Integrin Signaling in Angiogenesis and Metastatic Cancer Progression in the Brain

  • Mihaela Lorger
  • Brunhilde Felding-Habermann


Integrins have been identified as major contributors to the progression of brain cancer. This includes the development and spreading of primary brain tumors and, more recently, also metastatic disease originating from solid tumors outside the brain. In these processes, integrin functions affect not only the tumor cells themselves but also the reactions of host cells that respond to the presence of developing lesions within the brain microenvironment. Integrin functions can promote cell survival, proliferation, invasion and regulatory adjustments of signaling cascades ­triggered by other receptor types, including those for growth factors. Supported by the promise of ongoing clinical trials, specific targeting of certain integrins and their functions could thus prove successful for new therapeutic approaches against brain cancer and metastatic disease in the central nervous system.


Brain Metastasis Glioma Cell Cancer Stem Cell Focal Adhesion Kinase Primary Brain Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Brown MC, Staniszewska I, Lazarovici P, Tuszynski GP, Del VL, Marcinkiewicz C (2008) Regulatory effect of nerve growth factor in alpha9beta1 integrin-dependent progression of glioblastoma. Neuro Oncol 10:968–980PubMedCrossRefGoogle Scholar
  2. 2.
    Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ (2009) L-Thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296:C980–C991PubMedCrossRefGoogle Scholar
  3. 3.
    Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG (2004) Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 36:1046–1069PubMedCrossRefGoogle Scholar
  4. 4.
    D’Abaco GM, Kaye AH (2007) Integrins: molecular determinants of glioma invasion. J Clin Neurosci 14:1041–1048PubMedCrossRefGoogle Scholar
  5. 5.
    Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and ­therapeutic opportunities. Nat Rev Cancer 10:9–22PubMedCrossRefGoogle Scholar
  6. 6.
    Guo W, Giancotti FG (2004) Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 5:816–826PubMedCrossRefGoogle Scholar
  7. 7.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedCrossRefGoogle Scholar
  8. 8.
    Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516–523PubMedCrossRefGoogle Scholar
  9. 9.
    Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4:133–146PubMedCrossRefGoogle Scholar
  10. 10.
    Guo P, Xu L, Pan S, Brekken RA, Yang ST, Whitaker GB, Nagane M, Thorpe PE, Rosenbaum JS, Su Huang HJ et al (2001) Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res 61:8569–8577PubMedGoogle Scholar
  11. 11.
    Kawaguchi T, Yamashita Y, Kanamori M, Endersby R, Bankiewicz KS, Baker SJ, Bergers G, Pieper RO (2006) The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo. Cancer Res 66:11331–11340PubMedCrossRefGoogle Scholar
  12. 12.
    Lorger M, Krueger JS, O’Neal M, Staflin K, Felding-Habermann B (2009) Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci U S A 106:10666–10671PubMedCrossRefGoogle Scholar
  13. 13.
    Gingras MC, Roussel E, Bruner JM, Branch CD, Moser RP (1995) Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain ­tissue. J Neuroimmunol 57:143–153PubMedCrossRefGoogle Scholar
  14. 14.
    Paulus W, Baur I, Schuppan D, Roggendorf W (1993) Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 143:154–163PubMedGoogle Scholar
  15. 15.
    Baumann F, Leukel P, Doerfelt A, Beier CP, Dettmer K, Oefner PJ, Kastenberger M, Kreutz M, Nickl-Jockschat T, Bogdahn U et al (2009) Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol 11:368–380PubMedCrossRefGoogle Scholar
  16. 16.
    Platten M, Wick W, Wild-Bode C, Aulwurm S, Dichgans J, Weller M (2000) Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote glioma cell migration via Up-regulation of alpha(V)beta(3) integrin expression. Biochem Biophys Res Commun 268:607–611PubMedCrossRefGoogle Scholar
  17. 17.
    Adachi Y, Lakka SS, Chandrasekar N, Yanamandra N, Gondi CS, Mohanam S, Dinh DH, Olivero WC, Gujrati M, Tamiya T et al (2001) 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 276:47171–47177PubMedCrossRefGoogle Scholar
  18. 18.
    Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, Grone HJ, Hallahan DE, Reisfeld RA, Debus J et al (2005) Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res 11:6270–6279PubMedCrossRefGoogle Scholar
  19. 19.
