Summary
Treatment of adult brain tumors, in particular glioblastoma, remains a significant clinical challenge, despite modest advances in surgical technique, radiation, and chemotherapeutics. The formation of abnormal, dysfunctional tumor vasculature and glioma cell invasion along white matter tracts are believed to be major components of the inability to treat these tumors effectively. Recent insight into the fundamental processes governing glioma angiogenesis and invasion provide a renewed hope for development of novel strategies aimed at reducing the morbidity of this uniformly fatal disease. In this review, we discuss background biology of the blood brain barrier and its pertinence to blood vessel formation and tumor invasion. We will then focus our attention on the biology of glioma angiogenesis and invasion, and the key mediators of these processes. Last, we will briefly discuss recent and ongoing clinical trials targeting mediators of angiogenesis or invasion in glioma patients. The findings provide a renewed hope for those endeavoring to improve treatment of patients with glioma by providing a novel set of rational targets for translational drug discovery.
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Gilbertson RJ, Rich JN. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 2007;7: 733–736.
Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432: 396–401.
Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 2006;57: 1–18.
Folkman J. Angiogenesis. Annu Rev Med 2006;57: 1–18.
Plate KH, Mennel HD. Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol 1995;47: 89–94.
Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 1992;33: 2133–2137.
Kleihues P, Burger PC, Plate KH, Ohgaki H, Cavenee WK. Glioblastoma. In: Kleihues P, Cavenee WK, eds. Tumors of the Nervous System. Lyon: IARC Press; 2000. p. 16–26.
Hobbs SK, Monsky WL, Yuan F, et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 1998;95: 4607–4612.
Jain RK. Barriers to drug delivery in solid tumors. Sci Am 1994;271: 58–65.
Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med 2008;10: e23.
Aghi M, Chiocca EA. Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors. Mol Ther 2005;12: 994–1005.
Jouanneau E. Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery 2008;62: 31–50.
Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 2006;66: 9054–9064.
Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008;13: 206–220.
Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 2005;7: 452–464.
Reiss Y, Machein MR, Plate KH. The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 2005;15: 311–317.
Zagzag D, Amimovin R, Greco MA, et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 2000;80: 837–849.
Stratmann A, Risau W, Plate KH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 1998;153: 1459–1466.
Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284: 1994–1998.
Hu B, Guo P, Fang Q, et al. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc Natl Acad Sci U S A 2003;100: 8904–8909.
Rooprai HK, McCormick D. Proteases and their inhibitors in human brain tumours: a review. Anticancer Res 1997;17: 4151–4162.
Raithatha SA, Muzik H, Rewcastle NB, Johnston RN, Edwards DR, Forsyth PA. Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas. Neuro Oncol 2000;2: 145–150.
Rao JS, Yamamoto M, Mohaman S, et al. Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. Clin Exp Metastasis 1996;14: 12–18.
Guo P, Imanishi Y, Cackowski FC, et al. Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol 2005;166: 877–890.
Lakka SS, Gondi CS, Rao JS. Proteases and glioma angiogenesis. Brain Pathol 2005;15: 327–341.
Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 2003;3: 422–433.
Oz B, Karayel FA, Gazio NL, Ozlen F, Balci K. The distribution of extracellular matrix proteins and CD44S expression in human astrocytomas. Pathol Oncol Res 2000;6: 118–124.
Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994;264: 569–571.
Gladson CL. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 1996;55: 1143–1149.
Kim S, Bell K, Mousa SA, Vamer JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 2000;156: 1345–1362.
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438: 967–974.
Roberts WG, Whalen PM, Soderstrom E, et al. Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res 2005;65: 957–966.
Herold-Mende C, Mueller MM, Bonsanto MM, Schmitt HP, Kunze S, Steiner HH. Clinical impact and functional aspects of tenascin-C expression during glioma progression. Int J Cancer 2002;98: 362–369.
Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 2003;163: 1801–1815.
