Journal of Neuro-Oncology

, Volume 53, Issue 2, pp 129–147 | Cite as

Biological Mechanisms of Glioma Invasion and Potential Therapeutic Targets

  • Berit Bølge Tysnes
  • Rupavathana Mahesparan


The current understanding of glioma biology reveals targets for anti-invasive therapy which include manipulations of extracellular matrix and receptors, growth factors and cytokines, proteases, cytoskeletal components, oncogenes and tumor suppressor genes. A better understanding of the complex regulation and the signalling molecules involved in glioma invasion is still needed in order to design new and effective treatment modalities towards invasive tumor cells. Representative and valid in vitro experimental systems and animal models of gliomas are necessary for the characterization of the invasive phenotype and further development of anti-invasive therapy. In the future, it will probably be important to move from comparative genomic modelling through protein characterization based on advanced proteomic techniques to analyse tissue samples, where the aim for gliomas should be to compare invaded and non-invaded tissue. This will hopefully render promising new therapeutic targets for gliomas.

glioma invasion biological mechanisms experimental models anti-invasive therapy therapeutic targets invasive phenotype 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Russell DS, Rubinstein LJ: Tumours of central neuroepithelial origin. In: Pathology of Tumours of the Nervous System, 5th edn. Williams and Wilkins, London, 1989, pp 83–350Google Scholar
  2. 2.
    Pedersen P-H, Rucklidge GJ, Mørk SJ, Terzis AJA, Engebraaten O, Lund-Johansen M, Backlund E-O, Laerum OD, Bjerkvig R: Leptomeningeal tissue: a barrier 141 against brain tumor cell invasion. J Natl Cancer Inst 86: 1593–1599, 1994Google Scholar
  3. 3.
    Bjerkvig R, Lund-Johansen M, Edvardsen K: Tumor cell invasion and angiogenesis in the central nervous system. Curr Opin Oncol 9: 223–229, 1997Google Scholar
  4. 4.
    Pedersen P-H, Marienhagen K, Mørk S, Bjerkvig R: Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain. Cancer Res 53: 5158–5165, 1993Google Scholar
  5. 5.
    Thorsen F, Tysnes BB: Brain tumor cell invasion, anatomical and biological considerations. Anticancer Res 17: 4121–4126, 1997Google Scholar
  6. 6.
    Bigner SH, Burger PC, Wong AJ, Werner MH, Hamilton SR, Muhlbaier LH, Vogelstein B, Bigner DD: Gene amplification in malignant human gliomas: clinical and histopathologic aspects. J Neuropathol Exp Neurol 47: 191–205, 1988Google Scholar
  7. 7.
    Bigner SH, Vogelstein B: Cytogenetics and molecular genetics of malignant gliomas and medulloblastoma. Brain Pathol 1: 12–18, 1990Google Scholar
  8. 8.
    James CD, Carlbom E, Dumanski JP, Hansen M, Nordenskjold M, Collins VP, Cavenee WK: Clonal genomic alterations in glioma malignancy stages. Cancer Res 48: 5546–5551, 1988Google Scholar
  9. 9.
    James CD, Collins VP: Molecular genetic characterization of CNS tumor oncogenesis. Adv Cancer Res 58: 121–142, 1992Google Scholar
  10. 10.
    Furnari FB, Huang HJ, Cavenee WK: Genetics and malignant progression of human brain tumours. Cancer Surv 25: 233–275, 1995Google Scholar
  11. 11.
    Kleihues P, Lubbe J, Watanabe K, Von Ammon K, Ohgaki H: Genetic alterations associated with glioma progression. Verh Dtsch Ges Pathol 78: 43–47, 1994Google Scholar
  12. 12.
    Ohgaki H, Schauble B, Zur Hausen A, Von Ammon K, Kleihues P: Genetic alterations associated with the evolution and progression of astrocytic brain tumours. Virchows Arch 427: 113–118, 1995Google Scholar
  13. 13.
    Kleihues P, Cavenee WK: Pathology and Genetics of Tumours of the Nervous System, International Agency for Research on Cancer, Lyon, 1997, p 255Google Scholar
  14. 14.
    Ichimura K, Schmidt EE, Miyakawa A, Goike HM, Collins VP: Distinct patterns of deletion on 10p and 10q suggest involvement of multiple tumor suppressor genes in the development of astrocytic gliomas of different malignancy grades. Genes Chromosomes Cancer 22: 9–15, 1998Google Scholar
  15. 15.
    Von Deimling A, Fimmers R, Schmidt MC, Bender B, Fassbender F, Nagel J, Jahnke R, Kaskel P, Duerr EM, Koopmann J, Maintz D, Steinbeck S, Wick W, Platten M, Muller DJ, Przkora R, Waha A, Blumcke B, Wellenreuther R, Meyer-Puttlitz B, Schmidt O, Mollenhauer J, Poustka A, Stangl AP, Lenartz D, Von Ammon K: Comprehensive allelotype and genetic anaysis of 466 human nervous system tumors. J Neuropathol Exp Neurol 59: 544–558, 2000Google Scholar
  16. 16.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947, 1997Google Scholar
  17. 17.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362, 1997Google Scholar
  18. 18.
    Von Deimling A, Louis DN, Von Ammon K, Petersen I, Hoell T, Chung RY, Martuza RL, Schoenfeld DA, Yasargil MG, Wiestler OD, Seizinger BR: Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme. J Neurosurg 77: 295–301, 1992Google Scholar
  19. 19.
    Von Deimling A, Von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN: Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3: 19–26, 1993Google Scholar
  20. 20.
    Friedlander DR, Zagzag D, Shiff B, Cohen H, Allen JC, Kelly PJ, Grumet M: Migration of brain tumor cells on extracellular matrix proteins in vitro correlates with tumor type and grade and involves alphaV and beta1 integrins. Cancer Res 56: 1939–1947, 1996Google Scholar
  21. 21.
