Abstract
Angiogenesis is the outgrowth of new blood vessels from the preexistent vasculature. In 1971, Folkman hypothesized that solid tumors are dependent on angiogenesis for sustained growthand that anti-angiogenic treatment is a potential antineoplastictherapy. Because glioblastoma multiforma (GBM) frequently shows florid microvascular proliferation (MVP), this tumor has beenconsidered since then as a suitable candidate for such treatmentthat attempts to eradicate or control a neoplasm by interfering withits blood supply. Indeed, in animal models the growth of gliomaxenografts can be inhibited by targeting the angiogenic process.However, unlike many glioma xenografts, human infiltrating gliomassuch as GBMs have a diffuse infiltrative growth pattern, and preexistent vessels may suffice to provide many tumor cells with much of their blood supply, particularly in the critical peripheral infiltrative margins. Thus, while attractive in concept,anti-angiogenic therapy of GBM must address the anatomic vascularrealities of this neoplasm. Even if anti-angiogenic therapy ultimately has a role in infiltrative neoplasms, thereare a host of other intracranial neoplasms whose discrete architecture might make them attractive candidates for anti-angiogenic therapy. This review summarizes the angiogenic process in GBM and suggestsother types of tumors for which the efficacy of anti-angiogenic therapymight be studied.
Similar content being viewed by others
References
Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82: 4–6, 1990
Díaz Flores L, Gutiérrez R, Varela H: Angiogenesis: an update. Histol Histopathol 9: 807–843, 1994
Weidner N: Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol 147: 9–19, 1995
Folkman J: Clinical applications of research on angiogenesis. N Engl J Med 333: 1757–1763, 1995
Brem S, Cotran R, Folkman J: Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst 48: 347–356, 1972
Folkman J: Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175: 409–416, 1972
Brem SS, Zagzag D, Tsanaclis AMC, Gately S, Elkouby MP, Brien SE: Inhibition of angiogenesis and tumor growth in the brain; suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor. Am J Pathol 137: 1121–1142, 1990
Burger PC, Scheithauer BW: Tumors of the central nervous system. Atlas of Tumor Pathology, 3rd series, fascicle 10, Armed Forces Institute of Pathology, Washington DC, 1994
Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P: Grading of astrocytomas; a simple and reproducible method. Cancer 62: 2152–2165, 1988
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A: Glioblastoma growth inhibited in vivoby a dominant-negative Flk-1 mutant. Nature 367: 576–579, 1994
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, 1993
Takamiya Y, Brem H, Ojeifo J, Mineta T, Martuza RL: AGM-1470 inhibits the growth of human glioblastoma cells in vitroand in vivo. Neurosurgery 34: 869–875, 1994
Stan AC, Nemati MN, Pietsch T, Walter GF, Dietz H: In vivoinhibition of angiogenesis and growth of the human U-87 malignant glial tumor by treatment with an antibody against basic fibroblast growth factor. J Neurosurg 82: 1044–1052, 1995
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1: 27–31, 1995
Algire GH, Chalkley HW, Legallais FY, Park HD: Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6: 73–85, 1945
Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186, 1971
Ausprunk DH, Folkman J: Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14: 53–65, 1977
Senger DR: Molecular framework for angiogenesis; a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines. Am J Pathol 149: 1–7, 1996
Klagsbrun M, Dluz S: Smooth muscle cell and endothelial cell growth factors. Trends Cardiovasc Med 3: 213–217, 1993
Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxiainitiated angiogenesis. Nature 359: 843–845, 1992
Thomas KA: Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem 271: 603–606, 1996
Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991
Davis GE, Camarillo CW: Regulation of endothelial cell morphogenesis by integrins, mechanical forces, and matrix guidance pathways. Exp Cell Res 216: 113–123, 1995
Vernon RB, Sage EH: Between molecules and morphology; extracellular matrix and creation of vascular form. Am J Pathol 147: 873–883, 1995
Carey DJ: Control of growth and differentiation of vascular cells by extracellular matrix proteins. Annu Rev Physiol 53: 161–177, 1991
Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA: Definition of two angiogenic pathways by distinct ?v integrins. Science 270: 1500–1502, 1995