Vitolo D, Paradiso P, Uccini S, Ruco LP, Baroni CD. Expression of adhesion molecules and extracellular matrix proteins in glioblastomas: relation to angiogenesis and spread. Histopathology 1996;28: 521–528.
Wang D, Anderson JC, Gladson CL. The role of the extracellular matrix in angiogenesis in malignant glioma tumors. Brain Pathol 2005;15: 318–326.
Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4: 437–447.
Kaur B, Brat DJ, Calkins CC, Van Meir EG. Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 2003;162: 19–27.
Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 2005;7: 122–133.
Desbaillets I, Diserens AC, de Tribolet N, Hamou MF, Van Meir EG. Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene 1999;18: 1447–1456.
Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 2005;15: 297–310.
Kaur B, Tan C, Brat DJ, Post DE, Van Meir EG. Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 2004;70: 229–243.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86: 353–364.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407: 249–257.
Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20: 4368–4380.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25: 581–611.
Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol 2000;50: 109–120.
Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992;359: 845–848.
Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 1996;271: 10079–10086.
Grau SJ, Trillsch F, Herms J, et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol 2007;82: 141–150.
Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9: 685–693.
Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13: 1253–1259.
Vredenburgh JJ, Desjardins A, Hemdon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25: 4722–4729.
Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11: 83–95.
Tabatabai G, Frank B, Wick A, et al. Synergistic antiglioma activity of radiotherapy and enzastaurin. Ann Neurol 2007;61: 153–161.
Karcher S, Steiner HH, Ahmadi R, et al. Different angiogenic phenotypes in primary and secondary glioblastomas. Int J Cancer 2006;118: 2182–2189.
Yamada SM, Yamada S, Hayashi Y, Takahashi H, Teramoto A, Matsumoto K. Fibroblast growth factor receptor (FGFR) 4 correlated with the malignancy of human astrocytomas. Neurol Res 2002;24: 244–248.
Ueba T, Takahashi JA, Fukumoto M, et al. Expression of fibroblast growth factor receptor-1 in human glioma and meningioma tissues. Neurosurgery 1994;34: 221–225.
Morrison RS, Yamaguchi F, Bruner JM, Tang M, McKeehan W, Berger MS. Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Cancer Res 1994;54: 2794–2799.
Simons M. Integrative signaling in angiogenesis. Mol Cell Biochem 2004;264: 99–102.
Pintucci G, Moscatelli D, Saponara F, et al. Lack of ERK activation and cell migration in FGF-2-deficient endothelial cells. FASEB J 2002;16: 598–600.
Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 1996;2: 992–997.
Garkavtsev I, Kozin SV, Chernova O, et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 2004;428: 328–332.
Zagzag D, Lukyanov Y, Lan L, et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 2006;86: 1221–1232.
Bajetto A, Barbieri F, Dorcaratto A, et al. Expression of CXC chemokine receptors 1–5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 2006;49: 423–432.
Hattori K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001;97: 3354–3360.
Mamluk R, Klagsbrun M, Detmar M, Bielenberg DR. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis 2005;8: 217–227.
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92: 735–745.
Miao HQ, Klagsbrun M. Neuropilin is a mediator of angiogenesis. Cancer Metastasis Rev 2000;19: 29–37.
Kuijper S, Turner CJ, Adams RH. Regulation of angiogenesis by Eph-ephrin interactions. Trends Cardiovasc Med 2007;17: 145–151.
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000;407: 242–248.
Cirulli V, Yebra M. Netrins: beyond the brain. Nat Rev Mol Cell Biol 2007;8: 296–306.
Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 2007;134: 839–844.
Williams CK, Li JL, Murga M, Harris AL, Tosato G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 2006;107: 931–939.
Castellani P, Viale G, Dorcaratto A, et al. The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int J Cancer 1994;59: 612–618.
Zagzag D, Friedlander DR, Dosik J, et al. Tenascin-C expression by angiogenic vessels in human astrocytomas and by human brain endothelial cells in vitro. Cancer Res 1996;56: 182–189.
