Targeting Oncogenic Signaling Pathways in Human Astrocytomas

  • Gelareh Zadeh
  • Abhijit Guha
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Tumors of the central nervous system (CNS) can be categorized as primary or secondary. Metastatic or secondary tumors of the CNS are increasing in frequency, as we are better able to control local disease of common human cancers, resulting in longer life expectancy. Incidence of primary CNS tumors are also increasing for reasons that are currently unclear, with approximately 30,000 new cases diagnosed yearly in North America, according to the Central Brain Tumor Registry of the United States in 1998 (1). This represents about 4% of all cancer-related deaths in adults, and the most common pediatric cancer, second only to leukemias. The types, location, and molecular pathogenesis of pediatric CNS tumors are for the most part different from those in adults, with this article restricting its comments to adult tumors. More than 50% of all primary CNS tumors arise from glial cells (2,3), which are further characterized according to their presumed cell of origin, giving rise to astrocytomas, oligodendroglioma, ependymomas, and choroid plexus papillomas.


Vascular Endothelial Growth Factor Epidermal Growth Factor Receptor Malignant Glioma Mutant Epidermal Growth Factor Receptor Astrocytoma Cell 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Central Brain Tumor Registry of the United States. 1997 Annual Report. CBTRUS, Chicago, 1998.Google Scholar
  2. 2.
    Schoenberg BS, Christine BW, Whisnant JP. The descriptive epidemiology of primary intracranial neoplasms: the Connecticut experience. Am J Epidemiol 1976; 104: 499–510.PubMedGoogle Scholar
  3. 3.
    Zimmerman HM. The ten most common types of brain tumor. Semin Roentgenol 1971; 6: 48–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Kleihues P, Cavenee WK. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System. IARC Press, Lyon, 2000.Google Scholar
  5. 5.
    Kleihues P, Burger P, Scheithauer B. Histological Typing of Tumors of the Nervous System. Springer-Verlag, Berlin, 1991.Google Scholar
  6. 6.
    Mahaley MS Jr., Mettlin C, Natarajan N, Laws ER Jr, Peace BB. National survey of patterns of care for brain-tumor patients. J Neurosurg 1989; 71: 826–836.PubMedCrossRefGoogle Scholar
  7. 7.
    Recht LD, Lew R, Smith TW. Suspected low-grade glioma: is deferring treatment safe? Ann Neurol 1992; 31: 431–436.PubMedCrossRefGoogle Scholar
  8. 8.
    Watanabe K, Sato K, Biernat W, et al. Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res 1997; 3: 523–530.PubMedGoogle Scholar
  9. 9.
    Davis FG, Freels S, Grutsch J, Barlas S, Brem S. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on surveillance, epidemiology, and end results (SEER) data, 1973–1991. J Neurosurg 1998; 88: 1–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Feldkamp MM, Lala P, Lau N, Roncari L, Guha A. Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 1999; 45: 1442–1453.PubMedCrossRefGoogle Scholar
  11. 11.
    Walker MD, Hunt WE, MacCarty CS, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg 1978; 49: 333–343.PubMedCrossRefGoogle Scholar
  12. 12.
    Salcman M. Survival in glioblastoma: historical persepctive. Neurosurgery 1980; 7: 435–439.PubMedCrossRefGoogle Scholar
  13. 13.
    Jelsma R, Bucy PC. The treatment of glioblastoma multiforme of the brain. J Neurosurg 1967; 27: 388–400.PubMedCrossRefGoogle Scholar
  14. 14.
    Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995; 345: 1008–1012.PubMedCrossRefGoogle Scholar
  15. 15.
    Janinis J, Efstathiou E, Panopoulos C, et al. Phase II study of temozolomide in patients with relapsing high grade glioma and poor performance status. Med Oncol 2000; 17: 106–110.PubMedCrossRefGoogle Scholar
  16. 16.
    Yung WK. Temozolomide in malignant gliomas. Semin Oncol 2000; 27: 27–34.PubMedGoogle Scholar
  17. 17.
    Levin VA, Silver P, Hannigan J, et al. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 1990; 18: 321–324.PubMedCrossRefGoogle Scholar
  18. 18.
    Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90: 1473–1479.PubMedCrossRefGoogle Scholar
  19. 19.
    Kleihues P. Subsets of glioblastoma: clinical and histological vs. genetic typing. Brain Pathol 1998; 8: 667–668.PubMedCrossRefGoogle Scholar
  20. 20.
    Louis DN, Gusella JF. A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 1995; 11: 412–415.PubMedCrossRefGoogle Scholar
  21. 21.
    Li L, Ernsting BR, Wishart MJ, Lohse DL, Dixon JE. A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast. J Biol Chem 1997; 272: 29403–29406.PubMedCrossRefGoogle Scholar
  22. 22.
    Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15: 356–362.PubMedCrossRefGoogle Scholar
  23. 23.
    Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H. Expression of epidermal growth factor receptors in human brain tumors. Cancer Res 1984; 44: 753–760.PubMedGoogle Scholar
  24. 24.
    Yamazaki H, Fukui Y, Ueyama Y, et al. Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol 1988; 8: 1816–1820.PubMedGoogle Scholar
  25. 25.
    Louis DN. The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 1994; 53: 11–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VR. Amplification of multiple genes from chromosomal region 12813–14 in human malignant gliomas: preliminary mapping of the ampli-cons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res 1994; 54: 4299–4303.PubMedGoogle Scholar
  27. 27.
    Ichimura K, Schmidt EE, Goike HM, Collins VR. Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 1996; 13: 1065–1072.PubMedGoogle Scholar
  28. 28.
    Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res 1996; 56: 150–153.PubMedGoogle Scholar
  29. 29.
    Nishikawa R, Furnari FB, Lin H, et al. Loss of P16INK4 expression is frequent in high grade gliomas. Cancer Res 1995; 55: 1941–1945.PubMedGoogle Scholar
  30. 30.
    Guha A, Dashner K, Black PM, Wagner JA, Stiles CD. Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 1995; 60: 168–173.PubMedCrossRefGoogle Scholar
  31. 31.
    Guha A, Glowacka D, Carroll R, Dashner K, Black PM, Stiles CD. Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni syndrome. J Neurol Neurosurg Psychiatry 1995; 58: 711–714.PubMedCrossRefGoogle Scholar
  32. 32.
    Shamah SM, Stiles CD, Guha A. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 1993; 13: 7203–7212.PubMedGoogle Scholar
  33. 33.
    Antoniades HN, Galanopoulos T, Neville-Golden J, Maxwell M. Expression of insulin-like growth factors I and II and their receptor mRNAs in primary human astrocytomas and meningiomas; in vivo studies using in situ hybridization and immunocytochemistry. Int J Cancer 1992; 50: 215–222.PubMedCrossRefGoogle Scholar
  34. 34.
    Trojan J, Johnson TR, Rudin SD, Ilan J, Tykocinski ML. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Science 1993; 259: 94–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994; 367: 576–579.PubMedCrossRefGoogle Scholar
  36. 36.
    Plate KH, Breier G, Welch HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992; 359: 845–848.PubMedCrossRefGoogle Scholar
  37. 37.
    Libermann TA, Friesel R, et al. An angiogenic growth factor is expressed in human glioma cells. EMBO J 1987; 6: 1627–1632.PubMedGoogle Scholar
  38. 38.
    Morrison RS. Supression of basic fibroblastic growth factor by antisense oligodexynucleotides inhibits the growth of transformed human astrocytes. J Biol Chem 1991; 266: 728–734.PubMedGoogle Scholar
  39. 39.
    Ding H, Roncari L, Wu X, et al. Expression and hypoxic regulation of angiopoietins in human astrocytomas. J Neurooncol 2001; 3: 1–10.Google Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    Ko LJ, Prives C. p53: puzzle and paradigm. Genes Dev 1996; 10: 1054–1072.PubMedCrossRefGoogle Scholar
  42. 42.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997; 88: 323–331.PubMedCrossRefGoogle Scholar
  43. 43.
