Skip to main content
SpringerLink
Log in

Vascular Microenvironment in Gliomas

  • Chapter
Angiogenesis in Brain Tumors

Part of the book series: Cancer Treatment and Research ((CTAR,volume 117))

Abstract

Structural and functional abnormalities of the vascular microenvironment determine pathophysiological characteristics of gliomas, such as loss of blood-brain barrier function, tumor cell invasiveness, or permselectivity for large molecules. Moreover, the effectiveness of various therapeutic strategies critically depends upon the successful transvascular delivery of molecules. In order to shed more light on the vascular microenvironment in gliomas, a variety of experimental and clinical techniques have been applied to study the glioma microvasculature, including histology, vascular corrosion casts, microangiography, autoradiography, tracer washout techniques, magnetic resonance imaging, as well as intravital fluorescence microscopy. This review summarizes the characteristic features of vascular morphology, angio-architecture, tumor perfusion, microvascular permeability, and microvessel-related immunological competence in gliomas. An improved understanding of the vascular microenvironment in gliomas will help in the future to optimize glioma imaging and to improve delivery of vectors for gene therapy or encapsulated drug carriers for pharmacotherapy in patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cox DJ, Pilkington GJ, Lantos PL: The fine structure of blood vessels in ethylnitrosoureainduced tumours of the rat nervous system: with special reference to the breakdown of the blood-brain barrier. Br J Exp Pathol 57: 419–430, 1976.

    PubMed  CAS  Google Scholar 

  2. Vajkoczy P, Goldbrunner R, Farhadi M, Vince G, Schilling L, Tonn JC, Schmiedek P, Menger MD: Glioma cell migration is associated with glioma-induced angiogenesis in vivo. Int J Dev Neurosci 17: 557–563, 1999.

    Article  PubMed  CAS  Google Scholar 

  3. Schlageter KE, Molnar P, Lapin GD, Groothuis DR: Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties. Microvasc Res 58: 312–328, 1999.

    Article  PubMed  CAS  Google Scholar 

  4. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK: Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 95: 4607–4612, 1998.

    Article  PubMed  CAS  Google Scholar 

  5. Bedford JS, Mitchell JB: The effect of hypoxia on the growth and radiation response of mammalian cells in culture. Br J Radiol 47: 687–696, 1974.

    Article  PubMed  CAS  Google Scholar 

  6. Jones DP: Hypoxia and drug metabolism. Biochem Pharmacol 30: 1019–1023, 1981.

    Article  PubMed  CAS  Google Scholar 

  7. Jain RK: Transport of molecules in the tumor interstitium: a review. Cancer Res 47: 3039–3051, 1987.

    PubMed  CAS  Google Scholar 

  8. Jain RK: Determinants of tumor blood flow: a review. Cancer Res 48: 2641–2658, 1988.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Rainov NG, Ikeda K, Qureshi NH, Grover S, Herrlinger U, Pechan P, Chiocca EA, Breakefield XO, Barnett FH: Intraarterial delivery of adenovirus vectors and liposome-DNA complexes to experimental brain neoplasms. Hum Gene Ther 10: 311–318, 1999.

    Article  PubMed  CAS  Google Scholar 

  11. Plate KH, Risau W: Angiogenesis in malignant gliomas. Glia 15: 339–347, 1995.

    Article  PubMed  CAS  Google Scholar 

  12. Brem S, Cotran R, Folkman J: Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48: 347–356, 1972.

    PubMed  CAS  Google Scholar 

  13. Wesseling P, van der Laak JA, de Leeuw H, Ruiter DJ, Burger PC: Computer-assisted analysis of the microvasculature in untreated glioblastomas. J Neurooncol 24: 83–85, 1995.

    Article  PubMed  CAS  Google Scholar 

  14. Daumas-Duport C, Scheithauer B, O’Fallon J, Kelly P: Grading of astrocytomas. A simple and reproducible method. Cancer 62: 2152–2165, 1988.

