Abstract
Angiogenesis, the formation of new blood vessels, is required for the growth and expansion of tumours. Gliomas, the most common brain tumours, are particularly highly vascularized and, therefore, serve as a model to elucidate the process of tumour angiogenesis and to investigate new anti-angiogenic therapies. This review describes the role of angiogenic factors in glioma angiogenesis and new strategies to inhibit glioma growth by application of anti-angiogenic substances. We focus on vascular endothelial growth factor (VEGF), but also examine the role of angiopoietin and pleiotropic factors such as platelet-derived growth factor (PDGF), pleiotrophin and transforming growth factor-β (TFG-β). Strategies to inhibit glioma growth by reducing the action of angiogenic factors, by the application of anti-angiogenic substances such as angiostatin or endostatin, or inactivation of endothelial cells, are discussed. These new anti-angiogenic therapies appear to have a high potential not only for the treatment of gliomas, but also of other tumours.
Similar content being viewed by others
References
Albini A, Florio T, Giunciuglio D, Masiello L, Carlone S, Corsaro A, Thellung S, Cai T, Noonan DM, Schettini G (1999) Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis. FASEB J 13:647–655
Bates DO, Hillman NJ, Williams B, Neal CR, Pocock TM (2002) Regulation of microvascular permeability by vascular endothelial growth factors. J Anat 200:581–597
Bjerkvig R, Lund-Johansen M, Edvardsen K (1997) Tumor cell invasion and angiogenesis in the central nervous system. Curr Opin Oncol 9:223–229
Boehm T, Folkman J, Browder T, O'Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407
Bögler O, Huang HJS, Kleihues P, Cavenee WK (1995) The p53 gene and its role in human brain tumours. Glia 15:308–237
Breier G, Blum S, Peli J, Groot M, Wild C, Risau W, Reichmann E (2002) Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis. Int J Cancer 97:142–148
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257
Chaudhry IH, O'Donovan DG, Brenchley PE, Reid H, Roberts IS (2001) Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 39:409–415
Cheng S-Y, Huang HJ, Nagane M, Ji XD, Wang D, Shih CC, Arap W, Huang CM, Cavenee WK (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 93:8502–8507
Conn G, Soderman DD, Schaeffer MT, Wile M, Hatcher VB, Thomas KA (1990) Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci USA 87:1323–1327
Criscuolo GR, Merrill MJ, Oldfield EH (1998) Further characterization of malignant glioma-derived vascular permeability factor. J Neurosurg 69:254–262
Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584
Davies DC (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646
Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI (1994) P53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76:1013–1023
Dunn IF, Heese O, Black PM (2000) Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J Neuro-Oncol 50:121–137
Ferrara N (1999) Molecular and biological properties of vascular endothelial growth factor. J Mol Med 77:527–543
Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25
Flaumenhaft R, Kojima S, Abe M, Rifkin DB (1993) Activation of latent transforming growth factor beta. Adv Pharmacol 24:51–76
Folkman J (1996) Fighting cancer by attacking its blood supply. Sci Am September:150–154
Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934
Forstreuter F, Lucius R, Mentlein R (2002) Vascular endothelial growth factor (VEGF) induces chemotaxis and proliferation of microglial cells. J Neuroimmunol 132:93–98
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613
Funari FB, Huang HS, Cavenee WK (1995) Genetics and malignant progression of human brain tumours. Cancer Surv 25:233–275
Goldman E (1907) The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 2:1236–1240
Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C, Perricaudet M, Yeh P, Lu H (1998) Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci USA 95:6367–6372
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, Costa LT da, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353
Harada H, Nakagawa K, Iwata S, Saito M, Kumon Y, Sakaki S, Sato K, Hamada K (1999) Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas. Cancer Res 59:3783–3789