    Giaccia Ai, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 1998; 12: 2973–2983.PubMedCrossRefGoogle Scholar
  44. 44.
    el-Azouzi M, Chung RY, Farmer GE, et al. Loss of distinct regions on the short arm of chromosome 17 associated with tumorigenesis of human astrocytomas. Proc Natl Acad Sci USA 1989; 86: 7186–7190.PubMedCrossRefGoogle Scholar
  45. 45.
    Fulci G, Ishii N, Van Meir EG. p53 and brain tumors: from gene mutations to gene therapy. Brain Pathol 1998; 8: 599–613.PubMedCrossRefGoogle Scholar
  46. 46.
    Li Y, Millikan RC, Carozza S, et al. p53 mutations in malignant gliomas. Cancer Epidemiol Biomark-ers Prey 1998; 7: 303–308.Google Scholar
  47. 47.
    Chattopadhyay P, Rathore A, Mathur M, Sarkar C, Mahapatra AK, Sinha S. Loss of heterozygosity of a locus on 17p13.3, independent of p53, is associated with higher grades of astrocytic tumours. Oncogene 1997; 15: 871–874.PubMedCrossRefGoogle Scholar
  48. 48.
    Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 1996; 6:217–223; discussion 23–24.PubMedCrossRefGoogle Scholar
  49. 49.
    Louis DN. A molecular genetic model of astrocytoma histopathology. Brain Pathol 1997; 7: 755–764.PubMedCrossRefGoogle Scholar
  50. 50.
    Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126–1132.PubMedCrossRefGoogle Scholar
  51. 51.
    Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.PubMedCrossRefGoogle Scholar
  52. 52.
    Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997; 387: 299–303.PubMedCrossRefGoogle Scholar
  53. 53.
    Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD. Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 1999; 11: 162–167.PubMedCrossRefGoogle Scholar
  54. 54.
    Newcomb EW, Cohen H, Lee SR, et al. Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or Bc1–2 genes [see comment]. Brain Pathol 1998; 8: 655–667.PubMedCrossRefGoogle Scholar
  55. 55.
    Costello JF, Berger MS, Huang HS, Cavenee WK. Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res 1996; 56: 2405–2410.PubMedGoogle Scholar
  56. 56.
    Merlo A, Herman JG, Mao L, et al. 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995; 1: 686–692.PubMedCrossRefGoogle Scholar
  57. 57.
    Ono Y, Tamiya T, Ichikawa T, et al. Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices. J Neuropathol Exp Neurol 1996; 55: 1026–1031.PubMedGoogle Scholar
  58. 58.
    Biernat W, Tohma Y, Yonekawa Y, Kleihues P, Ohgaki H. Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol (Berl) 1997; 94: 303–309.CrossRefGoogle Scholar
  59. 59.
    Hermansson M, Nister M, Betsholtz C, Heldin CH, Westermark B, Funa K. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci USA 1988; 85: 7748–7752.PubMedCrossRefGoogle Scholar
  60. 60.
    Guha A. Platelet derived growth factor: a general review with emphasis on astrocytomas: Pediatr Neurosurg 1992; 17: 14–20.CrossRefGoogle Scholar
  61. 61.
    Haley J, Whittle N, Bennet P, Kinchington D, Ullrich A, Waterfield M. The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. Oncogene Res 1987; 1: 375–396.PubMedGoogle Scholar
  62. 62.
    Kondo I, Shimizu N. Mapping of the human gene for epidermal growth factor receptor (EGFR) on the p13 leads to q22 region of chromosome 7. Cytogenet Cell Genet 1983; 35: 9–14.PubMedCrossRefGoogle Scholar
  63. 63.
    Louis DN, Gusella JF. A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet 1995; 11: 412–415.PubMedCrossRefGoogle Scholar
  64. 64.
    Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 1987; 84: 6899–6903.PubMedCrossRefGoogle Scholar
  65. 65.
    Steck PA, Lee P, Hung MC, Yung WK. Expression of an altered epidermal growth factor receptor by human glioblastoma cells. Cancer Res 1988; 48: 5433–5439.PubMedGoogle Scholar
  66. 66.
    Ekstrand AJ, Longo N, Hamid ML, et al. Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Onco gene 1994; 9: 2313–2320.Google Scholar
  67. 67.
    Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994; 91: 7727–7731.PubMedCrossRefGoogle Scholar
  68. 68.