    Bunge RP, Bunge MB: Interrelationship between Schwann cell function and extracellular matrix production. Trends Neurosci 6: 499–505, 1983Google Scholar
  22. 22.
    Carbonetto S: The extracellular matrix of the nervous system. Trends Neurosci 7: 382–387, 1984Google Scholar
  23. 23.
    De Clerck YA, Shimada H, Gonzalez-Gomez I, Raffel C: Tumoral invasion in the central nervous system. J Neuro-Oncol 18: 111–121, 1994Google Scholar
  24. 24.
    Uhm JH, Gladson CL, Rao JS: The role of integrins in the malignant phenotype of gliomas. Front Biosci 4: D188–D199, 1999Google Scholar
  25. 25.
    Rutka JT, Apodaca G, Stern R, Rosenblum M: The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69: 155–170, 1988Google Scholar
  26. 26.
    Yasuhara O, Akiyama H, McGeer EG, McGeer PL: Immunohistochemical localization of hyaluronic acid in rat and human brain. Brain Res 635: 269–282, 1994Google Scholar
  27. 27.
    Delpech B, Maingonnat C, Girard N, Chauzy C, Maunoury R, Olivier A, Tayot J, Creissard P: Hyaluronan and hyaluronectin in the extracellular matrix of human brain tumour stroma. Eur J Cancer 29A: 1012–1017, 1993Google Scholar
  28. 28.
    Knott JCA, Mahesparan R, Garcia-Cabrera I, Bølge Tysnes B, Edvardsen K, Ness GO, Mørk S, Lund-Johansen M, Bjerkvig R: Stimulation of extracellular matrix components in the normal brain by invading glioma cells. Int J Cancer 75: 864–872, 1998Google Scholar
  29. 29.
    Tysnes BB, Larsen LF, Ness GO, Mahesparan R, Edvardsen K, Garcia-Cabrera I, Bjerkvig R: Stimulation of glioma-cell migration by laminin and inhibition by antialpha3 and anti-beta1 integrin antibodies. Int J Cancer 67: 777–784, 1996Google Scholar
  30. 30.
    Mahesparan R, Tysnes BB, Edvardsen K, Haugeland HK, Cabrera IG, Lund-Johansen M, Engebraaten O, Bjerkvig R: Role of high molecular weight extracellular matrix proteins in glioma cell migration. Neuropathol Appl Neurobiol 23: 102–112, 1997Google Scholar
  31. 31.
    Goldbrunner RH, Haugland HK, Klein CE, Kerkau S, Roosen K, Tonn JC: ECM dependent and integrin mediated tumor cell migration of human glioma and melanoma cell lines under serum-free conditions. Anticancer Res 16: 3679–3687, 1996Google Scholar
  32. 32.
    Haugland HK, Tysnes BB, Tysnes OB: Adhesion and migration of human glioma cells are differently dependent on extracellular matrix molecules. Anticancer Res 17: 1035–1042, 1997Google Scholar
  33. 33.
    Berens ME, Rief MD, Loo MA, Giese A: The role of extracellular matrix in human astrocytoma migration and proliferation studied in a microliter scale assay. Clin Exp Metastasis 12: 405–415, 1994Google Scholar
  34. 34.
    Giese A, Rief MD, Loo MA, Berens ME: Determinants of human astrocytoma migration. Cancer Res 54: 3897–3904, 1994Google Scholar
  35. 35.
    Koochekpour S, Merzak A, Pilkington GJ: Extracellular matrix proteins inhibit proliferation, upregulate migration and induce morphological changes in human glioma cell lines. Eur J Cancer 31A: 375–380, 1995Google Scholar
  36. 36.
    Mahesparan R, Tysnes BB, Read TA, Enger PØ, Bjerkvig R, Lund-Johansen M: Extracellular matrixinduced cell migration from glioblastoma biopsy specimens in vitro. Acta Neuropathol (Berl) 97: 231–239, 1999Google Scholar
  37. 37.
    Deryugina EI, Bourdon MA: Tenascin mediates human glioma cell migration and modulates cell migration on fibronectin. J Cell Sci 109: 643–652, 1996Google Scholar
  38. 38.
    Ohnishi T, Arita N, Hiraga S, Taki T, Izumoto S, Fukushima Y, Hayakawa T: Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity. Clin Exp Metastasis 15: 538–546, 1997Google Scholar
  39. 39.
    Ohnishi T, Hiraga S, Izumoto S, Matsumura H, Kanemura Y, Arita N, Hayakawa T: Role of fibronectinstimulated tumor cell migration in glioma invasion in vivo: clinical significance of fibronectin and fibronectin receptor expressed in human glioma tissues. Clin Exp Metastasis 16: 729–741, 1998Google Scholar
  40. 40.
    Gladson CL, Cheresh DA: Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 88: 1924–1932, 1991Google Scholar
  41. 41.
    Zagzag D, Friedlander DR, Miller DC, Dosik J, Cangiarella J, Kostianovsky M, Cohen H, Grumet M, Greco MA: Tenascin expression in astrocytomas correlates with angiogenesis. Cancer Res 55: 907–914, 1995Google Scholar
  42. 42.
    Zagzag D, Friedlander DR, Dosik J, Chikramane S, Chan W, Greco MA, Allen JC, Dorovini-Zis K, Grumet M: Tenascin-C expression by angiogenic vessels in human astrocytomas and by human brain endothelial cells in vitro. Cancer Res 56: 182–189, 1996Google Scholar
  43. 43.
    Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL: Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res 5: 1587–1594, 1999Google Scholar
  44. 44.
    Tysnes BB, Mahesparan R, Thorsen F, Haugland HK, Porwol T, Enger PO, Lund-Johansen M, Bjerkvig R: Laminin expression by glial fibrillary acidic protein positive cells in human gliomas. Int J Dev Neurosci 17: 531–539, 1999Google Scholar
  45. 45.
