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Genes and pathways driving glioblastomas in humans and murine disease models

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Abstract

Human malignant gliomas arise from neural progenitor cells and/or dedifferentiated astrocytes. By now, they are genetically so well characterized that several murine glioma models have emerged that faithfully reiterate the typical histological features of the disease. In experimental animals, only one or two elements of the growth factor/Ras, PI3K/PTEN/PKB, p53/ARF/HDM2, and p16/Rb/cyclinD/CDK4 pathways are targeted. In human gliomas, many additional genes and pathways are targeted due to a most severe mutator phenotype that leads to the accumulation of countless epigenetic and genetic alterations. Changes that convey a growth advantage are selected for, leading to overgrowth of precursor cell populations with increasingly malignant tumor cell clones. While murine models represent a powerful tool for elucidating the role of genetic pathways, mechanisms of response and resistance to new therapeutic agents might be fundamentally different due to the high degree of genomic instability in the human disease. In fact, little is known about the molecular causes of genomic instability involved in gliomas, except for the rare Turcot's syndrome, O6-methylguanine-DNA methyltransferase, and the apurinic/apyrimidinic endonuclease Ape-1. Novel approaches that selectively exploit fundamental metabolic differences between tumor and normal cells have to consider these fundamental differences between human disease and presently available, highly sophisticated animal models.

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References

  1. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) From the cover: neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97:12846–12851

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196

    Article  CAS  PubMed  Google Scholar 

  3. Albanell J, Rojo F, Baselga J (2001) Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839. Semin Oncol 28:56–66

    Article  CAS  PubMed  Google Scholar 

  4. Alleyne CH Jr, He J, Yang J, Hunter SB, Cotsonis G, James CD, Olson JJ (1999) Analysis of cyclin dependent kinase inhibitors in malignant astrocytomas. Int J Oncol 14:1111–1116

    CAS  PubMed  Google Scholar 

  5. Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, Tsao MS, Shannon P, Bolon B, Ivy GO, Mak TW (2001) Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 29:396–403

    Article  CAS  PubMed  Google Scholar 

  6. Bearzatto A, Szadkowski M, Macpherson P, Jiricny J, Karran P (2000) Epigenetic regulation of the MGMT and hMSH6 DNA repair genes in cells resistant to methylating agents. Cancer Res 60:3262–3270

    CAS  PubMed  Google Scholar 

  7. Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G (2000) Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6:447–450

    Article  CAS  PubMed  Google Scholar 

  8. Bergoglio V, Canitrot Y, Hogarth L, Minto L, Howell SB, Cazaux C, Hoffmann JS (2001) Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents. Oncogene 20:6181–6187

    Article  CAS  PubMed  Google Scholar 

  9. Birkenkamp KU, Esselink MT, Kruijer W, Vellenga E (2000) An inhibitor of PI3-K differentially affects proliferation and IL-6 protein secretion in normal and leukemic myeloid cells depending on the stage of differentiation. Exp Hematol 28:1239–1249

    Article  CAS  PubMed  Google Scholar 

  10. Bobola MS, Blank A, Berger MS, Stevens BA, Silber JR (2001) Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas. Clin Cancer Res 7:3510–3518

    CAS  PubMed  Google Scholar 

  11. Bratton SB, Cohen GM (2001) Apoptotic death sensor: an organelle's alter ego? Trends Pharmacol Sci 22:306–315

    Google Scholar 

  12. Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657–664

    Article  CAS  PubMed  Google Scholar 

  13. Bressler JP, Grotendorst GR, Levitov C, Hjelmeland LM (1985) Chemotaxis of rat brain astrocytes to platelet derived growth factor. Brain Res 344:249–254

    Article  CAS  PubMed  Google Scholar 

  14. Burns MJ, Roberts T, Matson T, Israel M, Tada T, Snyder E, Aboody K (2001) Neural stem cell delivery in a transgenic mouse model of glioma. Neuro-oncology 3:287

    Google Scholar 

  15. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486

    Article  CAS  PubMed  Google Scholar 

  16. Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, Dyson NJ (2001) Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res 7:2387–2395