    Feldkamp MM, Lala P, Lau N, Roncari L, Guha A. Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 1999; 45: 1442–1453.PubMedCrossRefGoogle Scholar
  69. 69.
    Feldkamp MM, Lau N, Rak J, Kerbel RS, Guha A. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int J Cancer 1999; 81: 118–124.PubMedCrossRefGoogle Scholar
  70. 70.
    Yamada N, Kato M, Yamashita H, et al. Enhanced expression of transforming growth factor-beta and its type-I and type-II receptors in human glioblastoma. Int J Cancer 1995; 62: 386–392.PubMedCrossRefGoogle Scholar
  71. 71.
    Horst HA, Scheithauer BW, Kelly PJ, Kovach JS. Distribution of transforming growth factor-beta 1 in human astrocytomas. Hum Pathol 1992; 23: 1284–1288.PubMedCrossRefGoogle Scholar
  72. 72.
    Jennings MT, Hart CE, Commers PA, et al. Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor. J Neurooncol 1997; 31: 233–254.PubMedCrossRefGoogle Scholar
  73. 73.
    Battegay EJ, Raines EW, Seifert RA, Bowen-Pope DF, Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 1990; 63: 515–524.PubMedCrossRefGoogle Scholar
  74. 74.
    Mandriota SJ, Pepper MS. Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci 1997; 110: 2293–2302.PubMedGoogle Scholar
  75. 75.
    Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996; 87: 1171–1180.PubMedCrossRefGoogle Scholar
  76. 76.
    Suri C, McClain J, Thurston G, et al. Increased vascularization in mice overexpressing angiopoietin1. Science 1998; 282: 468–471.PubMedCrossRefGoogle Scholar
  77. 77.
    Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol 1992; 3: 65–71.PubMedGoogle Scholar
  78. 78.
    Forsyth PA, Wong H, Laing TD, et al. Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 1999; 79: 1828–1835.PubMedCrossRefGoogle Scholar
  79. 79.
    Kachra Z, Beaulieu E, Delbecchi L, et al. Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 1999; 17: 555–566.PubMedCrossRefGoogle Scholar
  80. 80.
    Wagner S, Stegen C, Bouterfa H, et al. Expression of matrix metalloproteinases in human glioma cell lines in the presence of IL-10. JNeurooncol 1998; 40: 113–122.CrossRefGoogle Scholar
  81. 81.
    Webb KE, Henney AM, Anglin S, Humphries SE, McEwan JR. Expression of matrix metalloproteinases and their inhibitor TIMP-1 in the rat carotid artery after ballon injury. Arterioscler Thromb vast Biol 1997; 17: 1837–1844.CrossRefGoogle Scholar
  82. 82.
    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 1998; 153: 429–437.PubMedCrossRefGoogle Scholar
  83. 83.
    Bos JL. p2I ras: an oncoprotein functioning in growth factor-induced signal transduction. Eur J Cancer 1995; 31A:1051–1054.CrossRefGoogle Scholar
  84. 84.
    Guha A, Feldkamp MM, Lau N, Boss G, Pawson A. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 1997; 15: 2755–2765.PubMedCrossRefGoogle Scholar
  85. 85.
    Feldkamp MM, Lau N, Roncari L, Guha A. Isotype-specific Ras. GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. Cancer Res 2001; 61: 4425–4431.PubMedGoogle Scholar
  86. 86.
    Favata MF, Horiuchi KY, Manos EJ, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. JBiol Chem 1998; 273: 18623–18632.CrossRefGoogle Scholar
  87. 87.
    Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 1998; 8: 1195–1198.PubMedCrossRefGoogle Scholar
  88. 88.
    Furnari FB, Lin H, Huang HS, Cavenee WK. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 1997; 94: 12479–12484.PubMedCrossRefGoogle Scholar
  89. 89.
    Sun H, Lesche R, Li DM, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA 1999; 96: 6199–6204.PubMedCrossRefGoogle Scholar
  90. 90.
    Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999; 96: 4240–4245.PubMedCrossRefGoogle Scholar
  91. 91.
    Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 1995; 81: 727–736.PubMedCrossRefGoogle Scholar
  92. 92.
    Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95: 29–39.PubMedCrossRefGoogle Scholar
  93. 93.
    Steck PA, Lin H, Langford LA, et al. Functional and molecular analyses of 10q deletions in human gliomas. Genes Chromosom Cancer 1999; 24: 135–143.PubMedCrossRefGoogle Scholar
  94. 94.
    Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 1998; 95: 13513–13518.PubMedCrossRefGoogle Scholar
  95. 95.
    Maher EA, Furnari FB, Bachoo RM, et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev 2001; 15: 1311–1333.PubMedCrossRefGoogle Scholar
  96. 96.
    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 1993; 3: 19–26.CrossRefGoogle Scholar
  97. 97.
    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 Chromosom Cancer 1998; 22: 9–15.PubMedCrossRefGoogle Scholar
  98. 98.
    Mollenhauer J, Wiemann S, Scheurlen W, et al. DMBTI, a new member of the SRCR superfamily, on chromosome 10g25.3–26.1 is deleted in malignant brain tumours. Nat Genet 1997; 17: 32–39.PubMedCrossRefGoogle Scholar
  99. 99.
    Nishizuka Y. Intracellular signaling by hydrolysis of phopholipids and activation of protein kinase C. Science 1992; 258: 607–614.PubMedCrossRefGoogle Scholar
  100. 100.
    Honegger P. Protein kinase C-activating tumor promoters enhance the differentiation of astrocytes in aggregrating fetal brain cell cultures. J Neurochem 1986; 46: 1561–1566.PubMedCrossRefGoogle Scholar
  101. 101.
    Bhat NR. Role of protein kinase C in glial cell proliferation. J Neurosci Res 1989; 22: 20–27.PubMedCrossRefGoogle Scholar
  102. 102.
    Couldwell WT, 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 1992; 31:717–724; discussion 724.CrossRefGoogle Scholar
  103. 103.
    Xiao H, Goldthwait DA, Mapstone T. The identification of four protein kinase C isoforms in human glioblastoma cell lines: PKC alpha, gamma, epsilon, and zeta. J Neurosurg 1994; 81: 734–740.PubMedCrossRefGoogle Scholar
  104. 104.
    Ahmad S, Mineta T, Martuza RL, Glazer RI. Antisense expression of protein kinase C alpha inhibits the growth and tumorigenicity of human glioblastoma cells. Neurosurgery 1994; 35:904–908; discussion 908–909.PubMedCrossRefGoogle Scholar
  105. 105.
    Benzil DL, Finkelstein SD, Epstein MH, Finch PW. Expression pattern of alpha-protein kinase C in human astrocytomas indicates a role in malignant progression. Cancer Res 1992; 52: 2951–2956.PubMedGoogle Scholar
  106. 106.
    Weller M, Frei K, Groscurth P, Krammer PH, Yonekawa Y, Fontana A. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest 1994; 94: 954–964.PubMedCrossRefGoogle Scholar
  107. 107.
    Newcomb EW, Bhalla SK, Parrish CL, Hayes RL, Cohen H, Miller DC. bc1–2 protein expression in astrocytomas in relation to patient survival and p53 gene status. Acta Neuropathol (Berl) 1997; 94: 369–375.CrossRefGoogle Scholar
  108. 108.
    Jannot CB, Beerli RR, Mason S, Gullick WJ, Hynes NE. Intracellular expression of a single-chain antibody directed to the EGFR leads to growth inhibition of tumor cells. Oncogene 1996; 13: 275–282.PubMedGoogle Scholar
  109. 109.
    De Giovanni C, Landuzzi L, Frabetti F, et al. Antisense epidermal growth factor receptor transfection impairs the proliferative ability of human rhabdomyosarcoma cells. Cancer Res 1996; 56: 3898–3901.PubMedGoogle Scholar
  110. 110.
    Reist CJ, Archer GE, Kurpad SN, et al. Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts. Cancer Res 1995; 55: 4375–4382.PubMedGoogle Scholar
  111. 111.