Held-Feindt J, Lütjohann B, Ungefroren H, Mehdorn HM, Mentlein R (2003) Interaction of transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) in human glioma cells. J Neuro-Oncol 63:117–127
Herold-Mende C, Steiner HH, Andl T, Riede D, Buttler A, Reisser C, Fusenig NE, Mueller MM (1999) Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells. Lab Invest 79:1573–1582
Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE (1999) A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon alpha. Proc Natl Acad Sci USA 96:1553–1558
Hunter T (1997) Oncoprotein networks. Cell 88:333–346
Izumoto S, Arita N, Ohnishi T, Hiraga S, Taki T, Tomita N, Ohue M, Hayakawa T (1997) Microsatellite instability and mutated type II transforming growth factor-beta receptor gene in gliomas. Cancer Lett 112:251–256
Jennings MT, Maciunas RJ, Carver R, Bascom CC, Juneau P, Misulis K, Moses HL (1991) TGF beta 1 and TGF beta 2 are potential growth regulators for low-grade and malignant gliomas in vitro: evidence in support of an autocrine hypothesis. Int J Cancer 49:129–139
Joe YA, Hong YK, Chung DS, Yang YJ, Kang JK, Lee YS, Chang SI, You WK, Lee H, Chung SI (1999) Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1–3. Int J Cancer 82:694–699
Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312
Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739
Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659
Kleihues P, Cavenee W (2000) Tumors of the nervous system: pathology and genetics, 2nd edn. International Agency for Research on Cancer, Lyon, France
Kleihues P, Ohgaki H, Aguzzi A (1996) Gliomas. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, Oxford, pp 1044–1063
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844
Letterino JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309
Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333–13340
Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271:2746–2753
Libermann TA, Friesel R, Jaye M, Lyall RM, Westermark B, Drohan W, Schmidt A, Maciag T, Schlessinger J (1987) An angiogenic growth factor is expressed in human glioma cells. EMBO J 6:1627–1632
Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100:323–331
Massagué J (1998) TGF-β signal transduction. Annu Rev Biochem 67:753–791
Mentlein R, Held-Feindt J (2002) Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas. J Neurochem 83:747–753
Mentlein R, Eichler O, Forstreuter F, Held-Feindt J (2001) Somatostatin inhibits the production of vascular endothelial growth factor (VEGF) in glioma cells. Int J Cancer 92:545–550
Merzak A, McCrea S, Koocheckpour S, Pilkington GJ (1994) Control of human glioma cell growth, migration, and invasion in vitro by transforming growth factor-beta 1. Br J Cancer 70:199–203
Miyazono K, Ichijo H, Heldin CH (1993) Transforming growth factor-beta: latent forms, binding proteins and receptors. Growth Factors 8:11–22
Morimoto T, Aoyagi M, Tamaki M, Yoshino Y, Hori H, Duan L, Yano T, Shibata M, Ohno K, Hirakawa K, Yamaguchi N (2002) Increased levels of tissue endostatin in human malignant gliomas. Clin Cancer Res 8:2933–2938
Nagane M, Huang HJ, Cavenee WK (1997) Advances in the molecular genetics of gliomas. Curr Opin Oncol 9:215–222
Neufeld G, Cohen T, Gengrinovitch S, Poltrak Z (1999) Vascular endothelial growth factor and its receptors. FASEB J 13: 9–22
O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328
O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285
Papadopoulos MC, Saadoun S, Davies DC, Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15:101–108
Pelton RW, Saxena B, Jones M, Moses HL, Gold LI (1991) Immunohistochemical localization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol 115:1091–1105
Piek E, Westermark U, Kastemar M, Heldin CH, Zoelen EJ van, Nister M, Dijke P ten (1999) Expression of transforming growth factor T(TGF)-beta receptors and Smad proteins in glioblastoma cell lines with distinct responses to TGF-beta 1. Int J Cancer 80:756–763
Plate KH, Risau W (1995) Angiogenesis in malignant gliomas. Glia 15:339–347
Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848
Pore N, Liu S, Haas-Kogan DA, O'Rourke DM, Maity A (2003) PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 63:236–241
Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (2002) Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J Biol Chem 277:14153–14158