    Cordes N, Hansmeier B, Beinke C, Meineke V, van Beuningen D (2003) Irradiation differentially affects substratum-dependent survival, adhesion, and invasion of glioblastoma cell lines. Br J Cancer 89:2122–2132PubMedCrossRefGoogle Scholar
  20. 20.
    Wick W, Wick A, Schulz JB, Dichgans J, Rodemann HP, Weller M (2002) Prevention of ­irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res 62:1915–1919PubMedGoogle Scholar
  21. 21.
    Ding Q, Stewart J Jr, Olman MA, Klobe MR, Gladson CL (2003) The pattern of enhancement of Src kinase activity on platelet-derived growth factor stimulation of glioblastoma cells is affected by the integrin engaged. J Biol Chem 278:39882–39891PubMedCrossRefGoogle Scholar
  22. 22.
    Skuli N, Monferran S, Delmas C, Favre G, Bonnet J, Toulas C, Cohen-Jonathan ME (2009) Alphavbeta3/alphavbeta5 integrins-FAK-RhoB: a novel pathway for hypoxia regulation in glioblastoma. Cancer Res 69:3308–3316PubMedCrossRefGoogle Scholar
  23. 23.
    Perris R, Johansson S (1990) Inhibition of neural crest cell migration by aggregating chondroitin sulfate proteoglycans is mediated by their hyaluronan-binding region. Dev Biol 137:1–12PubMedCrossRefGoogle Scholar
  24. 24.
    Snow DM, Lemmon V, Carrino DA, Caplan AI, Silver J (1990) Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol 109:111–130PubMedCrossRefGoogle Scholar
  25. 25.
    Giese A, Westphal M (1996) Glioma invasion in the central nervous system. Neurosurgery 39:235–250PubMedCrossRefGoogle Scholar
  26. 26.
    Fiorilli P, Partridge D, Staniszewska I, Wang JY, Grabacka M, So K, Marcinkiewicz C, Reiss K, Khalili K, Croul SE (2008) Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation. Lab Invest 88:1143–1156PubMedCrossRefGoogle Scholar
  27. 27.
    Gladson CL, Cheresh DA (1991) Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 88:1924–1932PubMedCrossRefGoogle Scholar
  28. 28.
    Gladson CL, Wilcox JN, Sanders L, Gillespie GY, Cheresh DA (1995) Cerebral ­microenvironment influences expression of the vitronectin gene in astrocytic tumors. J Cell Sci 108(Pt 3):947–956PubMedGoogle Scholar
  29. 29.
    Higuchi M, Ohnishi T, Arita N, Hiraga S, Hayakawa T (1993) Expression of tenascin in human gliomas: its relation to histological malignancy, tumor dedifferentiation and angiogenesis. Acta Neuropathol 85:481–487PubMedCrossRefGoogle Scholar
  30. 30.
    Zagzag D, Friedlander DR, Miller DC, Dosik J, Cangiarella J, Kostianovsky M, Cohen H, Grumet M, Greco MA (1995) Tenascin expression in astrocytomas correlates with angiogenesis. Cancer Res 55:907–914PubMedGoogle Scholar
  31. 31.
    Ljubimova JY, Fugita M, Khazenzon NM, Das A, Pikul BB, Newman D, Sekiguchi K, Sorokin LM, Sasaki T, Black KL (2004) Association between laminin-8 and glial tumor grade, recurrence, and patient survival. Cancer 101:604–612PubMedCrossRefGoogle Scholar
  32. 32.
    Ljubimova JY, Lakhter AJ, Loksh A, Yong WH, Riedinger MS, Miner JH, Sorokin LM, Ljubimov AV, Black KL (2001) Overexpression of alpha4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res 61:5601–5610PubMedGoogle Scholar
  33. 33.
    Ohnishi T, Hiraga S, Izumoto S, Matsumura H, Kanemura Y, Arita N, Hayakawa T (1998) Role of fibronectin-stimulated tumor cell migration in glioma invasion in vivo: clinical significance of fibronectin and fibronectin receptor expressed in human glioma tissues. Clin Exp Metastasis 16:729–741PubMedCrossRefGoogle Scholar
  34. 34.
    Oz B, Karayel FA, Gazio NL, Ozlen F, Balci K (2000) The distribution of extracellular matrix proteins and CD44S expression in human astrocytomas. Pathol Oncol Res 6:118–124PubMedCrossRefGoogle Scholar
  35. 35.