    Ekstrand AJ, Liu L, He J, et al. Altered subcellular location of an activated and tumour-associated epidermal growth factor receptor. Oncogene 1995; 10: 1455–1460.PubMedGoogle Scholar
  112. 112.
    Graziani Y, Chayoth R, Karny N, Feldman B, Levy J. Regulation of protein kinases activity by quercetin in Ehrlich ascites tumor cells. Biochim Biophys Acta 1982; 714: 415–421.PubMedCrossRefGoogle Scholar
  113. 113.
    Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262: 5592–5595.PubMedGoogle Scholar
  114. 114.
    Onoda T, Isshiki K, Takeuchi T, Tatsuta K, Umezawa K. Inhibition of tyrosine kinase and epidermal growth factor receptor internalization by lavendustin A methyl ester in cultured A431 cells. Drugs Exp Clin Res 1990; 16: 249–253.PubMedGoogle Scholar
  115. 115.
    Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor tyrosine kinase. Science 1994; 265: 1093–1095.PubMedCrossRefGoogle Scholar
  116. 116.
    Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science 1995; 267: 1782–1788.PubMedCrossRefGoogle Scholar
  117. 117.
    Buchdunger E, Trinks U, Mett H, et al. 4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity. Proc Natl Acad Sci USA 1994; 91: 2334–2338.PubMedCrossRefGoogle Scholar
  118. 118.
    Mason W, Malkin M, Lieberman F, Cropp G, Hannah A. Pharmacokinetics of SU101, a novel signal transduction inhibitor, in patients with recurrent malignant glioma. Proc Am Assoc Cancer Res 1996; 37: 166.Google Scholar
  119. 119.
    Miyaji K, Tani E, Shindo H, Nakano A, Tokunaga T. Effect of tyrphostin on cell growth and tyrosine kinase activity of epidermal growth factor receptor in human gliomas. J Neurosurg 1994; 81: 411–419.PubMedCrossRefGoogle Scholar
  120. 120.
    Han Y, Caday CG, Nanda A, Cavenee WK, Huang HJ. Tyrphostin AG 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors. Cancer Res 1996; 56: 3859–3861.PubMedGoogle Scholar
  121. 121.
    Hook KE, Kunkel MW, Elliott WL, Howard CT, Leopold WR. Epidermal growth factor receptor tyrosine kinase in A431 xenografts: inhibition by PD 153035 (3-(3-bromoanilino)-6, 7dimethoxyquinazoline). Proc Am Assoc Cancer Res 1995; 36: 434.Google Scholar
  122. 122.
    Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6: 4885–4892.PubMedGoogle Scholar
  123. 123.
    Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001; 7: 1459–1465.PubMedGoogle Scholar
  124. 124.
    Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989; 57: 1167–1177.PubMedCrossRefGoogle Scholar
  125. 125.
    Marshall CJ. Protein prenylation: a mediator of protein-protein interactions. Science 1993; 259: 1865–1866.PubMedCrossRefGoogle Scholar
  126. 126.
    Farrell FX, Yamamoto K, Lapetina EG. Prenyl group identification of rap2 proteins: a ras superfamily member other than ras that is farnesylated. Biochem J 1993; 289: 349–355.PubMedGoogle Scholar
  127. 127.
    Lebowitz PF, Davide JP, Prendergast GC. Evidence that farnesyltransferase inhibitors suppress Ras transformation by interfering with Rho activity. Mol Cell Biol 1995; 15: 6613–6622.PubMedGoogle Scholar
  128. 128.
    Yan N, Ricca C, Fletcher J, Glover T, Seizinger BR, Manne V. Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype. Cancer Res 1995; 55: 3569–3575.PubMedGoogle Scholar
  129. 129.
    Sepp-Lorenzino L, Ma Z, Rands E, et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995; 55: 5302–5309.PubMedGoogle Scholar
  130. 130.
    Kohl NE, Omer CA, Conner MW, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995; 1: 792–797.PubMedCrossRefGoogle Scholar
  131. 131.
    Feldkamp MM, Lau N, Roncari L, Guha A. Isotype-specific Ras•GTP-levels predict the efficacy of famesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status, Cancer Res. 2001; 61: 4425–4431.PubMedGoogle Scholar
  132. 132.