    Eddleston M, Mucke L: Molecular profile of reactive astrocytes – implications for their role in neurologic disease. Neuroscience 54: 15–36, 1993Google Scholar
  46. 46.
    Thorgeirsson UP, Lindsay CK, Cottam DW, Gomez DE: Tumor invasion, proteolysis, and angiogenesis. J Neuro-Oncol 18: 89–103, 1994Google Scholar
  47. 47.
    Brooks PC, Stromblad S, Sanders LC, Von Schalscha TL, Aimes RT, S tetler-Stevenson WG, Quigley JP, Cheresh DA: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85: 683–693, 1996Google Scholar
  48. 48.
    Mohanam S, Sawaya RE, Yamamoto M, Bruner JM, Nicholson GL, Rao JS: Proteolysis and invasiveness of brain tumors: role of urokinase-type plasminogen activator receptor. J Neuro-Oncol 22: 153–160, 1994Google Scholar
  49. 49.
    Romanic AM, Madri JA: Extracellular matrix-degrading proteinases in the nervous system. Brain Pathol 4: 145–156, 1994Google Scholar
  50. 50.
    Stetler-Stevenson WG, Aznavoorian S, Liotta LA: Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9: 541–573, 1993Google Scholar
  51. 51.
    Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, Tryggvason K: Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science 284: 1667–1670, 1999Google Scholar
  52. 52.
    Rooprai HK, McCormick D: Proteases and their inhibitors in human brain tumours: a review. Anticancer Res 17: 4151–4162, 1997Google Scholar
  53. 53.
    Vince GH, Wagner S, Pietsch T, Klein R, Goldbrunner RH, Roosen K, Tonn JC: Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas. Int J Dev Neurosci 17: 437–445, 1999Google Scholar
  54. 54.
    Rao JS, Steck PA, Mohanam S, Stetler-Stevenson WG, Liotta LA, Sawaya R: Elevated levels of M(r) 92,000 type IV collagenase in human brain tumors. Cancer Res 53: 2208–2211, 1993Google Scholar
  55. 55.
    Nakagawa T, Kubota T, Kabuto M, Sato K, Kawano H, Hayakawa T, Okada Y: Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors. J Neurosurg 81: 69–77, 1994Google Scholar
  56. 56.
    Khokha R, Denhardt DT: Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a reviewof their role in tumorigenesis and tissue invasion. Invasion Metastasis 9: 391–405, 1989Google Scholar
  57. 57.
    Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991Google Scholar
  58. 58.
    Uhm JH, Dooley NP, Villemure JG, Yong VW: Mechanisms of glioma invasion: role of matrix-metalloproteinases. Can J Neurol Sci 24: 3–15, 1997Google Scholar
  59. 59.
    Conese M, Blasi F: The urokinase/urokinase-receptor system and cancer invasion. Baillieres Clin Haematol 8: 365–389, 1995Google Scholar
  60. 60.
    Landau BJ, Kwaan HC, Verrusio EN, Brem SS: Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant human brain tumors. Cancer Res 54: 1105–1108, 1994Google Scholar
  61. 61.
    Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K, Rao VH, Tomonaga M, Nicolson GL, 143 Rao JS: Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo. Cancer Res 54: 3656–3661, 1994Google Scholar
  62. 62.
    Yamamoto M, Sawaya R, Mohanam S, Loskutoff DJ, Bruner JM, Rao VH, Oka K, Tomonaga M, Nicolson GL, Rao JS: Expression and cellular localization of messenger RNA for plasminogen activator inhibitor type 1 in human astrocytomas in vivo. Cancer Res 54: 3329–3332, 1994Google Scholar
  63. 63.
    Rempel SA, Rosenblum ML, Mikkelsen T, Yan PS, Ellis KD, Golembieski WA, Sameni M, Rozhin J, Ziegler G, Sloane BF: Cathepsin B expression and localization in glioma progression and invasion. Cancer Res 54: 6027–6031, 1994Google Scholar
  64. 64.
    Mikkelsen T, Yan PS, Ho KL, Sameni M, Sloane BF, Rosenblum ML: Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis. J Neurosurg 83: 285–290, 1995Google Scholar
  65. 65.
    Sivaparvathi M, Sawaya R, Wang SW, Rayford A, Yamamoto M, Liotta LA, Nicolson GL, Rao JS: Overexpression and localization of cathepsin B during the progression of human gliomas. Clin Exp Metastasis 13: 49–56, 1995Google Scholar
  66. 66.
    Berquin IM, Sloane BF: Cathepsin B expression in human tumors. Adv Exp Med Biol 389: 281–294, 1996Google Scholar
  67. 67.
    Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260–1270, 1997Google Scholar
  68. 68.
    Hynes RO: Integrins: versatility, modulation, and signalling in cell adhesion. Cell 69: 11–25, 1992Google Scholar
  69. 69.
    Kumar CC: Signaling by integrin receptors. Oncogene 17: 1365–1373, 1998Google Scholar
  70. 70.
    Paulus W, Baur I, Schuppan D, Roggendorf W: Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 143: 154–163, 1993Google Scholar
  71. 71.
    Gingras MC, Roussel E, Bruner JM, Branch CD, Moser RP: Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue. J Neuroimmunol 57: 143–153, 1995Google Scholar
  72. 72.
    PaulusW: Brain extracellular matrix, adhesion molecules, and glioma invasion. In: Mikkelsen T, Bjerkvig R, Laerum OD, Rosenblum ML (eds) Brain Tumor Invasion: Biological, Clinical, and Therapeutic Considerations. Wiley-Liss, New York, 1998, pp 301–322Google Scholar
  73. 73.
    Fukushima Y, Ohnishi T, Arita N, Hayakawa T, Sekiguchi K: Integrin alpha3beta1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells. Int J Cancer 76: 63–72, 1998Google Scholar
  74. 74.
    Humphries MJ: Towards a structural model of an integrin. Biochem Soc Symp 65: 63–78, 1999Google Scholar
  75. 75.
    Horwitz AF: Integrins and health. SciAm 276: 46–53, 1997Google Scholar
  76. 76.
    Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J 18: 882–892, 1999Google Scholar
  77. 77.
    Gladson CL: Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 55: 1143–1149, 1996Google Scholar
  78. 78.
    Rosales C, O'Brien V, Kornberg L, Juliano R: Signal transduction by cell adhesion receptors. Biochim Biophys Acta 1242: 77–98, 1995Google Scholar
  79. 79.
    Asano K, Kubo O, Tajika Y, Huang MC, Takakura K, Ebina K, Suzuki S: Expression and role of cadherins in astrocytic tumors. Brain Tumor Pathol 14: 27–33, 1997Google Scholar
  80. 80.
    Tews DS, Nissen A: Expression of adhesion factors and degrading proteins in primary and secondary glioblastomas and their precursor tumors. Invasion Metastasis 18: 271–284, 1998Google Scholar
  81. 81.
    Edvardsen K, Brunner N, Spang-Thomsen M, Walsh FS, Bock E: Migratory, invasive and metastatic capacity of NCAM transfected rat glioma cells. Int J Dev Neurosci 11: 681–690, 1993Google Scholar
  82. 82.
    Edvardsen K, Pedersen P-H, Bjerkvig R, Hermann GG, Zeuthen J, Laerum OD, Walsh FS, Bock E: Transfection of glioma cells with the neural-cell adhesion molecule NCAM: effect on glioma-cell invasion and growth in vivo. Int J Cancer 58: 116–122, 1994Google Scholar
  83. 83.
    Owens GC, Orr EA, DeMasters BK, Muschel RJ, Berens ME, Kruse CA: Overexpression of a transmembrane isoform of neural cell adhesion molecule alters the invasiveness of rat CNS-1 glioma. Cancer Res 58: 2020–2028, 1998Google Scholar
  84. 84.
    Kleinschmidt-DeMasters BK, Orr EA, Savelieva E, Owens GC, Kruse CA: Paucity of retinoic acid receptor alpha (RAR alpha) nuclear immunostaining in gliomas and inability of retinoic acid to influence neural cell adhesion molecule (NCAM) expression. J Neuro-Oncol 41: 31–42, 1999Google Scholar
  85. 85.
    Kuppner MC, Van Meir E, Gauthier T, Hamou MF, De Tribolet N: Differential expression of the CD44 molecule in human brain tumours. Int J Cancer 50: 572–577, 1992Google Scholar
  86. 86.
    Merzak A, Koocheckpour S, Pilkington GJ: CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res 54: 3988–3992, 1994Google Scholar
  87. 87.
    Sneath RJS, Mangham DC: The normal structure and function of CD44 and its role in neoplasia. Mol Pathol 51: 191–200, 1998Google Scholar
  88. 88.
    Feldkamp MM, Lau N, Guha A: Signal transduction pathways and their relevance in human astrocytomas. J Neuro-Oncol 35: 223–248, 1997Google Scholar
  89. 89.
    Lund-Johansen M, Bjerkvig R, Humphrey PA, Bigner SH, Bigner DD, Laerum OD: Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro. Cancer Res 50: 6039–6044, 1990Google Scholar
  90. 90.
    Lund-Johansen M, Forsberg K, Bjerkvig R, Laerum OD: Effects of growth factors on a human glioma cell line during invasion into rat brain aggregates in culture. Acta Neuropathol 84: 190–197, 1992Google Scholar
  91. 91.
    Engebraaten O, Bjerkvig R, Pedersen P-H, Laerum OD: Effects of EGF, bFGF, NGF and PDGF (bb) on cell proliferative, migratory and invasive capacities of human braintumour biopsies in vitro. Int J Cancer 53: 209–214, 1993Google Scholar
  92. 92.
    Pedersen P-H, Ness GO, Engebraaten O, Bjerkvig R, Lillehaug JR, Laerum OD: Heterogeneous response to the growth factors (EGF, PDGF (bb), TGF-a, bFGF, IL-2) on glioma spheroid growth, migration and invasion. Int J Cancer 56: 255–261, 1994Google Scholar
  93. 93.
    Panayotou G, End P, Aumailley M, Timpl R, Engel J: Domains of laminin with growth-factor activity. Cell 56: 93–101, 1989Google Scholar
  94. 94.
    Tysnes BB, Haugland HK, Bjerkvig R: Epidermal growth factor and laminin receptors contribute to migratory and invasive properties of gliomas. Invasion Metastasis 17: 270–280, 1997Google Scholar
  95. 95.
    Matsumoto K, Ziober BL, Yao CC, Kramer RH: Growth factor regulation of integrin-mediated cell motility. Cancer Metastasis Rev 14: 205–217, 1995Google Scholar
  96. 96.
    Juliano R: Signal transduction by integrins and its role in the regulation of tumor growth. Cancer Metastasis Rev 13: 25–30, 1994Google Scholar
  97. 97.
    Boudreau NJ, Jones PL: Extracellular matrix and integrin signalling: the shape of things to come. Biochem J 339: 481–488, 1999Google Scholar
  98. 98.
    Dedhar S, Williams B, Hannigan G: Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling. Trends Cell Biol 9: 319–323, 1999Google Scholar
  99. 99.
    Clezardin P: Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci 54: 541–548, 1998Google Scholar
  100. 100.
    Chicoine MR, Silbergeld DL: Assessment of brain tumor cell motility in vivo and in vitro. J Neurosurg 82: 615–622, 1995Google Scholar
  101. 101.
    Brauner T, Schmid A, Hulser DF: Tumor cell invasion and gap junctional communication. I. Normal and malignant cells confronted in monolayer cultures. Invasion Metastasis 10: 18–30, 1990Google Scholar
  102. 102.
    Brauner T, Hulser DF: Tumor cell invasion and gap junctional communication. II. Normal and malignant cells confronted in multicell spheroids. Invasion Metastasis 10: 31–48, 1990Google Scholar
  103. 103.