Pufe T, Petersen W, Tillmann B, Mentlein R (2001) The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum 44:1082–1088
Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R (2003a) Pleiotrophin, an embryonic growth and differentiation factor, is expressed in rheumatoid arthritis. Arthritis Rheum 48:660–667
Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R (2003b) Pleiotrophin, an embryonic differentiation and growth factor, is expressed in osteoarthritis. Osteoarthritis Cartilage 11:260–264
Ratel D, Nasser V, Dupre I, Benabid AL, Berger F (2000) Antibodies to endostatin in a multifocal glioblastoma patient. Lancet 356:1656–1657
Reiss M (1997) Transforming growth factor-beta and cancer: a love-hate relationship? Oncol Res 9:447–457
Rifkin DB, Mazzieri R, Munger JS, Noguera I, Sung J (1999) Proteolytic control of growth factor availability. Apmis 107:80–85
Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865
Rosen L (2000) Antiangiogenic strategies and agents in clinical trials. Oncologist 5:20–27
Rosenstein JM, Mani N, Silverman WF, Krum JM (1998) Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. Proc Natl Acad Sci USA 95:7086–7091
Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K, Kuwano M (1996) Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells: possible roles of SP-1. J Biol Chem 271:28220–28228
Sehgal A (1998) Molecular changes during the genesis of human gliomas. Semin Surg Oncol 14:3–12
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985
Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845
Strik HM, Schluesener HJ, Seid K, Meyermann R, Deininger MH (2001) Localization of endostatin in rat and human gliomas. Cancer 91:1013–1019
Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shrai S, Nose T (1996) Concentration of vascular endothelial growth factor in the serum and tumour tissue of brain tumour patients. Cancer Res 56:2185–2190
Tannock IF, Hill RP (1987) The basic science of oncology. Pergamon, New York
Vajkoczy P, Menger MD (2000) Vascular microenvironments in gliomas. J Neuro-Oncol 50:99–108
Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K (2000) Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203–212
Wojtowicz-Praga S (1997) Reversal of tumor-induced tumor-suppression: a new approach to cancer therapy. J Immunother 20:165–177
Wrann M, Bodmer S, de Martin R, Siepl C, Hofer-Warbinek R, Frei K, Hofer E, Fontana A (1987) T-cell suppressor factor from human glioblastoma cells is a 12.5 kDa protein closely related to transforming growth factor-beta. EMBO J 6:1633–1636
Yamada N, Kato M, Yamashita H, Nister M, Miyazono K, Heldin CH, Funa K (1995) Enhanced expression of transforming growth factor-beta and its type-I and type-II receptors in human glioblastoma. Int J Cancer 62:386–392
Yamamoto T, Noble NA, Miller DE, Gold LI, Hishida A, Nagase M, Cohen AH, Border WA (1999) Increased levels of transforming growth factor-beta in HIV-associated nephropathy. Kidney Int 55:579–592
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248
Zadeh G, Guha A (2003) Neoangiogenesis in human astrocytomas: expression and functional role of angiopoietins and their cognate receptors. Front Biosci 8:E128–137
Zagzag D (1995) Angiogenic growth factors in neural embryogenesis and neoplasia. Am J Pathol 146:293–309
Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R (2000) The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer 83:63–68
Acknowledgements
Our own experimental studies in this field were supported by grants from the Deutsche Forschungsgemeinschaft, Interdisziplinäres Zentrum für Krebsforschung der Universität Kiel and Fonds der Chemischen Industrie zur Förderung von Chemie und Biochemie. We thank Prof. Dr. Olav Jansen, Clinic of Neurosurgery/Neuroradiology, University of Kiel, for MRT data; Prof. Dr. Ulrike Blömer, Clinic of Neurosurgery, for critical reading of the manuscript; Martina Burmester, Dagmar Freier and Miriam Lemmer for their expert technical assistance; and Clemens Franke for drawing the Figures.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mentlein, R., Held-Feindt, J. Angiogenesis factors in gliomas: a new key to tumour therapy?. Naturwissenschaften 90, 385–394 (2003). https://doi.org/10.1007/s00114-003-0449-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00114-003-0449-9