Mignatti P, Rifkin DB: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161–195, 1993
Schlingemann RO, Rietveld FJR, De Waal RMW, Ferrone S, Ruiter DJ: Expression of the high molecular weight melanoma-associated antigen by pericytes during angiogenesis in tumors and in healing wounds. Am J Pathol 136: 1393–1405, 1990
Schlingemann RO, Rietveld FJR, Kwaspen F, Van de Kerkhof PCM, De Waal RMW, Ruiter DJ: Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am J Pathol 138: 1335–1347, 1991
Haddad SF, Moore SA, Schelper RL, Goeken JA: Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme. J Neuropathol Exp Neurol 51: 488–492, 1992
Wesseling P, Vandersteenhoven JJ, Downey BT, Ruiter DJ, Burger PC: Cellular components of microvascular proliferation in human glial and metastatic neoplasms; a light microscopic and immunohistochemical study of formalin-fixed, routinely processed material. Acta Neuropathol 85: 508–514, 1993
Wesseling P, Schlingemann RO, Rietveld FJR, 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
Nehls V, Schuchardt E, Drenckhahn D: The effect of fibroblasts, vascular smooth muscle cells, and pericytes on sprout formation of endothelial cells in a fibrin gel angiogenesis system. Microvasc Res 48: 349–363, 1994
Nicosia RF, Villaschi S: Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro. Lab Invest 73: 658–666, 1995
Orlidge A, D'Amore PA: Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol 105: 1455–1462, 1987
Antonelli-Orlidge A, Saunders KB, Smith SR, D'Amore PA: An activated form of transforming growth factor ??is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci USA 86: 4544–4548, 1989
Sato Y, Rifkin DB: Inhibition of endothelial cell movement by pericytes and smooth muscle cells: Activation of a latent transforming growth factor-?1-like molecule by plasmin during co-culture. J Cell Biol 109: 309–315, 1989
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J, Yamamoto H: Possible participation of autocrine and paracrine vascular endothelial growth factors in hypoxia-induced proliferation of endothelial cells and pericytes. J Biol Chem 270: 28316–28324, 1995
Skalli O, Pelte MF, Peclet MC, Gabbiani G, Gugliotta P, Bussolati G, Ravazzola M, Orci L: ?-Smooth muscle actin, a differentiation marker of smooth muscle cells, is present in microfilamentous bundles of pericytes. J Histochem Cytochem 37: 315–321, 1989
Verbeek MM, Otte-Höller I, Wesseling P, Ruiter DJ, De Waal RMW: Induction of ?-smooth muscle actin expression in cultured human brain pericytes by transforming growth factor-?1. Am J Pathol 144: 372–382, 1994
Schlingemann RO, Oosterwijk E, Wesseling P, Rietveld FJR, Ruiter DJ: Aminopeptidase-A is a constituent of activated pericytes in angiogenesis. J Pathol 179: 436–442, 1996
Kleihues P, Burger PC, Scheithauer BW: Histological typing of tumours of the central nervous system. 2nd Ed. Springer Verlag, Berlin, 1993
Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3: 255–268, 1993
Aho R, Ekfors T, Haltia M, Kalimo H: Pathogenesis of primary central nervous system lymphoma: invasion of malignant lymphoid cells into and within the brain parenchyme. Acta Neuropathol 86: 71–76, 1993
Scherer H: The forms of growth in gliomas and their practical significance. Brain 63: 1–35, 1940
Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66: 865–874, 1987
Burger PC, Heinz ER, Shibata T, Kleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68: 698–704, 1988
Watanabe M, Tanaka R, Takeda N: Magnetic resonance imaging and histopathology of cerebral gliomas. Neuroradiol 34: 463–469, 1992
Tovi M: MR imaging in cerebral gliomas; analysis of tumour tissue components. Acta Radiol 384: 1–24, 1993
Friedlander DR, Zagzag D, Shiff B, Cohen H, Allen JC, Kelly PJ, Grumet M: Migration of brain tumor cells on extracellular matrix proteins in vitrocorrelates with tumor type and grade and involves ?v and ?1 integrins. Cancer Res 56: 1939–1947, 1996
Rutka JT, Apodaca G, Stern R, Rosenblum M: The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69: 155–170, 1988
Pilkington GJ: Tumour cell migration in the central nervous system. Brain Pathol 4: 157–166, 1994
Frank S, Rihs H, Stöcker W, Müller J, Dumont B, Baur X, Schackert HK, Schackert G: Combined detection of CD44 isoforms by exon-specific RT-PCR and immunohistochemistry in primary human brain tumors and brain metastases. Biochem Biophys Res Comm 222: 794–801, 1996