    Feldkamp MM, 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 1999; 18: 7514–7526.PubMedCrossRefGoogle Scholar
  133. 133.
    Feldkamp MM, Lau N, Rak J, Kerbel RS, Guha A. Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras. Int J Cancer 1999; 81: 118–124.PubMedCrossRefGoogle Scholar
  134. 134.
    Kokunai T, Urui S, Tornita H, Tamaki N. Overcoming of radioresistance in human gliomas by p21WAF1/CIP1 antisense oligonucleotide. J Neurooncol 2001; 51: 111–119.PubMedCrossRefGoogle Scholar
  135. 135.
    James G, Goldstein JL, Brown MS. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Ratl cells. Proc Natl Acad Sci USA 1996; 93: 4454–4458.PubMedCrossRefGoogle Scholar
  136. 136.
    Lerner EC, Qian Y, Blaskovich MA, et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem 1995; 270: 26802–26806.PubMedCrossRefGoogle Scholar
  137. 137.
    Pollack IF, Randall MS, Kristofik MP, Kelly RH, Selker RG, Vertosick FT Jr. Response of malignant glioma cell lines to activation and inhibition of protein kinase C-mediated pathways. J Neurosurg 1990; 73: 98–105.PubMedCrossRefGoogle Scholar
  138. 138.
    Couldwell WT, Hinton DR, Law RE. Protein kinase C and growth regulation in malignant gliomas. Neurosurgery 1994; 35: 1184–1186.PubMedCrossRefGoogle Scholar
  139. 139.
    Pollack IF, Randall MS, Kristofik MP, Kelly RH, Selker R, Vertosick FT Jr. Effect of tamoxifen on DNA synthesis and proliferation of human malignant glioma lines in vitro. Cancer Res 1990; 50: 7134–7138.PubMedGoogle Scholar
  140. 140.
    Baltuch GH, Couldwell WT, Villemure J-G, Yong VW. Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines. A comparison between staurosporine and tamoxifen. Neurosurgery 1993; 33: 495–501.PubMedCrossRefGoogle Scholar
  141. 141.
    Couldwell WT, Weiss MH, DeGiorgio CM, et al. Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 1993; 32:485–489; discussion 489–490.PubMedCrossRefGoogle Scholar
  142. 142.
    Couldwell WT, Hinton DR, Surnock AA, et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin Cancer Res 1996; 2: 619–622.PubMedGoogle Scholar
  143. 143.
    Pollack IF, Kawecki S, Lazo JS. Blocking of glioma proliferation in vitro and in vivo and potentiating the effects of BCNU and cisplatin: UCN-01, a selective protein kinase C inhibitor. JNeurosurg 1996; 84: 1024–1032.CrossRefGoogle Scholar
  144. 144.
    Folkman J. Angiogenesis and angiogenesis inhibition: an overview. EXS 1997; 79: 1–8.PubMedGoogle Scholar
  145. 145.
    Cheng SY, Huang HJ, Nagane M, et al. Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 1996; 93: 8502–8507.PubMedCrossRefGoogle Scholar
  146. 146.
    Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of anti-sense vascular endothelial growth factor sequence. Cancer Res 1996; 56: 393–401.PubMedGoogle Scholar
  147. 147.
    Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994; 367: 576–579.PubMedCrossRefGoogle Scholar
  148. 148.
    Puduvalli VK, Sawaya R. Antiangiogenesis–therapeutic strategies and clinical implications for brain tumors. J Neurooncol 2000; 50: 189–200.PubMedCrossRefGoogle Scholar
  149. 149.
    Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18: 708–715.PubMedGoogle Scholar
  150. 150.
    Cha S, Knopp EA, Johnson G, et al. Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin. AJNR Ani J Neuroradiol 2000; 21: 881–890.Google Scholar
  151. 151.
    Meneses PI, Abrey LE, Hajjar KA, et al. Simplified production of a recombinant human angiostatin derivative that suppresses intracerebral glial tumor growth. Clin Cancer Res 1999; 5: 3689–3694.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2003

Authors and Affiliations

  • Gelareh Zadeh
  • Abhijit Guha

There are no affiliations available

Personalised recommendations