    Article  PubMed  CAS  Google Scholar 

  15. Leon SP, Folkerth RD, Black PM: Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372, 1996.

    Article  PubMed  CAS  Google Scholar 

  16. Schiffer D, Chio A, Giordana MT, Leone M, Soffietti R: Prognostic value of histologic factors in adult cerebral astrocytoma. Cancer 61: 1386–1393, 1988.

    Article  PubMed  CAS  Google Scholar 

  17. Zama A, Tamura M, Inoue HK: Three-dimensional observations on microvascular growth in rat glioma using a vascular casting method. J Cancer Res Clin Oncol 117: 396–402, 1991.

    Article  PubMed  CAS  Google Scholar 

  18. Orita T, Nishizaki T, Kamiryo T, Aoki H, Harada K, Okamura T: The microvascular architecture of human malignant glioma. A scanning electron microscopic study of a vascular cast. Acta Neuropathol (Berl) 76: 270–274, 1988.

    Article  CAS  Google Scholar 

  19. Stewart PA, Farrell CL, Del Maestro RF: The effect of cellular microenvironment on vessels in the brain. Part 1: Vessel structure in tumour, peritumour and brain from humans with malignant glioma. Int J Radiat Biol 60: 125–130, 1991.

    Article  PubMed  CAS  Google Scholar 

  20. Scatliff JH, Radcliffe WB, Pittman HH, Park CH: Vascular structures of glioblastoma. Am J Roentgenol 105: 795–805, 1969.

    Article  CAS  Google Scholar 

  21. Bemsen HJ, Rijken PF, Oostendorp T, van der Kogel AJ: Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. Br J Cancer 71: 721–726, 1995.

    Article  Google Scholar 

  22. Whittle IR, Collins F, Kelly PA, Ritchie I, Ironside JW: Nitric oxide synthase is expressed in experimental malignant glioma and influences tumour blood flow. Acta Neurochir (Wien) 138: 870–875, 1996

    Article  CAS  Google Scholar 

  23. Abramovitch R, Meir G, Neeman M: Neovascularization induced growth of implanted C6.glioma multicellular spheroids: magnetic resonance microimaging. Cancer Res 55: 1956–1962, 1995.

    Google Scholar 

  24. 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, 1999.

    Article  PubMed  CAS  Google Scholar 

  25. Vajkoczy P, Schilling L, Ullrich A, Schmiedek P, Menger MD: Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse. J Cereb Blood Flow Metab 18: 510–520, 1998.

    Article  PubMed  CAS  Google Scholar 

  26. Patan S, Munn LL, Jain RK: Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc Res 51: 260–272, 1996.

    Article  PubMed  CAS  Google Scholar 

  27. 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: 1994–1998, 1999.

    Article  PubMed  CAS  Google Scholar 

  28. Vajkoczy P, Farhadi M, Gaumann A, Heidenreich R, Erber R, Wunder A, Tonn JC, Menger MD, Breier G: Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest 109: 777–785., 2002.

    PubMed  CAS  Google Scholar 

  29. Stewart PA, Hayakawa K, Hayakawa E, Farrell CL, Del Maestro RF: A quantitative study of blood-brain barrier permeability ultrastructure in a new rat glioma model. Acta Neuropathol (Berl) 67: 96–102, 1985.

    Article  CAS  Google Scholar 

  30. Vick NA, Bigner DD: Microvascular abnormalities in virally-induced canine brain tumors. Structural bases for altered blood-brain barrier function. J Neurol Sci 17: 29–39, 1972.

    Article  PubMed  CAS  Google Scholar 

  31. Waggener JD, Beggs JL: Vasculature of Neural Neoplasms. Adv Neurol 15: 27–49, 1976.

    PubMed  CAS  Google Scholar 

  32. Deane BR, Lantos PL: The vasculature of experimental brain tumours. Part 2. A quantitative assessment of morphological abnormalities. J Neurol Sci 49: 67–77, 1981.

    Article  PubMed  CAS  Google Scholar 

  33. Balabanov R, Dore-Duffy P: Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res 53: 637–644, 1998.

    Article  PubMed  CAS  Google Scholar 

  34. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E: Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103: 159–165, 1999.