Zagzag D, Shiff B, Jallo GI, et al. Tenascin-C promotes microvascular cell migration and phosphorylation of focal adhesion kinase. Cancer Res 2002;62: 2660–2668.
Akabani G, Reardon DA, Coleman RE, et al. Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study. J Nucl Med 2005;46: 1042–1051.
Mariani G, Lasku A, Balza E, et al. Tumor targeting potential of the monoclonal antibody BC-1 against oncofetal fibronectin in nude mice bearing human tumor implants. Cancer 1997;80: 2378–2384.
Fujita M, Khazenzon NM, Ljubimov AV, et al. Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Angiogenesis 2006;9: 183–191.
Wahl ML, Kenan DJ, Gonzalez-Gronow M, Pizzo SV. Angiostatin’s molecular mechanism: aspects of specificity and regulation elucidated. J Cell Biochem 2005;96: 242–261.
O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79: 315–328.
Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM. Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 1998;58: 4654–4659.
Joe YA, Hong YK, Chung DS, et al. Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1–3. Int J Cancer 1999;82: 694–699.
Tarui T, Miles LA, Takada Y. Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem 2001;276: 39562–39568.
Chekenya M, Hjelstuen M, Enger PO, et al. NG2 proteoglycan promotes angiogenesis-dependent tumor growth in CNS by sequestering angiostatin. FASEB J 2002;16: 586–588.
Davidson DJ, Haskell C, Majest S, et al. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. Cancer Res 2005;65: 4663–4672.
Perri SR, Nalbantoglu J, Annabi B, et al. Plasminogen kringle 5-engineered glioma cells block migration of tumor-associated macrophages and suppress tumor vascularization and progression. Cancer Res 2005;65: 8359–8365.
Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol 2004;36: 961–968.
Nor JE, Mitra RS, Sutorik MM, Mooney DJ, Castle VP, Polverini PJ. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res 2000;37: 209–218.
Simantov R, Silverstein RL. CD36: a critical anti-angiogenic receptor. Front Biosci 2003;8: s874-s882.
Anderson JC, Grammer JR, Wang W, et al. ABT-510, a modified type 1 repeat peptide of thrombospondin, inhibits malignant glioma growth in vivo by inhibiting angiogenesis. Cancer Biol Ther 2007;6: 454–462.
Fears CY, Grammer JR, Stewart JE, Jr., et al. Low-density lipoprotein receptor-related protein contributes to the antiangiogenic activity of thrombospondin-2 in a murine glioma model. Cancer Res 2005;65: 9338–9346.
Strik HM, Weller M, Frank B, et al. Heat shock protein expression in human gliomas. Anticancer Res 2000;20: 4457–4462.
Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 2006;312: 594–607.
Heljasvaara R, Nyberg P, Luostarinen J, et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp Cell Res 2005;307: 292–304.
Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct anti-angiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci U S A 2003;100: 4766–4771.
Morimoto T, Aoyagi M, Tamaki M, et al. Increased levels of tissue endostatin in human malignant gliomas. Clin Cancer Res 2002;8: 2933–2938.
Barnett FH, Scharer-Schuksz M, Wood M, Yu X, Wagner TE, Friedlander M. Intra-arterial delivery of endostatin gene to brain tumors prolongs survival and alters tumor vessel ultrastructure. Gene Ther 2004;11: 1283–1289.
Sorensen DR, Read TA, Porwol T, et al. Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma. Neuro Oncol 2002;4: 1–8.
Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem 2000;275: 23745–23750.
Mundel TM, Kalluri R. Type IV collagen-derived angiogenesis inhibitors. Microvasc Res 2007;74: 85–89.
Koh JT, Kook H, Kee HJ, et al. Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking alphavbeta5 integrin. Exp Cell Res 2004;294: 172–184.
Kang X, Xiao X, Harata M, et al. Antiangiogenic activity of BAI1 in vivo: implications for gene therapy of human glioblastomas. Cancer Gene Ther 2006;13: 385–392.
