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 by injection of dyes, blood flow measurements by 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, as well as 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 delivery of vectors for gene therapy or encapsulated drug carriers in patients.
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Valtonen S, Timonen U, Toivanen P, Kalimo H, Kivipelto L, Heiskanen O, Unsgaard G, Kuurne T: Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41: 44-48, 1997
Nelson DF, Curran WJ Jr, Scott C, Nelson JS, Weinstein AS, Ahmad K, Constine LS, Murray K, Powlis WD, Mohiuddin M et al.: Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma-possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys 25: 193-207, 1993
Cox DJ, Pilkington GJ, Lantos PL: The fine structure of blood vessels in ethylnitrosourea-induced 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
Goldbrunner RH, Bernstein JJ, Tonn JC: Cell-extracellular matrix interaction in glioma invasion. Acta Neurochir (Wien) 141: 295-305, 1999
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
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
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 USA 95: 4607-4612, 1998
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
Jones DP: Hypoxia and drug metabolism. Biochem Pharmacol 30: 1019-1023, 1981
Jain RK: Transport of molecules in the tumor interstitium: a review. Cancer Res 47: 3039-3051, 1987
Jain RK: Determinants of tumor blood flow: a review. Cancer Res 48: 2641-2658, 1988
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
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
Plate KH, Risau W: Angiogenesis in malignant gliomas. Glia 15: 339-347, 1995
Brem S, Cotran R, Folkman J: Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48: 347-356, 1972
Wesseling P, van der Laak JA, de Leeuw H, Ruiter DJ, Burger PC: Computer-assisted analysis of the microvasculature in untreated glioblastomas. J Neuro-Oncol 24: 83-85, 1995
Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P: Grading of astrocytomas. A simple and reproducible method. Cancer 62: 2152-2165, 1988
Leon SP, Folkerth RD, Black PM: Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362-372, 1996
Schiffer D, Chio A, Giordana MT, Leone M, Soffietti R: Prognostic value of histologic factors in adult cerebral astrocytoma. Cancer 61: 1386-1393, 1988
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
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
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
Ekelund L, Jonsson N, Lunderquist A: Tumor vessels. Angiographic-histopathologic correlation. Radiologe 17: 95-102, 1977
Scatliff JH, Radcliffe WB, Pittman HH, Park CH: Vascular structures of glioblastoma. Am J Roentgenol 105: 795-805, 1969
Bernsen 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
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
Yamada K, Hayakawa T, Ushio Y, Arita N, Kato A, Mogami H: Regional blood flow and capillary permeability in the ethylnitrosourea-induced rat glioma. J Neurosurg 55: 922-928, 1981
Abramovitch R, Meir G, Neeman M: Neovascularization induced growth of implanted C6 glioma multicellular spheroids: magnetic resonance microimaging. Cancer Res 55: 1956-1962, 1995
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
Vajkoczy P, Ullrich A, Menger MD: Intravital fluorescence videomicroscopy to study tumor angiogenesis and microcirculation. Neoplasia (in press) 2000
Dvorak HF, Brown LF, Detmar M, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146: 1029-1039, 1995
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
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
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
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
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
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
Waggener JD, Beggs JL: Vasculature of neural neoplasms. Adv Neurol 15: 27-49, 1976
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
Shibata S: Ultrastructure of capillary walls in human brain tumors. Acta Neuropathol (Berl) 78: 561-571, 1989
Balabanov R, Dore-Duffy P: Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res 53: 637-644, 1998
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
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
Endrich B, Intaglietta M, Reinhold HS, Gross JF: Hemodynamic characteristics in microcirculatory blood channels during early tumor growth. Cancer Res 39: 17-23, 1979
Asaishi K, Endrich B, Gotz A, Messmer K: Quantitative analysis of microvascular structure and function in the amelanotic melanoma A-Mel-3. Cancer Res 41: 1898-1904, 1981
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
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
Heiss JD, Papavassiliou E, Merrill MJ, Nieman L, Knightly JJ, Walbridge S, Edwards NA, Oldfield EH: Mechanism of dexamethasone suppression of brain tumorassociated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest 98: 1400-1408, 1996
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
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
Guerin C, Wolff JE, Laterra J, Drewes LR, Brem H, Goldstein GW: Vascular differentiation and glucose transporter expression in rat gliomas: effects of steroids. Ann Neurol 31: 481-487, 1992
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
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 P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. Br J Cancer 76: 445-450, 1997
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
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
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
Hossman KA, Bloink M: Blood flow and regulation of blood flow in experimental peritumoral edema. Stroke 12: 211-217, 1981
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
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
Hardebo JE, Kahrstrom J, Salford LG: Lack of neural control and reactivity to vasoactive agents in malignant glioma arteries. J Neurosurg 74: 633-635, 1991
Panther LA, Baumbach GL, Bigner DD, Piegors D, Groothuis DR, Heistad DD: Vasoactive drugs produce selective changes in flow to experimental brain tumors. Ann Neurol 18: 712-715, 1985
Feinstein DL, Galea E, Roberts S, Berquist H, Wang H, Reis DJ: Induction of nitric oxide synthase in rat C6 glioma cells. J Neurochem 62: 315-321, 1994
Bakshi A, Nag TC, Wadhwa S, Mahapatra AK, Sarkar C: The expression of nitric oxide synthases in human brain tumours and peritumoral areas. J Neurol Sci 155: 196-203, 1998
Stiles JD, Ostrow PT, Balos LL, Greenberg SJ, Plunkett R, Grand W, Heffner RR Jr: Correlation of endothelin-1 and transforming growth factor beta 1 with malignancy and vascularity in human gliomas. J Neuropathol Exp Neurol 56: 435-439, 1997
Bearer EL, Orci L: Endothelial fenestral diaphragms: a quick-freeze, deep-etch study. J Cell Biol 100: 418-428, 1985
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
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
von Andrian UH, Arfors KE: Neutrophil-endothelial cell interactions in vivo: a chain of events characterized by distinct molecular mechanisms. Agents Actions Suppl 41: 153-164, 1993
Springer TA: Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57: 827-872, 1995
Menger MD, Vollmar B: Adhesion molecules as determinants of disease: from molecular biology to surgical research. Br J Surg 83: 588-601, 1996
Vajkoczy P, Schilling L, Schmiedek P, Menger MD: Glioma angiogenesis and vascularization: significance of leukocyte/edothelium-interaction. J Cerebr Blood Flow Metab 17 (Suppl 1): S179, 1997
Morioka T, Baba T, Black KL, Streit WJ: Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors. Neurosurgery 30: 891-896, 1992
Stokkel M, Stevens H, Taphoorn M, Van Rijk P: Differentiation between recurrent brain tumour and post-radiation necrosis: the value of 201Tl SPET versus 18F-FDG PET using a dual-headed coincidence camera-a pilot study. Nucl Med Commun 20: 411-417, 1999
Eary JF, Mankoff DA, Spence AM, Berger MS, Olshen A, Link JM, ÓSullivan F, Krohn KA: 2-[C-11]thymidine imaging of malignant brain tumors. Cancer Res 59: 615-621, 1999
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
Tedeschi G, Lundbom N, Raman R, Bonavita S, Duyn JH, Alger JR, Di Chiro G: Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 87: 516-524, 1997
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Vajkoczy, P., Menger, M.D. Vascular Microenvironment in Gliomas. J Neurooncol 50, 99–108 (2000). https://doi.org/10.1023/A:1006474832189
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DOI: https://doi.org/10.1023/A:1006474832189