    Article  PubMed  CAS  Google Scholar 

  35. Wesseling P, Schlingemann RO, Rietveld 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: 304–310, 1995.

    Article  PubMed  CAS  Google Scholar 

  36. Vajkoczy P, Menger MD: Vascular microenvironment in gliomas. J Neurooncol 50: 99–108, 2000.

    Google Scholar 

  37. Vajkoczy P, Menger MD, Vollmar B, Schilling L, Schmiedek P, Hirth KP, Ullrich A, Fong TAT: Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy. Neoplasia 1:31–41, 1999.

    Article  PubMed  CAS  Google Scholar 

  38. Asaishi K, Endrich B, Gotz A, Messmer K: Quantitative analysis of microvascular structure and function in the amelanotic melanoma A-Me1–3. Cancer Res 41: 1–3, 1981.

    PubMed  CAS  Google Scholar 

  39. Hatva E, Kaipainen 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, 1995.

    PubMed  CAS  Google Scholar 

  40. Deane BR, Lantos PL: The vasculature of experimental brain tumours. Part 1. A sequential light and electron microscope study of angiogenesis. J Neurol Sci 49: 55–66, 1981.

    Article  PubMed  CAS  Google Scholar 

  41. Heiss JD, Papavassiliou E, Merrill MJ, Nieman L, Knightly JJ, Walbridge S, Edwards NA, Oldfield EH: Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest 98: 1400–1408, 1996.

    Article  PubMed  CAS  Google Scholar 

  42. Machein MR, Kullmer J, Ronicke V, Machein U, Krieg M, Damert A, Breier G, Risau W, Plate KH: Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol 25: 104–112, 1999.

    Article  PubMed  CAS  Google Scholar 

  43. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT: Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246: 1309–1312, 1989.

    Article  PubMed  CAS  Google Scholar 

  44. Jones N, Iljin K, Dumont DJ, Alitalo K: Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2: 257–267, 2001.

    Article  PubMed  CAS  Google Scholar 

  45. Guerin C, Laterra J, Hruban RH, Brem H, Drewes LR, Goldstein GW: The glucose transporter and blood-brain barrier of human brain tumors. Ann Neurol 28: 758–765, 1990.

    Article  PubMed  CAS  Google Scholar 

  46. Takamiya Y, Abe Y, Tanaka Y, Tsugu A, Kazuno M, Oshika Y, Maruo K, Ohnishi Y, Sato O, Yamazaki H, Kijima H, Ueyama Y, Tamaoki N, Nakamura M: Murine Pglycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. Br J Cancer 76: 445–450, 1997.

    Article  PubMed  CAS  Google Scholar 

  47. Isaka T, Yoshimine T, Maruno M, Kuroda R, Ishii H, Hayakawa T: Altered expression of antithrombotic molecules in human glioma vessels. Acta Neuropathol (Berl) 87: 81–85, 1994.

    Article  CAS  Google Scholar 

  48. Blasberg RG, Kobayashi T, Horowitz M, Rice JM, Groothuis D, Molnar P, Fenstermacher JD: Regional blood flow in ethylnitrosourea-induced brain tumors. Ann Neurol 14: 189–201, 1983.

    Article  PubMed  CAS  Google Scholar 

  49. Groothuis DR, Pasternak JF, Fischer JM, Blasberg RG, Bigner DD, Vick NA: Regional measurements of blood flow in experimental RG-2 rat gliomas. Cancer Res 43: 3362–3367, 1983.

    PubMed  CAS  Google Scholar 

  50. Hossman KA, Bloink M: Blood flow and regulation of blood flow in experimental peritumoral edema. Stroke 12: 211–217, 1981.

    Article  PubMed  CAS  Google Scholar 

  51. Baish JW, Gazit Y, Berk DA, Nozue M, Baxter LT, Jain RK: Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. Microvasc Res 51: 327–346, 1996.

    Article  PubMed  CAS  Google Scholar 

  52. Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RF, Jain RK: Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res 54: 4564–4568, 1994.