    Al-Shamy G, Sawaya R (2009) Management of brain metastases: the indispensable role of surgery. J Neurooncol 92:275–282PubMedCrossRefGoogle Scholar
  36. 36.
    Santarelli JG, Sarkissian V, Hou LC, Veeravagu A, Tse V (2007) Molecular events of brain metastasis. Neurosurg Focus 22:E1PubMedCrossRefGoogle Scholar
  37. 37.
    Kusters B, Westphal JR, Smits D, Ruiter DJ, Wesseling P, Keilholz U, de Waal RM (2001) The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin alpha(v)beta(3) expression. Int J Cancer 92:176–180PubMedCrossRefGoogle Scholar
  38. 38.
    Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 176(6):2958–2971PubMedCrossRefGoogle Scholar
  39. 39.
    Carbonell WS, Ansorge O, Sibson N, Muschel R (2009) The vascular basement membrane as “soil” in brain metastasis. PLoS One 4:e5857PubMedCrossRefGoogle Scholar
  40. 40.
    Yoshimasu T, Sakurai T, Oura S, Hirai I, Tanino H, Kokawa Y, Naito Y, Okamura Y, Ota I, Tani N et al (2004) Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci 95:142–148PubMedCrossRefGoogle Scholar
  41. 41.
    Belot N, Rorive S, Doyen I, Lefranc F, Bruyneel E, Dedecker R, Micik S, Brotchi J, Decaestecker C, Salmon I et al (2001) Molecular characterization of cell substratum attachments in human glial tumors relates to prognostic features. Glia 36:375–390PubMedCrossRefGoogle Scholar
  42. 42.
    Berens ME, Rief MD, Loo MA, Giese A (1994) The role of extracellular matrix in human astrocytoma migration and proliferation studied in a microliter scale assay. Clin Exp Metastasis 12:405–415PubMedCrossRefGoogle Scholar
  43. 43.
    Giese A, Loo MA, Rief MD, Tran N, Berens ME (1995) Substrates for astrocytoma invasion. Neurosurgery 37:294–301PubMedCrossRefGoogle Scholar
  44. 44.
    Giese A, Rief MD, Loo MA, Berens ME (1994) Determinants of human astrocytoma migration. Cancer Res 54:3897–3904PubMedGoogle Scholar
  45. 45.
    Merzak A, Koochekpour S, Pilkington GJ (1995) Adhesion of human glioma cell lines to fibronectin, laminin, vitronectin and collagen I is modulated by gangliosides in vitro. Cell Adhes Commun 3:27–43PubMedCrossRefGoogle Scholar
  46. 46.
    Singh P, Carraher C, Schwarzbauer JE (2010) Assembly of fibronectin extracellular matrix. Annu Rev Cell Dev Biol 26:397–419PubMedCrossRefGoogle Scholar
  47. 47.
    Giese A, Laube B, Zapf S, Mangold U, Westphal M (1998) Glioma cell adhesion and migration on human brain sections. Anticancer Res 18:2435–2447PubMedGoogle Scholar
  48. 48.
    Chintala SK, Sawaya R, Gokaslan ZL, Rao JS (1996) Modulation of matrix metalloprotease-2 and invasion in human glioma cells by alpha 3 beta 1 integrin. Cancer Lett 103:201–208PubMedCrossRefGoogle Scholar
  49. 49.
    Cordes N, Seidler J, Durzok R, Geinitz H, Brakebusch C (2006) beta1-integrin-mediated ­signaling essentially contributes to cell survival after radiation-induced genotoxic injury. Oncogene 25:1378–1390PubMedCrossRefGoogle Scholar
  50. 50.
    Hu B, Jarzynka MJ, Guo P, Imanishi Y, Schlaepfer DD, Cheng SY (2006) Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway. Cancer Res 66:775–783PubMedCrossRefGoogle Scholar
  51. 51.
    Muir D, Johnson J, Rojiani M, Inglis BA, Rojiani A, Maria BL (1996) Assessment of laminin-mediated glioma invasion in vitro and by glioma tumors engrafted within rat spinal cord. J Neurooncol 30:199–211PubMedCrossRefGoogle Scholar
  52. 52.