    Lund-Johansen M, Engebraaten O, Bjerkvig R, Laerum OD: Invasive glioma cells in tissue culture. Anticancer Res 10: 1135–1151, 1990Google Scholar
  104. 104.
    Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, Mcewan RN: Arapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 47: 3239–3245, 1987Google Scholar
  105. 105.
    De Ridder LI, Laerum OD: Invasion of rat neurogenic cell lines in embryonic chick heart fragments in vitro. J Natl Cancer Inst 66: 723–728, 1981Google Scholar
  106. 106.
    Bjerkvig R, Laerum OD, Mella O: Glioma cell interactions with fetal rat brain aggregates in vitro and with brain tissue in vivo. Cancer Res 46: 4071–4079, 1986Google Scholar
  107. 107.
    Rogers JP, Moss SJ, Pilkington GJ: Invasiveness of human and animal cells into three-dimentional human optic nerve cultures (Abstract). Neuropathol Appl Neurobiol 19: 190, 1993Google Scholar
  108. 108.
    Ohnishi T, Matsumura H, Izumoto S, Hiraga S, Hayakawa T: A novel model of glioma cell invasion using organotypic brain slice culture. Cancer Res 58: 2935–2940, 1998Google Scholar
  109. 109.
    Jung S, Ackerley C, Ivanchuk S, Mondal S, Becker LE, Rutka JT: Tracking the invasiveness of human astrocytoma cells by using green fluorescent protein in an organotypical brain slice model. J Neurosurg 94: 80–89, 2001Google Scholar
  110. 110.
    McKeever PE, Davenport RD, Shakui P: Patterns of antigenic expression of human glioma cells. Crit Rev Neurobiol 6: 119–147, 1991Google Scholar
  111. 111.
    Mork SJ, Laerum OD: Modal DNA content of human intracranial neoplasms studied by flow cytometry. J Neurosurg 53: 198–204, 1980Google Scholar
  112. 112.
    Paulus W, Huettner C, Tonn JC: Collagens, integrins and the mesenchymal drift in glioblastomas: a comparison of biopsy specimens, spheroids and early monolayer cultures. Int J Cancer 58: 841–846, 1994Google Scholar
  113. 113.
    Onda K, Tanaka R, Washiyama K, Takeda N, Kumanishi T: Correlation of DNA ploidy and morphological features of human glioma cell cultures with the establishment of cell lines. Acta Neuropathol 76: 433–440, 1988Google Scholar
  114. 114.
    Bjerkvig R, Tønnesen A, Laerum OD, Backlund EO: Multicellular tumor spheroids from human gliomas maintained in organ culture. J Neurosurg 72: 463–475, 1990Google Scholar
  115. 115.
    Kaaijk P, Troost D, Das PK, Leenstra S, Bosch DA: Longterm culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas. Neuropathol Appl Neurobiol 21: 386–391, 1995Google Scholar
  116. 116.
    Peterson DL, Sheridan PJ, Brown WE Jr: Animal models for brain tumors: historical perspectives and future directions. J Neurosurg 80: 865–876, 1994Google Scholar
  117. 117.
    Barth RF: Rat brain tumor models in experimental neurooncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neuro-Oncol 36: 91–102, 1998Google Scholar
  118. 118.
    Bigner DD, Swenberg JA: Janisch and Schreiber's Experimental Tumors of the Central Nervous System. 1st English edn. The Upjohn Company, Kalmazoo, 1977Google Scholar
  119. 119.
    Druckrey H, Ivankovic S, Gimmy J: Cancerogenic effects of methyl-and ethyl-nitrosourea(MNUand ENU) at single intracerebral and intracarotidal injection in newborn and young BD-rats. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 79: 282–297, 1973Google Scholar
  120. 120.
    Russell DS, Rubinstein LJ: Experimental tumours of the nervous system. Pathology of tumours of the nervous system. 5th edn. Williams and Wilkins, London, 1989, pp. 58–82Google Scholar
  121. 121.
    Lantos PL, Vandenberg SR, Kleihues P: Tumours of the nervous system. In: Graham DI, Lantos PL (eds) Greenfield's Neuropathology. II. Arnold, London, 1997 pp 583–879Google Scholar
  122. 122.
    Benda P, Someda K, Messer J, Sweet WH: Morphological and immunochemical studies of rat glial tumors and clonal strains propagated in culture. J Neurosurg 34: 310–323, 1971Google Scholar
  123. 123.
    Kooistra KL, Rodriguez M, Powis G, Yaksh TL, Harty GJ, Hilton JF, Laws ER Jr: Development of experimental models for meningeal neoplasia using intrathecal injection of 9L gliosarcoma andWalker 256 carcinosarcoma in the rat. Cancer Res 46: 317–323, 1986Google Scholar
  124. 124.
    Laerum OD, Rajewsky MF, Schachner M, Stavrou D, Haglid KG, Haugen Å: Phenotypic properties of neoplastic cell lines developed from fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. Z Krebsforsch 89: 273–295, 1977Google Scholar
  125. 125.
    Holland EC: A mouse model for glioma: biology, pathology, and therapeutic opportunities. Toxicol Pathol 28: 171–177, 2000Google Scholar
  126. 126.
    Holland EC, Li Y, Celestino J, Dai C, Schaefer L, Sawaya RA, Fuller GN: Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol 157: 1031–1037, 2000Google Scholar
  127. 127.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN: Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25: 55–57, 2000Google Scholar
  128. 128.
    Weissenberger J, Steinbach JP, Malin G, Spada S, Rulicke T, Aguzzi A: Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 14: 2005–2013, 1997Google Scholar
  129. 129.
    Stromblad LG, Brun A, Salford LG, Stenevi U: A model for xenotransplantation of human malignant astrocytomas into the brain of normal adult rats. Acta Neurochir 65: 217–226, 1982Google Scholar
  130. 130.