Ariza A, López D, Mate JL, Isamat M, Musulén E, Pujol M, Ley A, Navas-Palacios JJ: Role of CD44 in the invasiveness of glioblastoma multiforme and the noninvasiveness of meningioma: an immunohistochemistry study. Hum Pathol 26: 1144–1147, 1995
Tooth HH: Some observations on the growth and survival-period of intracranial tumours, based on the records of 500 cases, with special reference to the pathology of the gliomata. Brain 35: 61–108, 1912
Gaudin PB, Rosai J: Florid vascular proliferation associated with neural and neuroendocrine neoplasms; a diagnostic clue and potential pitfall. Am J Surg Pathol 19: 642–652, 1995
Barker II FG, Davis RL, Chang SM, Prados MD: Necrosis as a prognostic factor in glioblastoma multiforme. Cancer 77: 1161–1166, 1996
Burger PC, Scheithauer BW, Vogel FS: Surgical pathology of the nervous system and its coverings. 3rd Ed. Churchill Livingstone Inc., New York, 1991
Feigin I, Allen LB, Lipkin L, Gross SW: The endothelial hyperplasia of the cerebral blood vessels with brain tumors, and its sarcomatous transformation. Cancer 11: 264–277, 1958
McComb RD, Bigner DD: The biology of malignant gliomas–a comprehensive survey. Clin Neuropathol 3: 93–106, 1984
Rønnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ: The origin of th myofibroblasts in breast cancer; recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95: 859–873, 1995
Rønnov-Jessen L, Petersen OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 76: 69–125, 1996
Haddad SF, Moore SA, Schelper RL, Goeken JA: Smooth muscle can comprise the sarcomatous component of gliosarcomas. J Neuropathol Exp Neurol 51: 493–498, 1992
Paulus W, Bayas A, Ott G, Roggendorf W: Interphase cytogenetics of glioblastoma and gliosarcoma. Acta Neuropathol 88: 420–425, 1994
Biernat W, Aguzzi A, Sure U, Grant JW, Kleihues P, Hegi ME: Identical mutations of the p53 tumor suppressor gene in the gliomatous and the sarcomatous components of gliosarcomas suggest a common origin from glial cells. J Neuropathol Exp Neurol 54: 651–656, 1995
Plate KH, Breier G, Risau W: Molecular mechanisms of developmental and tumor angiogenesis. Brain Pathol 4: 207–218, 1994
Zagzag D: Angiogenic growth factors in neural embryogenesis and neoplasia. Am J Pathol 146: 293–309, 1995
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 vivoregulatory mechanisms. Int J Cancer 59: 520–529, 1994
Hatva E, Böhling T, Jääskeläinen J, Persico MG, Haltia M, Alitalo K: Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 148: 763–775, 1996
Böhling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M: Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol 55: 522–527, 1996
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
Sundberg C, Ljungström M, Lindmark G, Gerdin B, Rubin K: Microvascular pericytes express platelet-derived growth factor-??receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol 143: 1377–1388, 1993
Weller RO, Davis BE, Wilson POG, Mitchell J: Capillary proliferation in cerebral infarction, gliomas, angioblastic meningiomas, and hemangioblastomas. In: Cervós-Navarro J, Fritschka E (eds) Cerebral Microcirculation and Metabolism. Raven Press, New York 41–48, 1981
Luthert PJ, Lantos PL: A morphometric study of the microvasculature of a rat glioma. Neuropathol Appl Neurobiol 11: 461–473, 1985
Kepes JJ; Vascular proliferation. Am J Surg Pathol 20: 384–386, 1996 (Letter)
Paulus W, Bauer I, Schuppan D, Roggendorf W: Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 143: 154–163, 1993
Gladson CL, Cheresh DA: Glioblastoma expression of vitronectin and the ?v?3 integrin; adhesion mechanism for transformed glial cells. J Clin Invest 88: 1924–1932, 1991
Gingras MC, Roussel E, Bruner JM, Branch CD, Moser RP: Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologus normal brain tissue. J Neuroimmunol 57: 143–153, 1995
Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K, Rao VH, Tomonaga M, Nicolson GL, Rao JS: Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo. Cancer Res 54: 3656–3661, 1994
Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicolson GL, Rao JS: Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 54: 5015–5020, 1994
Sivaparvathi M, Sawaya R, Wang SW, Rayford A, Yamamoto M, Liotta LA, Nicolson GL, Rao JS: Overexpression and localization of cathepsin B during the progression of human gliomas. Clin Exp Metastasis 13: 49–56, 1995
Mikkelsen T, Yan P, Ho K, Sameni M, Sloane BF, Rosenblum ML: Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J Neurosurg 83: 285–290, 1995