    CAS  PubMed  Google Scholar 

  17. Chan DW, Gately DP, Urban S, Galloway AM, Lees-Miller SP, Yen T, Allalunis-Turner J (1998) Lack of correlation between ATM protein expression and tumour cell radiosensitivity. Int J Radiat Biol 74:217–224

    Article  CAS  PubMed  Google Scholar 

  18. Cho SY, Klemke RL (2000) Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J Cell Biol 149:223–236

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Cichowski K, Jacks T (2001) NF1 tumor suppressor gene function: narrowing the GAP. Cell 104:593–604

    Article  CAS  PubMed  Google Scholar 

  20. Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M, Carroll D, Gautier J (2001) Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Mol Cell 8:137–147

    Article  CAS  PubMed  Google Scholar 

  21. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913–1925

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Dennis PB, Fumagalli S, Thomas G (1999) Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curr Opin Genet Dev 9:49–54

    Article  CAS  PubMed  Google Scholar 

  23. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP (1998) Pten is essential for embryonic development and tumour suppression. Nat Genet 19:348–355

    Article  Google Scholar 

  24. Ding H, Roncari L, Shannon P, Wu X, Lau N, Karaskova J, Gutmann DH, Squire JA, Nagy A, Guha A (2001) Astrocyte-specific expression of activated p21-Ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res 61:3826–3836

    CAS  PubMed  Google Scholar 

  25. Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Collins VP (1991) Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51:2164–2172

    CAS  PubMed  Google Scholar 

  26. Ekstrand AJ, Liu L, He J, Hamid ML, Longo N, Collins VP, James CD (1995) Altered subcellular location of an activated and tumour-associated epidermal growth factor receptor. Oncogene 10:1455–1460

    CAS  PubMed  Google Scholar 

  27. Fahraeus R, Lane DP (1999) The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts. Embo J 18:2106–2118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Fanton CP, McMahon M, Pieper RO (2001) Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. J Biol Chem 276:18871–18877

    Article  CAS  PubMed  Google Scholar 

  29. Forsberg-Nilsson K, Behar TN, Afrakhte M, Barker JL, McKay RD (1998) Platelet-derived growth factor induces chemotaxis of neuroepithelial stem cells. J Neurosci Res 53:521–530

    Article  CAS  PubMed  Google Scholar 

  30. Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387

    CAS  PubMed  Google Scholar 

  31. Friedman HS, McLendon RE, Kerby T, Dugan M, Bigner SH, Henry AJ, Ashley DM, Krischer J, Lovell S, Rasheed K, Marchev F, Seman AJ, Cokgor I, Rich J, Stewart E, Colvin OM, Provenzale JM, Bigner DD, Haglund MM, Friedman AH, Modrich PL (1998) DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851–3857

    CAS  PubMed  Google Scholar 

  32. Frisch SM, Ruoslahti E (1997) Integrins and anoikis. Curr Opin Cell Biol 9:701–706

    Article  CAS  PubMed  Google Scholar 

  33. Fulci G, Labuhn M, Maier D, Lachat Y, Hausmann O, Hegi ME, Janzer RC, Merlo A, Van Meir EG (2000) p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 19:3816–3822

    Article  CAS  PubMed  Google Scholar 

  34. Fulci G, Van Meir EG (1999) p53 and the CNS: tumors and developmental abnormalities. Mol Neurobiol 19:61–77

    Article  CAS  PubMed  Google Scholar 

  35. Furnari FB, Huang HJ, Cavenee WK (1998) The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res 58:5002–5008

    CAS  PubMed  Google Scholar 

  36. Gomez-Manzano C, Mitlianga P, Fueyo J, Lee HY, Hu M, Spurgers KB, Glass TL, Koul D, Liu TJ, McDonnell TJ, Yung WK (2001) Transfer of E2F-1 to human glioma cells results in transcriptional up-regulation of Bcl-2. Cancer Res 61:6693–6697

    CAS  PubMed  Google Scholar 

  37. Guha A, Feldkamp MM, Lau N, Boss G, Pawson A (1997) Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15:2755–2765

    Article  CAS  PubMed  Google Scholar 

  38. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B et al (1995) The molecular basis of Turcot's syndrome. N Engl J Med 332:839–847