    Engebraaten O, Hjortland GO, Hirschberg H, Fodstad O: Growth of precultured human glioma specimens in nude rat brain. J Neurosurg 90: 125–132, 1999Google Scholar
  131. 131.
    Paulus W, Baur I, Beutler AS, Reeves SA: Diffuse brain invasion of glioma cells requires beta 1 integrins. Lab Invest 75: 819–826, 1996Google Scholar
  132. 132.
    Treasurywala S, Berens ME: Migration arrest in glioma cells is dependent on the alphav integrin subunit. Glia 24: 236–243, 1998Google Scholar
  133. 133.
    Mizejewski GJ: Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med 222: 124–138, 1999Google Scholar
  134. 134.
    Tonn JC, Wunderlich S, Kerkau S, Klein CE, Roosen K: Invasive behaviour of human gliomas is mediated by interindividually different integrin patterns. Anticancer Res 18: 2599–2605, 1998Google Scholar
  135. 135.
    Paulus W, Tonn JC: Basement membrane invasion of glioma cells mediated by integrin receptors. J Neurosurg 80: 515–519, 1994Google Scholar
  136. 136.
    Bigner DD, Brown MT, Friedman AH, Coleman RE, Akabani G, Friedman HS, Thorstad WL, McLendon RE, Bigner SH, Zhao XG, Pegram CN, Wikstrand CJ, Herndon JE, II, Vick NA, Paleologos N, Cokgor I, Provenzale JM, Zalutsky MR: Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol 16: 2202–2212, 1998Google Scholar
  137. 137.
    Blasberg RG, Nakagawa H, Bourdon MA, Groothuis DR, Patlak CS, Bigner DD: Regional localization of a gliomaassociated antigen defined by monoclonal antibody 81C6 in vivo: kinetics and implications for diagnosis and therapy. Cancer Res 47: 4432–4443, 1987Google Scholar
  138. 138.
    Carnemolla B, Castellani P, Ponassi M, Borsi L, Urbini S, Nicolo G, Dorcaratto A, Viale G, Winter G, Neri D, Zardi L: Identification of a glioblastoma-associated tenascin-C isoform by a high affinity recombinant antibody. Am J Pathol 154: 1345–1352, 1999Google Scholar
  139. 139.
    Foulon CF, Bigner DD, Zalutsky MR: Preparation and characterization of anti-tenascin monoclonal antibody – streptavidin conjugates for pretargeting applications. Bioconjug Chem 10: 867–876, 1999Google Scholar
  140. 140.
    Lee Y, Bullard DE, Humphrey PA, Colapinto EV, Friedman HS, Zalutsky MR, Coleman RE, Bigner DD: Treatment of intracranial human glioma xenografts with 131I-labeled anti-tenascin monoclonal antibody 81C6. Cancer Res 48: 2904–2910, 1988Google Scholar
  141. 141.
    Lee YS, Bullard DE, Zalutsky MR, Coleman RE, Wikstrand CJ, Friedman HS, Colapinto EV, Bigner DD: Therapeutic efficacy of anti-glioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model. Cancer Res 48: 559–566, 1988Google Scholar
  142. 142.
    Paganelli G, Grana C, Chinol M, Cremonesi M, De Cicco C, De Braud F, Robertson C, Zurrida S, Casadio C, Zoboli S, Siccardi AG, Veronesi U: Antibodyguided three-step therapy for high grade glioma with yttrium-90 biotin. Eur J Nucl Med 26: 348–357, 1999Google Scholar
  143. 143.
    Riva P, Franceschi G, Frattarelli M, Lazzari S, Riva N, Giuliani G, Casi M, Sarti G, Guiducci G, Giorgetti G, Gentile R, Santimaria M, Jermann E, Maeke HR: Locoregional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study. Clin Cancer Res 5: 3275–3280, 1999Google Scholar
  144. 144.
    Riva P, Franceschi G, Frattarelli M, Riva N, Guiducci G, Cremonini AM, Giuliani G, Casi M, Gentile R, Jekunen AA, Kairemo KJ: 131I radioconjugated antibodies for the locoregional radioimmunotherapy of high-grade malignant glioma – phase I and II study. Acta Oncol 38: 351–359, 1999Google Scholar
  145. 145.
    Mohanam S, Wang SW, Rayford A, Yamamoto M, Sawaya R, Nakajima M, Liotta LA, Nicolson GL, Stetler-Stevenson WG, Rao JS: Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo. Clin Exp Metastasis 13: 57–62, 1995Google Scholar
  146. 146.
    Nakano A, Tani E, Miyazaki K, Yamamoto Y, Furuyama J: Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. J Neurosurg 83: 298–307, 1995Google Scholar
  147. 147.
    Lampert K, Machein U, Machein MR, Conca W, Peter HH, Volk B: Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol 153: 429–437, 1998Google Scholar
  148. 148.
    Matsuzawa K, Fukuyama K, Hubbard SL, Dirks PB, Rutka JT: Transfection of an invasive human astrocytoma cell line with a TIMP-1 cDNA: modulation of astrocytoma invasive potential. J Neuropathol Exp Neurol 55: 88–96, 1996Google Scholar
  149. 149.
    Tonn JC, Kerkau S, Hanke A, Bouterfa H, Mueller JG, Wagner S, Vince GH, Roosen K: Effect of synthetic matrixmetalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int J Cancer 80: 764–772, 1999Google Scholar
  150. 150.
    Mohanam S, Gladson CL, Rao CN, Rao JS: Biological significance of the expression of urokinase-type plasminogen activator receptors (uPARs) in brain tumors. Front Biosci 4: D178–D187, 1999Google Scholar
  151. 151.
    Mohan PM, Lakka SS, Mohanam S, Kin Y, Sawaya R, Kyritsis AP, Nicolson GL, Rao JS: Downregulation of the urokinase-type plasminogen activator receptor through inhibition of translation by antisense oligonucleotide suppresses invasion of human glioblastoma cells. Clin Exp Metastasis 17: 617–621, 1999Google Scholar
  152. 152.