Kaur B, Brat DJ, Devi NS, Van Meir EG. Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 2005;24: 3632–3642.
Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 2002;14: 608–616.
Lane TF, Iruela-Arispe ML, Johnson RS, Sage EH. SPARC is a source of copper-binding peptides that stimulate angiogenesis. J Cell Biol 1994;125: 929–943.
Yan Q, Sage EH, Hendrickson AE. SPARC is expressed by ganglion cells and astrocytes in bovine retina. J Histochem Cytochem 1998;46: 3–10.
Lane TF, Sage EH. The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB J 1994;8: 163–173.
Yunker CK, Golembieski W, Lemke N, et al. SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. Int J Cancer 2008;122: 2735–2743.
Rempel SA, Golembieski WA, Ge S, et al. SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas. J Neuropathol Exp Neurol 1998;57: 1112–1121.
Golembieski WA, Ge S, Nelson K, Mikkelsen T, Rempel SA. Increased SPARC expression promotes U87 glioblastoma invasion in vitro. Int J Dev Neurosci 1999;17: 463–472.
Schultz C, Lemke N, Ge S, Golembieski WA, Rempel SA. Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo. Cancer Res 2002;62: 6270–6277.
Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6: 553–563.
Zhou Q, Guo P, Gallo JM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res 2008;14: 1540–1549.
Giannini C, Sarkaria JN, Saito A, et al. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro-oncol 2005;7: 164–176.
Alcantara Llaguno S, Chen J, Kwon CH, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 2009;15: 45–56.
Zheng H, Ying H, Yan H, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 2008;455: 1129–1133.
Adachi Y, Lakka SS, Chandrasekar N, et al. Down-regulation of integrin alpha(v)beta(3) expression and integrin-mediated signaling in glioma cells by adenovirus-mediated transfer of antisense urokinase-type plasminogen activator receptor (uPAR) and sense p16 genes. J Biol Chem 2001;276: 47171–47177.
Natarajan M, Stewart JE, Golemis EA, et al. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene 2006;25: 1721–1732.
Rao JS. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 2003;3: 489–501.
Li L, Gondi CS, Dinh DH, Olivero WC, Gujrati M, Rao JS. Transfection with anti-p65 intrabody suppresses invasion and angiogenesis in glioma cells by blocking nuclear factor-kappaB transcriptional activity. Clin Cancer Res 2007;13: 2178–2190.
Song H, Li Y, Lee J, Schwartz AL, Bu G. Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 2009;69: 879–886.
Kleber S, Sancho-Martinez I, Wiestler B, et al. Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 2008;13: 235–248.
Wang H, Shen W, Huang H, et al. Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res 2003;63: 4315–4321.
Levitt RJ, Georgescu MM, Pollak M. PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2. Biochem Biophys Res Commun 2005;336: 1056–1061.
Martens T, Schmidt NO, Eckerich C, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006;12: 6144–6152.
Eckerich C, Zapf S, Fillbrandt R, Loges S, Westphal M, Lamszus K. Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration. Int J Cancer 2007;121: 276–283.
Beadle C, Assanah MC, Monzo P, Vallee R, Rosenfeld SS, Canoll P. The role of myosin II in glioma invasion of the brain. Mol Biol Cell 2008;19: 3357–3368.
Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15: 220–231.
Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 2008;70: 779–787.
Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther 2007;7: 1537–1560.
Lamszus K, Kunkel P, Westphal M. Invasion as limitation to anti-angiogenic glioma therapy. Acta Neurochir Suppl 2003;88: 169–177.
Reardon DA, Fink KL, Mikkelsen T, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008;26: 5610–5617.
Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2002;2: 826–835.
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Tate, M.C., Aghi, M.K. Biology of angiogenesis and invasion in glioma. Neurotherapeutics 6, 447–457 (2009). https://doi.org/10.1016/j.nurt.2009.04.001
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DOI: https://doi.org/10.1016/j.nurt.2009.04.001