Seitz RJ, Wechsler W: Vascularization in human cerebral gliomas: a lectin-cytochemical and morphometric study. In: Walker MD, Thomas DGT (eds) Biology of Brain Tumour. Martinus Nijhoff Publishers, Boston 131–137, 1986
Wesseling P, Van der Laak JAWM, De Leeuw H, Ruiter DJ, Burger PC: Quantitative immunohistological analysis of the microvasculature in untreated human glioblastoma multiforme; computer-assisted image analysis on whole tumor sections. J Neurosurg 81: 902–909, 1994
Wesseling P, Van der Laak JAWM, Link M, Methorst AJ, Teepen HLJM, Ruiter DJ: Quantitative analysis of microvascular changes during malignant progression in astrocytic neoplasms. J Neuropathol Exp Neurol 55: 607, 1996 (Abstract)
Chintala SK, Sawaya R, Gokaslan ZL, Fuller G, Rao JS: Immunohistochemical localization of extracellular matrix proteins in human glioma, both in vivoand in vitro. Cancer Lett 101: 107–114, 1996
Higuchi M, Ohnishi T, Arita N, Hiraga S, Hayakawa T: Expression of tenascin in human gliomas: its relation to histological malignancy, tumor dedifferentiation and angiogenesis. Acta Neuropathol 85: 481–487, 1993
Zagzag D, Friedlander DR, Miller DC, Dosik J, Cangiarella J, Kostianovsky M, Cohen H, Grumet M, Greco MA: Tenascin expression in astrocytomas correlates with angiogenesis. Cancer Res 55: 907–914, 1995
Saitoh Y, Kuratsu J, Takeshima H, Yamamoto S, Ushio Y: Expression of osteopontin in human glioma; its correlation with the malignancy. Lab Invest 72: 55–63, 1995
Thompson WD, Shiach KJ, Fraser RA, McIntosh LC, Simpson JG: Tumours acquire their vasculature by vessel incorporation, not vessel ingrowth. J Pathol 151: 323–332, 1987
Leon SP, Folkerth RD, Black PM: Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372, 1996
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: 82–86, 1994
Schiffer D, Chiò A, Giordana MT, Mauro A, Migheli A, Vigliani MC: The vascular response to tumor infiltration in malignant gliomas; morphometric and reconstruction study. Acta Neuropathol 77: 369–378, 1989
Jain RK: Determinants of tumor blood flow: a review. Cancer Res 48: 2641–2658, 1988
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: 121–133, 1993
Schiffer D: Blood vessel architecture and angiogenesis in gliomas. In: Schiffer D (ed) Brain Tumors; Pathology and its Biological Correlates. Springer Verlag, Berlin 148–152, 1993
Bernsen HJJA, Rijken PFJW, 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
Huang P, Allam A, Taghian A, Freeman J, Duffy M, Suit HD: Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. J Neurosurg 83: 308–315, 1995
Lund-Johansen M, Engebraaten O, Bjerkvig R, Laerum OD: Invasive glioma cells in tissue culture. Anticancer Res 10: 1135–1151, 1990
Li H, Hamou M, De Tribolet N, Jaufeerally R, Hofmann M, Diserens AC, Van Meir EG: Variant CD44 adhesion molecules are expressed in human brain metastases but not in glioblastomas. Cancer Res 53: 5345–5349, 1993
Martin K, Akinwunmi J, Rooprai HK, Kennedy AJ, Linke A, Ognjenovic N, Pilkington GJ: Nonexpression of CD15 by neoplastic glia: a barrier to metastasis? Anticancer Res 15: 1159–1165, 1995
Holmgren L, O'Reilly MS, Folkman J: Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1: 149–153, 1995
Denekamp J: Endothelial cell proliferation as a novel approach to targeting tumour therapy. Br J Cancer 45: 136–139, 1982
Auerbach W, Auerbach R: Angiogenesis inhibition: a review. Pharmac Ther 63: 265–311, 1994
Baillie CT, Winslet MC, Bradley NJ: Tumour vasculature–a potential therapeutic target. Br J Cancer 72: 257–267, 1995
Criscuolo GR: The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66: 277–314, 1993
Plate KH, Mennel HD: Vascular morphology and angiogenesis in glial tumors. Exp Toxic Pathol 47: 89–94, 1995
Bernstein JJ, Goldberg WJ, Laws Jr ER: Human malignant astrocytoma xenografts migrate in rat brain: a model for central nervous system cancer research. J Neurosci Res 22: 134–143, 1989
Pedersen PH, Marienhagen K, Mørk S, Bjerkvig R: Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain. Cancer Res 53: 5158–5165, 1993
Nieuwenhuys R, Voogd J, Van Huijzen C: The human central nervous system; a synopsis and atlas. 3rd Ed. Springer-Verlag, Berlin, 1988
Burger PC, Kleihues P: Cytologic composition of the untreated glioblastoma with implications for evaluation of needle biopsies. Cancer 63: 2014–2023, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wesseling, P., Ruiter, D.J. & Burger, P.C. Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neurooncol 32, 253–265 (1997). https://doi.org/10.1023/A:1005746320099
Issue Date:
DOI: https://doi.org/10.1023/A:1005746320099