    Mohan PM, Chintala SK, Mohanam S, Gladson CL, Kim ES, Gokaslan ZL, Lakka SS, Roth JA, Fang B, 146 Sawaya R, Kyritsis AP, Rao JS: Adenovirus-mediated delivery of antisense gene to urokinase-type plasminogen activator receptor suppresses glioma invasion and tumor growth. Cancer Res 59: 3369–3373, 1999Google Scholar
  153. 153.
    Maidment SL: The cytoskeleton and brain tumour cell migration. Anticancer Res 17: 4145–4149, 1997Google Scholar
  154. 154.
    Terzis AJ, Thorsen F, Heese O, Visted T, Bjerkvig R, Dahl O, Arnold H, Gundersen G: Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro. Br J Cancer 75: 1744–1452, 1997Google Scholar
  155. 155.
    Yoshida D, Piepmeier JM, Teramoto A: In vitro inhibition of cell proliferation, viability, and invasiveness in U87MG human glioblastoma cells by estramustine phosphate. Neurosurgery 39: 360–366, 1996Google Scholar
  156. 156.
    Hynes RO, Destree AT: 10 nm filaments in normal and transformed cells. Cell 13: 151–163, 1978Google Scholar
  157. 157.
    Tonn JC, Haugland HK, Saraste J, Roosen K, Laerum OD: Differential effects of vincristine and phenytoin on the proliferation, migration, and invasion of human glioma cell lines. J Neurosurg 82: 1035–1043, 1995Google Scholar
  158. 158.
    Haugland HK, Nygaard SJ, Tysnes OB: Combined effect of alkyl-lysophospholipid and vincristine on proliferation, migration and invasion in human glioma cell lines in vitro. Anticancer Res 19: 149–156, 1999Google Scholar
  159. 159.
    Couldwell WT, Uhm JH, Antel JP, Yong VW: Enhanced protein kinase C activity correlates with the growth rate of malignant gliomas in vitro. Neurosurgery 29: 880–887, 1991Google Scholar
  160. 160.
    CouldwellWT, Antel JP, Yong VW: Protein kinase C activity correlates with the growth rate of malignant gliomas: Part II. Effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31: 717–724, 1992Google Scholar
  161. 161.
    Janik P, Szaniawska B, Miloszewska J, Pietruszewska E, Kowalczyk D: The role of protein kinase C in migration of rat glioma cells from spheroid cultures. Cancer Lett 63: 167–170, 1992Google Scholar
  162. 162.
    Baltuch GH, Yong VW: Signal transduction for proliferation of glioma cells in vitro occurs predominantly through a protein kinase C-mediated pathway. Brain Res 710: 143–149, 1996Google Scholar
  163. 163.
    Zhang W, Law RE, Hinton DR, Couldwell WT: Inhibition of human malignant glioma cell motility and invasion in vitro by hypericin, a potent protein kinase C inhibitor. Cancer Lett 120: 31–38, 1997Google Scholar
  164. 164.
    Yuen AR, Halsey J, Fisher GA, Holmlund JT, Geary RS, Kwoh TJ, Dorr A, Sikic BI: Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. Clin Cancer Res 5: 3357–3363, 1999Google Scholar
  165. 165.
    Nemunaitis J, Holmlund JT, Kraynak M, Richards D, Bruce J, Ognoskie N, Kwoh TJ, Geary R, Dorr A, Von Hoff D, Eckhardt SG: Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 17: 3586–3595, 1999Google Scholar
  166. 166.
    GreenDW, Roh H, Pippin J, Drebin JA: Antisense oligonucleotides: an evolving technology for the modulation of gene expression in human disease. J Am Coll Surg 191: 93–105, 2000Google Scholar
  167. 167.
    Pollack IF, Darosso RC, Robertson PL, Jakacki RL, Mirro JR Jr, Blatt J, Nicholson S, Packer RJ, Allen JC, Cisneros A, Jordan VC: A phase I study of highdose tamoxifen for the treatment of refractory malignant gliomas of childhood. Clin Cancer Res 3: 1109–1115, 1997Google Scholar
  168. 168.
    O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB: Inhibition of protein kinase C by tamoxifen. Cancer Res 45: 2462–2465, 1985Google Scholar
  169. 169.
    Butta A, MacLennan K, Flanders KC, Sacks NP, Smith I, McKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M, Colletta AA: Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 52: 4261–4264, 1992Google Scholar
  170. 170.
    Vertosick FT Jr, Selker RG, Pollack IF, Arena V: The treatment of intracranial malignant gliomas using orally administered tamoxifen therapy: preliminary results in a series of ‘failed’ patients. Neurosurgery 30: 897–903, 1992Google Scholar
  171. 171.
    Couldwell WT, Weiss MH, DeGiorgio CM, Weiner LP, Hinton DR, Ehresmann GR, Conti PS, Apuzzo ML: Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 32: 485–490, 1993Google Scholar
  172. 172.
    Vertosick FT Jr, Selker RG, Randall MS, Kristofik MP, Rehn T: A comparison of the relative chemosensitivity of human gliomas to tamoxifen and n-desmethyltamoxifen in vitro. J Neuro-Oncol 19: 97–103, 1994Google Scholar
  173. 173.
    Couldwell WT, Hinton DR, Surnock AA, DeGiorgio CM, Weiner LP, Apuzzo ML, Masri L, Law RE, Weiss MH: Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 2: 619–622, 1996Google Scholar
  174. 174.
    Chamberlain MC, Kormanik PA: Salvage chemotherapy with tamoxifen for recurrent anaplastic astrocytomas. Arch Neurol 56: 703–708, 1999Google Scholar
  175. 175.
    Guha A, Feldkamp MM, Lau N, Boss G, Pawson A: Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15: 2755–2765, 1997Google Scholar
  176. 176.
    Spaargaren M, Bischoff JR, McCormick F: Signal transduction by Ras-like GTPases: a potential target for anticancer drugs. Gene Expr 4: 345–356, 1995Google Scholar
  177. 177.