    Paulus W, Baur I, Beutler AS, Reeves SA (1996) Diffuse brain invasion of glioma cells requires beta 1 integrins. Lab Invest 75:819–826PubMedGoogle Scholar
  53. 53.
    Paulus W, Tonn JC (1994) Basement membrane invasion of glioma cells mediated by integrin receptors. J Neurosurg 80:515–519PubMedCrossRefGoogle Scholar
  54. 54.
    VanMeter TE, Rooprai HK, Kibble MM, Fillmore HL, Broaddus WC, Pilkington GJ (2001) The role of matrix metalloproteinase genes in glioma invasion: co-dependent and interactive proteolysis. J Neurooncol 53:213–235PubMedCrossRefGoogle Scholar
  55. 55.
    Gladson CL (1996) Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 55:1143–1149PubMedCrossRefGoogle Scholar
  56. 56.
    Lim M, Guccione S, Haddix T, Sims L, Cheshier S, Chu P, Vogel H, Harsh G (2005) alpha(v)beta(3) Integrin in central nervous system tumors. Hum Pathol 36:665–669PubMedCrossRefGoogle Scholar
  57. 57.
    Schnell O, Krebs B, Wagner E, Romagna A, Beer AJ, Grau SJ, Thon N, Goetz C, Kretzschmar HA, Tonn JC et al (2008) Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 18:378–386PubMedCrossRefGoogle Scholar
  58. 58.
    Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM et al (2001) Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 61:8730–8736PubMedGoogle Scholar
  59. 59.
    Tonn JC, Wunderlich S, Kerkau S, Klein CE, Roosen K (1998) Invasive behaviour of human gliomas is mediated by interindividually different integrin patterns. Anticancer Res 18:2599–2605PubMedGoogle Scholar
  60. 60.
    Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85:683–693PubMedCrossRefGoogle Scholar
  61. 61.
    Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA (1996) Regulation of integrin function by the urokinase receptor. Science 273:1551–1555PubMedCrossRefGoogle Scholar
  62. 62.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998PubMedCrossRefGoogle Scholar
  63. 63.
    MacDonald TJ, Ladisch S (2001) Antisense to integrin alpha v inhibits growth and induces apoptosis in medulloblastoma cells. Anticancer Res 21:3785–3791PubMedGoogle Scholar
  64. 64.
    Taga T, Suzuki A, Gonzalez-Gomez I, Gilles FH, Stins M, Shimada H, Barsky L, Weinberg KI, Laug WE (2002) alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98:690–697PubMedCrossRefGoogle Scholar
  65. 65.
    Hodivala-Dilke K (2008) alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol 20:514–519PubMedCrossRefGoogle Scholar
  66. 66.
    Maeshima Y, Colorado PC, Torre A, Holthaus KA, Grunkemeyer JA, Ericksen MB, Hopfer H, Xiao Y, Stillman IE, Kalluri R (2000) Distinct antitumor properties of a type IV collagen domain derived from basement membrane. J Biol Chem 275:21340–21348PubMedCrossRefGoogle Scholar
  67. 67.
    Chatterjee S, Matsumura A, Schradermeier J, Gillespie GY (2000) Human malignant glioma therapy using anti-alpha(v)beta3 integrin agents. J Neurooncol 46:135–144PubMedCrossRefGoogle Scholar
  68. 68.
    Kanamori M, Kawaguchi T, Berger MS, Pieper RO (2006) Intracranial microenvironment reveals independent opposing functions of host alphaVbeta3 expression on glioma growth and angiogenesis. J Biol Chem 281:37256–37264PubMedCrossRefGoogle Scholar
  69. 69.
    Kanamori M, Vanden Berg SR, Bergers G, Berger MS, Pieper RO (2004) Integrin beta3 ­overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme. Cancer Res 64:2751–2758PubMedCrossRefGoogle Scholar
  70. 70.
    MacDonald TJ, Taga T, Shimada H, Tabrizi P, Zlokovic BV, Cheresh DA, Laug WE (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48:151–157PubMedGoogle Scholar
  71. 71.
    Riemenschneider MJ, Mueller W, Betensky RA, Mohapatra G, Louis DN (2005) In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation. Am J Pathol 167:1379–1387PubMedCrossRefGoogle Scholar
  72. 72.
