 1993Google Scholar
  119. 119.
    Breier G, Albrecht U, Sterrr S, Risau W: Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114: 521-532, 1992Google Scholar
  120. 120.
    Heiss JD, Papavassiliou E, Merill MJ, Niemann L, Knightly JJ, Walbridge S, Edwards NA, and Oldfield EH: Mechanism of dexamethasone suppression of brain tumor associated vascular permeability in rats. J Clin Invest 98: 1400-1408, 1996Google Scholar
  121. 121.
    Machein MR, Kullmer J, Rönicke V, Machein U, Krieg M, Damert A, Breier G, Risau R, Plate KH: Differential down-regulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropath Appl Neurobiol 25: 104-112, 1999Google Scholar
  122. 122.
    Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362: 841-844, 1993Google Scholar
  123. 123.
    Saleh M, Stacker SA, Wilks AF: Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 393: 393-401, 1996Google Scholar
  124. 124.
    Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579, 1994Google Scholar
  125. 125.
    Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM: Dominant-negative inhibitin of flk-1 suppresses the growth of many tumors in vivo. Cancer Res 56: 1615-1620, 1996Google Scholar
  126. 126.
    Machein MR, Risau W, Plate KH: Anti-angiogenic gene therapy in rat glioma model using a dominant-negative vascular endothelial growth factor receptor 2: Hum Gene Ther 10: 1117-1128, 1999Google Scholar
  127. 127.
    Lin P, Sankar S, Shan S, Dewhirst MW, Polverini PJ, Quinn TQ, Peters KG: Inhibition of tumor growth by targeting endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ 9: 49-58, 1998Google Scholar
  128. 128.
    Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Ievitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau R, Flamme I, Ulrich A, Hirth KP, Shawver LK: Flk-1 as a target for tumor growth inhibition. Cancer Res 56: 3540-3545, 1996Google Scholar
  129. 129.
    Kong HL, Hecht D, Song W, Kovesdi I, Hackett NR, Yayon A, Crystal RG: Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of flt-1 vascular endothelial growth factor receptor. Hum Gene Ther: 823-833, 1998Google Scholar
  130. 130.
    Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillepsie GY, Siegal GP, Mao X, Huckle WR, Thomas KA, Curiel DT: Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis and mortality rate. Proc Natl Acad Sci USA 95: 8795-8800, 1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Marcia Regina Machein
    • 1
  • Karl Heinz Plate
    • 2
  1. 1.Department of NeurosurgeryNeurocenter, Freiburg University Medical SchoolFreiburg
  2. 2.Department of NeuropathologyErlangen-Nürnberg University Medical SchoolErlangenGermany

Personalised recommendations