    De Gunzburg J: Proteins of the Ras pathway as novel potential anticancer therapeutic targets. Cell Biol Toxicol 15: 345–358, 1999Google Scholar
  178. 178.
    Bredel M, Pollack IF: The p21-Ras signal transduction pathway and growth regulation in human high-grade gliomas. Brain Res Brain Res Rev 29: 232–249, 1999Google Scholar
  179. 179.
    FeldkampMM, Lau N, Guha A: Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene 18: 7514–7526, 1999Google Scholar
  180. 180.
    Bouterfa HL, Sattelmeyer V, Czub S, Vordermark D, Roosen K, Tonn JC: Inhibition of Ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human glioblastoma cells. Anticancer Res 20: 2761–2771, 2000Google Scholar
  181. 181.
    Bansal K, Engelhard HH: Gene Therapy for Brain Tumors. Curr Oncol Rep 2: 463–472, 2000Google Scholar
  182. 182.
    Robbins PD, Ghivizzani SC: Viral vectors for gene therapy. Pharmacol Ther 80: 35–47, 1998Google Scholar
  183. 183.
    Gupta N: Current status of viral gene therapy for brain tumours. Expert Opin Investig Drugs 9: 713–726, 2000Google Scholar
  184. 184.
    Markovitz NS, Roizman B: Replication-competent herpes simplex viral vectors for cancer therapy. Adv Virus Res 55: 409–424, 2000Google Scholar
  185. 185.
    Alemany R, Balague C, Curiel DT: Replicative adenoviruses for cancer therapy. Nat Biotechnol 18: 723–727, 2000Google Scholar
  186. 186.
    Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY: From the cover: neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97: 12846–12851, 2000Google Scholar
  187. 187.
    Ourednik V, Ourednik J, Park KI, Teng YD, Aboody KA, Auguste KI, Taylor RM, Tate BA, Snyder EY: Neural stem cells are uniquely suited for cell replacement and gene therapy in the CNS. Novartis Found Symp 231: 242–262, 2000Google Scholar
  188. 188.
    Herrlinger U, Woiciechowski C, Sena-Esteves M, Aboody KS, Jacobs AH, Rainov NG, Snyder EY, Breakefield XO: Neural precursor cells for delivery of replication-conditional HSV-1 vectors to intracerebral gliomas. Mol Ther 1: 347–357, 2000Google Scholar
  189. 189.
    Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280: 1614–1617, 1998Google Scholar
  190. 190.
    Tamura M, Gu J, Takino T, Yamada KM: Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res 59: 442–449, 1999Google Scholar
  191. 191.
    Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM: PTEN interactions with focal adhesion kinase and suppression of the extracellular matrixdependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 274: 20693–20703, 1999Google Scholar
  192. 192.
    Tamura M, Gu J, Tran H, Yamada KM: PTEN gene and integrin signaling in cancer. J Natl Cancer Inst 91: 1820–1828, 1999Google Scholar
  193. 193.
    Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K, Yamada KM: Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol 146: 389–403, 1999Google Scholar
  194. 194.
    McDonoughW, Tran N, Giese A, Norman SA, Berens ME: Altered gene expression in human astrocytoma cells selected for migration: I. Thromboxane synthase. J Neuropathol Exp Neurol 57: 449–455, 1998Google Scholar
  195. 195.
    Giese A, Hagel C, Kim EL, Zapf S, Djawaheri J, Berens ME, Westphal M: Thromboxane synthase regulates the migratory phenotype of human glioma cells. Neuro-Oncology 1: 3–13, 1999Google Scholar
  196. 196.
    Liang P, Pardee AB: Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967–971, 1992Google Scholar
  197. 197.
    Liang P, Pardee AB: Differential display. A general protocol. Mol Biotechnol 10: 261–267, 1998.Google Scholar
  198. 198.
    Velculescu VE, Zhang L, Vogelstein B, Kinzler KW: Serial analysis of gene expression. Science 270: 484–487, 1995Google Scholar
  199. 199.
    Velculescu VE: Essay: Amersham Pharmacia Biotech & Science prize. Tantalizing transcriptomes – SAGE and its use in global gene expression analysis [published erratum appears in Science 1999 Dec 10; 286(5447): 2085]. Science 286: 1491–1492, 1999Google Scholar
  200. 200.
    Lal A, Lash AE, Altschul SF, Velculescu V, Zhang L, McLendon RE, Marra MA, Prange C, Morin PJ, Polyak K, Papadopoulos N, Vogelstein B, Kinzler KW, Strausberg RL, Riggins GJ: A public database for gene expression in human cancers. Cancer Res 59: 5403–5407, 1999Google Scholar
  201. 201.
    Perou CM, Jeffrey SS, VanDe Rijn M, Rees CA, Eisen MB, Ross DT, Pergamenschikov A, Williams CF, Zhu SX, Lee JC, Lashkari D, Shalon D, Brown PO, Botstein D: Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci USA 96: 9212–9217, 1999Google Scholar
  202. 202.
    Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO: Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23: 41–46, 1999Google Scholar
  203. 203.
    Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van De Rijn M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO: Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24: 227–235, 2000Google Scholar
  204. 204.
    Oliver S: Guilt-by-association goes global. Nature 403: 601–603, 2000Google Scholar
  205. 205.
    Banks RE, Dunn MJ, Hochstrasser DF, Sanchez JC, Blackstock W, Pappin DJ, Selby PJ: Proteomics: new perspectives, new biomedical opportunities. Lancet 356: 1749–1756, 2000Google Scholar
  206. 206.
    Chambers G, Lawrie L, Cash P, Murray GI: Proteomics: a new approach to the study of disease. J Pathol 192: 280–288, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Berit Bølge Tysnes
    • 1
  • Rupavathana Mahesparan
    • 1
  1. 1.Department of Anatomy and Cell BiologyUniversity of BergenBergenNorway

Personalised recommendations