    Tchaicha JH, Mobley AK, Hossain MG, Aldape KD, McCarty JH (2010) A mosaic mouse model of astrocytoma identifies alphavbeta8 integrin as a negative regulator of tumor angiogenesis. Oncogene 29:4460–4472PubMedCrossRefGoogle Scholar
  73. 73.
    Cambier S, Gline S, Mu D, Collins R, Araya J, Dolganov G, Einheber S, Boudreau N, Nishimura SL (2005) Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am J Pathol 166:1883–1894PubMedCrossRefGoogle Scholar
  74. 74.
    Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, Lemke N, Brown SL, Hahn D, Neuteboom B et al (2009) Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 124:2719–2727PubMedCrossRefGoogle Scholar
  75. 75.
    Monferran S, Skuli N, Delmas C, Favre G, Bonnet J, Cohen-Jonathan-Moyal E, Toulas C (2008) Alphavbeta3 and alphavbeta5 integrins control glioma cell response to ionising radiation through ILK and RhoB. Int J Cancer 123:357–364PubMedCrossRefGoogle Scholar
  76. 76.
    Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL (1999) Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 5:1587–1594PubMedGoogle Scholar
  77. 77.
    Hsu AR, Veeravagu A, Cai W, Hou LC, Tse V, Chen X (2007) Integrin alpha v beta 3 antagonists for anti-angiogenic cancer treatment. Recent Pat Anticancer Drug Discov 2:143–158PubMedCrossRefGoogle Scholar
  78. 78.
    Yamada S, Bu XY, Khankaldyyan V, Gonzales-Gomez I, McComb JG, Laug WE (2006) Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery 59:1304–1312PubMedCrossRefGoogle Scholar
  79. 79.
    Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM et al (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610–5617PubMedCrossRefGoogle Scholar
  80. 80.
    Reardon DA, Nabors LB, Stupp R, Mikkelsen T (2008) Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs 17:1225–1235PubMedCrossRefGoogle Scholar
  81. 81.
    Tabatabai G, Weller M, Nabors B, Picard M, Reardon D, Mikkelsen T, Ruegg C, Stupp R (2010) Targeting integrins in malignant glioma. Target Oncol 5:175–181PubMedCrossRefGoogle Scholar
  82. 82.
    Kita D, Takino T, Nakada M, Takahashi T, Yamashita J, Sato H (2001) Expression of dominant-negative form of Ets-1 suppresses fibronectin-stimulated cell adhesion and migration through down-regulation of integrin alpha5 expression in U251 glioma cell line. Cancer Res 61:7985–7991PubMedGoogle Scholar
  83. 83.
    Maglott A, Bartik P, Cosgun S, Klotz P, Ronde P, Fuhrmann G, Takeda K, Martin S, Dontenwill M (2006) The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells. Cancer Res 66:6002–6007PubMedCrossRefGoogle Scholar
  84. 84.
    Martin S, Cosset EC, Terrand J, Maglott A, Takeda K, Dontenwill M (2009) Caveolin-1 regulates glioblastoma aggressiveness through the control of alpha(5)beta(1) integrin expression and modulates glioblastoma responsiveness to SJ749, an alpha(5)beta(1) integrin antagonist. Biochim Biophys Acta 1793:354–367PubMedCrossRefGoogle Scholar
  85. 85.
    Martinkova E, Maglott A, Leger DY, Bonnet D, Stiborova M, Takeda K, Martin S, Dontenwill M (2010) alpha5beta1 integrin antagonists reduce chemotherapy-induced premature senescence and facilitate apoptosis in human glioblastoma cells. Int J Cancer 127:1240–1248PubMedCrossRefGoogle Scholar
  86. 86.
    Carter A (2010) Integrins as target: first phase III trial launches, but questions remain. J Natl Cancer Inst 102:675–677PubMedCrossRefGoogle Scholar
  87. 87.
    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMedGoogle Scholar
  88. 88.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  89. 89.
    Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5PubMedCrossRefGoogle Scholar
  90. 90.
    Dave B, Chang J (2009) Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia 14:79–82PubMedCrossRefGoogle Scholar
  91. 91.
    Ischenko I, Seeliger H, Schaffer M, Jauch KW, Bruns CJ (2008) Cancer stem cells: how can we target them? Curr Med Chem 15:3171–3184PubMedCrossRefGoogle Scholar
  92. 92.
    Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421–432PubMedCrossRefGoogle Scholar
  93. 93.
    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.The Scripps Research InstituteLa JollaUSA

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