    PubMed  CAS  Google Scholar 

  53. 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: 10–18., 1999.

    Article  PubMed  CAS  Google Scholar 

  54. Bearer EL, Orci L: Endothelial fenestral diaphragms: a quick-freeze, deep-etch study. J Cell Biol 100: 418–428, 1985.

    Article  PubMed  CAS  Google Scholar 

  55. Kohn S, Nagy JA, Dvorak HF, Dvorak AM: Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest 67: 596–607, 1992.

    PubMed  CAS  Google Scholar 

  56. Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM: Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 183: 1981–1986, 1996.

    Article  PubMed  CAS  Google Scholar 

  57. Papadopoulos MC, Saadoun S, Davies DC, Bell BA: Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15: 101–108., 2001.

    Article  PubMed  CAS  Google Scholar 

  58. Papadopoulos MC, Saadoun S, Woodrow CJ, Davies DC, Costa-Martins P, Moss RF, Krishna S,Bell BA: Occludin expression in microvessels of neoplastic and non-neoplastic human brain. Neuropathol Appl Neurobiol 27: 384–395., 2001.

    Article  PubMed  CAS  Google Scholar 

  59. Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H,Wolburg H: Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol (Berl) 100: 323–331., 2000.

    Article  CAS  Google Scholar 

  60. Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA: Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry 72: 262265., 2002.

    Article  CAS  Google Scholar 

  61. Edelman RR, Mattle HP, Atkinson DJ, Hill T, Finn JP, Mayman C, Ronthal M, Hoogewoud HM, Kleefield J: Cerebral blood flow: assessment with dynamic contrast-enhanced T2*-weighted MR imaging at 1.5 T. Radiology 176: 211–220., 1990.

    PubMed  CAS  Google Scholar 

  62. Roberts HC, Roberts TP, Brasch RC, Dillon WP: Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am J Neuroradiol 21: 891–899., 2000.

    PubMed  CAS  Google Scholar 

  63. Jackson A, Kassner A, Annesley-Williams D, Reid H, Zhu XP, Li KL: Abnormalities in the recirculation phase of contrast agent bolus passage in cerebral gliomas. comparison with relative blood volume and tumor grade. AJNR Am J Neuroradiol 23: 7–14., 2002.

    PubMed  Google Scholar 

  64. Stokkel M, Stevens H, Taphoorn M, Van Rijk P: Differentiation between recurrent brain tumour and post-radiation necrosis: the value of 201T1 SPET versus 18F-FDG PET using a dual-headed coincidence camera--a pilot study. Nucl Med Commun 20: 411–417, 1999.

    Article  PubMed  CAS  Google Scholar 

  65. Eary JF, Mankoff DA, Spence AM, Berger MS, Olshen A, Link JM, O’Sullivan F, Krohn KA: 2-(C-I1)thymidine imaging of malignant brain tumors. Cancer Res 59: 615–621, 1999.

    PubMed  CAS  Google Scholar 

  66. Nelson SJ, Vigneron DB, Dillon WP: Serial evaluation of patients with brain tumors using volume MRI and 3D 1H MRSI. NMR Biomed 12: 123–138, 1999.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, D-68167, Mannheim, Germany

    Peter Vajkoczy

  2. Institute for Clinical and Experimental Surgery, University of Saarland, D-66421, Homburg/Saar, Germany

    Michael D. Menger

Authors
  1. Peter Vajkoczy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael D. Menger
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Neurosurgery Carl Gustav Carus Hospital, Technical University of Dresden, Dresden, Germany

    Matthias Kirsch

  2. Neurosurgery Children’s Hospital Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter McL. Black

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Vajkoczy, P., Menger, M.D. (2004). Vascular Microenvironment in Gliomas. In: Kirsch, M., Black, P.M. (eds) Angiogenesis in Brain Tumors. Cancer Treatment and Research, vol 117. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8871-3_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-8871-3_15

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4699-9

  • Online ISBN: 978-1-4419-8871-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation