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Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Jul;6(3):447–457. doi: 10.1016/j.nurt.2009.04.001

Biology of angiogenesis and invasion in glioma

Matthew C Tate 1, Manish K Aghi 1,
PMCID: PMC5084181  PMID: 19560735

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.

Key Words: Angiogenesis, glioblastoma, VEGF, invasion, extracellular matrix

References

  • 1.Gilbertson RJ, Rich JN. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer. 2007;7:733–736. doi: 10.1038/nrc2246. [DOI] [PubMed] [Google Scholar]
  • 2.Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. doi: 10.1038/nature03128. [DOI] [PubMed] [Google Scholar]
  • 3.Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2006;57:1–18. doi: 10.1038/nrn2175. [DOI] [PubMed] [Google Scholar]
  • 4.Folkman J. Angiogenesis. Annu Rev Med. 2006;57:1–18. doi: 10.1146/annurev.med.57.121304.131306. [DOI] [PubMed] [Google Scholar]
  • 5.Plate KH, Mennel HD. Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol. 1995;47:89–94. doi: 10.1016/S0940-2993(11)80292-7. [DOI] [PubMed] [Google Scholar]
  • 6.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. [PubMed] [Google Scholar]
  • 7.Kleihues P, Burger PC, Plate KH, Ohgaki H, Cavenee WK. Glioblastoma. In: Kleihues P, Cavenee WK, editors. Tumors of the Nervous System. Lyon: IARC Press; 2000. pp. 16–26. [Google Scholar]
  • 8.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. doi: 10.1073/pnas.95.8.4607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jain RK. Barriers to drug delivery in solid tumors. Sci Am. 1994;271:58–65. doi: 10.1038/scientificamerican0794-58. [DOI] [PubMed] [Google Scholar]
  • 10.Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med. 2008;10:e23–e23. doi: 10.1017/S1462399408000768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Aghi M, Chiocca EA. Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors. Mol Ther. 2005;12:994–1005. doi: 10.1016/j.ymthe.2005.07.693. [DOI] [PubMed] [Google Scholar]
  • 12.Jouanneau E. Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery. 2008;62:31–50. doi: 10.1227/01.NEU.0000311060.65002.4E. [DOI] [PubMed] [Google Scholar]
  • 13.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. doi: 10.1158/0008-5472.CAN-05-3759. [DOI] [PubMed] [Google Scholar]
  • 14.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. doi: 10.1016/j.ccr.2008.01.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 2005;7:452–464. doi: 10.1215/S1152851705000232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Reiss Y, Machein MR, Plate KH. The role of angiopoietins during angiogenesis in gliomas. Brain Pathol. 2005;15:311–317. doi: 10.1111/j.1750-3639.2005.tb00116.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.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. doi: 10.1038/labinvest.3780088. [DOI] [PubMed] [Google Scholar]
  • 18.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. doi: 10.1016/S0002-9440(10)65733-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.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. doi: 10.1126/science.284.5422.1994. [DOI] [PubMed] [Google Scholar]
  • 20.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. doi: 10.1073/pnas.1533394100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Rooprai HK, McCormick D. Proteases and their inhibitors in human brain tumours: a review. Anticancer Res. 1997;17:4151–4162. [PubMed] [Google Scholar]
  • 22.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. doi: 10.1093/neuonc/2.3.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.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. doi: 10.1007/BF00157681. [DOI] [PubMed] [Google Scholar]
  • 24.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. doi: 10.1016/S0002-9440(10)62308-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Lakka SS, Gondi CS, Rao JS. Proteases and glioma angiogenesis. Brain Pathol. 2005;15:327–341. doi: 10.1111/j.1750-3639.2005.tb00118.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3:422–433. doi: 10.1038/nrc1094. [DOI] [PubMed] [Google Scholar]
  • 27.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. doi: 10.1007/BF03032361. [DOI] [PubMed] [Google Scholar]
  • 28.Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264:569–571. doi: 10.1126/science.7512751. [DOI] [PubMed] [Google Scholar]
  • 29.Gladson CL. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol. 1996;55:1143–1149. doi: 10.1097/00005072-199611000-00005. [DOI] [PubMed] [Google Scholar]
  • 30.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. doi: 10.1016/S0002-9440(10)65005-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967–974. doi: 10.1038/nature04483. [DOI] [PubMed] [Google Scholar]
  • 32.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. [PubMed] [Google Scholar]
  • 33.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. doi: 10.1002/ijc.10233. [DOI] [PubMed] [Google Scholar]
  • 34.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. doi: 10.1016/S0002-9440(10)63540-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.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. doi: 10.1046/j.1365-2559.1996.d01-471.x. [DOI] [PubMed] [Google Scholar]
  • 36.Wang D, Anderson JC, Gladson CL. The role of the extracellular matrix in angiogenesis in malignant glioma tumors. Brain Pathol. 2005;15:318–326. doi: 10.1111/j.1750-3639.2005.tb00117.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–447. doi: 10.1038/nrc1367. [DOI] [PubMed] [Google Scholar]
  • 38.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. doi: 10.1016/S0002-9440(10)63794-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.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. doi: 10.1215/S1152851704001061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.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. doi: 10.1038/sj.onc.1202424. [DOI] [PubMed] [Google Scholar]
  • 41.Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol. 2005;15:297–310. doi: 10.1111/j.1750-3639.2005.tb00115.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.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. doi: 10.1007/s11060-004-2752-5. [DOI] [PubMed] [Google Scholar]
  • 43.Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–364. doi: 10.1016/S0092-8674(00)80108-7. [DOI] [PubMed] [Google Scholar]
  • 44.Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257. doi: 10.1038/35025220. [DOI] [PubMed] [Google Scholar]
  • 45.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. doi: 10.1200/JCO.2002.10.088. [DOI] [PubMed] [Google Scholar]
  • 46.Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611. doi: 10.1210/er.2003-0027. [DOI] [PubMed] [Google Scholar]
  • 47.Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000;50:109–120. doi: 10.1023/A:1006416003964. [DOI] [PubMed] [Google Scholar]
  • 48.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. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  • 49.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. doi: 10.1074/jbc.271.17.10079. [DOI] [PubMed] [Google Scholar]
  • 50.Grau SJ, Trillsch F, Herms J, et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol. 2007;82:141–150. doi: 10.1007/s11060-006-9272-4. [DOI] [PubMed] [Google Scholar]
  • 51.Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. [DOI] [PubMed] [Google Scholar]
  • 52.Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13:1253–1259. doi: 10.1158/1078-0432.CCR-06-2309. [DOI] [PubMed] [Google Scholar]
  • 53.Vredenburgh JJ, Desjardins A, Hemdon JE, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–4729. doi: 10.1200/JCO.2007.12.2440. [DOI] [PubMed] [Google Scholar]
  • 54.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. doi: 10.1016/j.ccr.2006.11.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Tabatabai G, Frank B, Wick A, et al. Synergistic antiglioma activity of radiotherapy and enzastaurin. Ann Neurol. 2007;61:153–161. doi: 10.1002/ana.21057. [DOI] [PubMed] [Google Scholar]
  • 56.Karcher S, Steiner HH, Ahmadi R, et al. Different angiogenic phenotypes in primary and secondary glioblastomas. Int J Cancer. 2006;118:2182–2189. doi: 10.1002/ijc.21648. [DOI] [PubMed] [Google Scholar]
  • 57.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. doi: 10.1179/016164102101199864. [DOI] [PubMed] [Google Scholar]
  • 58.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. doi: 10.1227/00006123-199402000-00003. [DOI] [PubMed] [Google Scholar]
  • 59.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. [PubMed] [Google Scholar]
  • 60.Simons M. Integrative signaling in angiogenesis. Mol Cell Biochem. 2004;264:99–102. doi: 10.1023/B:MCBI.0000044379.25823.03. [DOI] [PubMed] [Google Scholar]
  • 61.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. doi: 10.1096/fj.01-0815fje. [DOI] [PubMed] [Google Scholar]
  • 62.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. doi: 10.1038/nm0996-992. [DOI] [PubMed] [Google Scholar]
  • 63.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. doi: 10.1038/nature02329. [DOI] [PubMed] [Google Scholar]
  • 64.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. doi: 10.1038/labinvest.3700482. [DOI] [PubMed] [Google Scholar]
  • 65.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. doi: 10.1016/j.neuint.2006.03.003. [DOI] [PubMed] [Google Scholar]
  • 66.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. doi: 10.1182/blood.V97.11.3354. [DOI] [PubMed] [Google Scholar]
  • 67.Mamluk R, Klagsbrun M, Detmar M, Bielenberg DR. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis. 2005;8:217–227. doi: 10.1007/s10456-005-9009-6. [DOI] [PubMed] [Google Scholar]
  • 68.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. doi: 10.1016/S0092-8674(00)81402-6. [DOI] [PubMed] [Google Scholar]
  • 69.Miao HQ, Klagsbrun M. Neuropilin is a mediator of angiogenesis. Cancer Metastasis Rev. 2000;19:29–37. doi: 10.1023/A:1026579711033. [DOI] [PubMed] [Google Scholar]
  • 70.Kuijper S, Turner CJ, Adams RH. Regulation of angiogenesis by Eph-ephrin interactions. Trends Cardiovasc Med. 2007;17:145–151. doi: 10.1016/j.tcm.2007.03.003. [DOI] [PubMed] [Google Scholar]
  • 71.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. doi: 10.1038/35025215. [DOI] [PubMed] [Google Scholar]
  • 72.Cirulli V, Yebra M. Netrins: beyond the brain. Nat Rev Mol Cell Biol. 2007;8:296–306. doi: 10.1038/nrm2142. [DOI] [PubMed] [Google Scholar]
  • 73.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. doi: 10.1242/dev.003244. [DOI] [PubMed] [Google Scholar]
  • 74.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. doi: 10.1182/blood-2005-03-1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.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. doi: 10.1002/ijc.2910590507. [DOI] [PubMed] [Google Scholar]
  • 76.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. [PubMed] [Google Scholar]
  • 77.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. [PubMed] [Google Scholar]
  • 78.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. [PubMed] [Google Scholar]
  • 79.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. doi: 10.1002/(SICI)1097-0142(19971215)80:12+<2378::AID-CNCR7>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  • 80.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. doi: 10.1007/s10456-006-9046-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.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. doi: 10.1002/jcb.20480. [DOI] [PubMed] [Google Scholar]
  • 82.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. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  • 83.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. [PubMed] [Google Scholar]
  • 84.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. doi: 10.1002/(SICI)1097-0215(19990827)82:5<694::AID-IJC12>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  • 85.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. doi: 10.1074/jbc.M101815200. [DOI] [PubMed] [Google Scholar]
  • 86.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. doi: 10.1096/fj.01-0632fje. [DOI] [PubMed] [Google Scholar]
  • 87.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. doi: 10.1158/0008-5472.CAN-04-3426. [DOI] [PubMed] [Google Scholar]
  • 88.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. doi: 10.1158/0008-5472.CAN-05-0508. [DOI] [PubMed] [Google Scholar]
  • 89.Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol. 2004;36:961–968. doi: 10.1016/j.biocel.2004.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.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. doi: 10.1159/000025733. [DOI] [PubMed] [Google Scholar]
  • 91.Simantov R, Silverstein RL. CD36: a critical anti-angiogenic receptor. Front Biosci. 2003;8:s874–s882. doi: 10.2741/1168. [DOI] [PubMed] [Google Scholar]
  • 92.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. doi: 10.4161/cbt.6.3.3630. [DOI] [PubMed] [Google Scholar]
  • 93.Fears CY, Grammer JR, Stewart JE, 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. doi: 10.1158/0008-5472.CAN-05-1560. [DOI] [PubMed] [Google Scholar]
  • 94.Strik HM, Weller M, Frank B, et al. Heat shock protein expression in human gliomas. Anticancer Res. 2000;20:4457–4462. [PubMed] [Google Scholar]
  • 95.Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res. 2006;312:594–607. doi: 10.1016/j.yexcr.2005.11.015. [DOI] [PubMed] [Google Scholar]
  • 96.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. doi: 10.1016/j.yexcr.2005.03.021. [DOI] [PubMed] [Google Scholar]
  • 97.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. doi: 10.1073/pnas.0730882100. [DOI] [PMC free article] [PubMed] [Google Scholar] [Research Misconduct Found]
  • 98.Morimoto T, Aoyagi M, Tamaki M, et al. Increased levels of tissue endostatin in human malignant gliomas. Clin Cancer Res. 2002;8:2933–2938. [PubMed] [Google Scholar]
  • 99.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. doi: 10.1038/sj.gt.3302287. [DOI] [PubMed] [Google Scholar]
  • 100.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. doi: 10.1215/15228517-4-1-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.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. doi: 10.1074/jbc.C000186200. [DOI] [PubMed] [Google Scholar]
  • 102.Mundel TM, Kalluri R. Type IV collagen-derived angiogenesis inhibitors. Microvasc Res. 2007;74:85–89. doi: 10.1016/j.mvr.2007.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.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. doi: 10.1016/j.yexcr.2003.11.008. [DOI] [PubMed] [Google Scholar]
  • 104.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. doi: 10.1038/sj.cgt.7700898. [DOI] [PubMed] [Google Scholar]
  • 105.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. doi: 10.1038/sj.onc.1208317. [DOI] [PubMed] [Google Scholar]
  • 106.Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14:608–616. doi: 10.1016/S0955-0674(02)00361-7. [DOI] [PubMed] [Google Scholar]
  • 107.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. doi: 10.1083/jcb.125.4.929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Yan Q, Sage EH, Hendrickson AE. SPARC is expressed by ganglion cells and astrocytes in bovine retina. J Histochem Cytochem. 1998;46:3–10. doi: 10.1177/002215549804600102. [DOI] [PubMed] [Google Scholar]
  • 109.Lane TF, Sage EH. The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB J. 1994;8:163–173. [PubMed] [Google Scholar]
  • 110.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. doi: 10.1002/ijc.23450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.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. doi: 10.1097/00005072-199812000-00002. [DOI] [PubMed] [Google Scholar]
  • 112.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. doi: 10.1016/S0736-5748(99)00009-X. [DOI] [PubMed] [Google Scholar]
  • 113.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. [PubMed] [Google Scholar]
  • 114.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. doi: 10.1016/j.ccr.2004.10.011. [DOI] [PubMed] [Google Scholar]
  • 115.Zhou Q, Guo P, Gallo JM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res. 2008;14:1540–1549. doi: 10.1158/1078-0432.CCR-07-4544. [DOI] [PubMed] [Google Scholar]
  • 116.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. doi: 10.1215/S1152851704000821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.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. doi: 10.1016/j.ccr.2008.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.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. doi: 10.1038/nature07443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.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. doi: 10.1074/jbc.M104334200. [DOI] [PubMed] [Google Scholar]
  • 120.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. doi: 10.1038/sj.onc.1209199. [DOI] [PubMed] [Google Scholar]
  • 121.Rao JS. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer. 2003;3:489–501. doi: 10.1038/nrc1121. [DOI] [PubMed] [Google Scholar]
  • 122.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. doi: 10.1158/1078-0432.CCR-06-1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.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. doi: 10.1158/0008-5472.CAN-08-3379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.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. doi: 10.1016/j.ccr.2008.02.003. [DOI] [PubMed] [Google Scholar]
  • 125.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. [PubMed] [Google Scholar]
  • 126.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. doi: 10.1016/j.bbrc.2005.08.229. [DOI] [PubMed] [Google Scholar]
  • 127.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. doi: 10.1158/1078-0432.CCR-05-1418. [DOI] [PubMed] [Google Scholar]
  • 128.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. doi: 10.1002/ijc.22679. [DOI] [PubMed] [Google Scholar]
  • 129.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. doi: 10.1091/mbc.E08-03-0319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.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. doi: 10.1016/j.ccr.2009.01.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008;70:779–787. doi: 10.1212/01.wnl.0000304121.57857.38. [DOI] [PubMed] [Google Scholar]
  • 132.Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther. 2007;7:1537–1560. doi: 10.1586/14737140.7.11.1537. [DOI] [PubMed] [Google Scholar]
  • 133.Lamszus K, Kunkel P, Westphal M. Invasion as limitation to anti-angiogenic glioma therapy. Acta Neurochir Suppl. 2003;88:169–177. doi: 10.1007/978-3-7091-6090-9_23. [DOI] [PubMed] [Google Scholar]
  • 134.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. doi: 10.1200/JCO.2008.16.7510. [DOI] [PubMed] [Google Scholar]
  • 135.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. doi: 10.1038/nrc925. [DOI] [PubMed] [Google Scholar]

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