    Article  CAS  PubMed  Google Scholar 

  39. Hatten ME (1990) Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain. Trends Neurosci 13:179–184

    Article  CAS  PubMed  Google Scholar 

  40. He J, Olson JJ, James CD (1995) Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. Cancer Res 55:4833–4836

    CAS  PubMed  Google Scholar 

  41. Herceg Z, Hulla W, Gell D, Cuenin C, Lleonart M, Jackson S, Wang ZQ (2001) Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet 29:206–211

    Article  CAS  PubMed  Google Scholar 

  42. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219

    CAS  PubMed  Google Scholar 

  43. Hobson JP, Rosenfeldt HM, Barak LS, Olivera A, Poulton S, Caron MG, Milstien S, Spiegel S (2001) Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291:1800–1803

    Article  CAS  PubMed  Google Scholar 

  44. Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    Article  CAS  PubMed  Google Scholar 

  45. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57

    Article  CAS  PubMed  Google Scholar 

  46. Hunter KE, Hatten ME (1995) Radial glial cell transformation to astrocytes is bidirectional: regulation by a diffusible factor in embryonic forebrain. Proc Natl Acad Sci U S A 92:2061–2065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Ignatoski KM, Maehama T, Markwart SM, Dixon JE, Livant DL, Ethier SP (2000) ERBB-2 overexpression confers PI 3' kinase-dependent invasion capacity on human mammary epithelial cells. Br J Cancer 82:666–674

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH (1998) Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol 143:547–560

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377:539–544

    Article  CAS  PubMed  Google Scholar 

  50. Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG (1999) Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9:469–479

    Article  CAS  PubMed  Google Scholar 

  51. James CD, Olson JJ (1996) Molecular genetics and molecular biology advances in brain tumors. Curr Opin Oncol 8:188–195

    Article  CAS  PubMed  Google Scholar 

  52. Jiricny J, Nystrom-Lahti M (2000) Mismatch repair defects in cancer. Curr Opin Genet Dev 10:157–161

    Article  CAS  PubMed  Google Scholar 

  53. Jones G, Machado J Jr, Merlo A (2001) Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptor-dependent migration and induces aggregation of nh(2)-terminal FAK in the nuclei of apoptotic glioblastoma cells. Cancer Res 61:4978–4981

    CAS  PubMed  Google Scholar 

  54. Jones G, Machado J Jr, Tolnay M, Merlo A (2001) PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). Cancer Res 61:5688–5691

    CAS  PubMed  Google Scholar 

  55. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659

    Article  CAS  PubMed  Google Scholar 

  56. Khanna KK (2000) Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 92:795–802

    Article  CAS  PubMed  Google Scholar 

  57. Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27:247–54

    Article  CAS  PubMed  Google Scholar 

  58. Kleihues P CW (2000) Histological typing of tumors of the central nervous system. WHO/IARC 3, Lyon

  59. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A (2001) Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413:83–86

    Article  CAS  PubMed  Google Scholar 

  60. Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG, Burger PC, Baker SJ (2001) Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 29:404–411

    Article  CAS  PubMed  Google Scholar 

  61. Labuhn M, Jones G, Speel EJ, Maier D, Zweifel C, Gratzl O, Van Meir EG, Hegi ME, Merlo A (2001) Quantitative real-time PCR does not show selective targeting of p14(ARF) but concomitant inactivation of both p16(INK4A) and p14(ARF) in 105 human primary gliomas. Oncogene 20:1103–1109

    Article  CAS  PubMed  Google Scholar 

  62. Lafuente JV, Adan B, Alkiza K, Garibi JM, Rossi M, Cruz-Sanchez FF (1999) Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor-beta (PDGFR-beta) in human gliomas. J Mol Neurosci 13:177–185

    Article  CAS  PubMed  Google Scholar 

  63. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (1999) Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99:323–334

    Article  CAS  PubMed  Google Scholar 

  64. Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129

    CAS  PubMed  Google Scholar 

  65. 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 (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    Article  CAS  PubMed  Google Scholar 

  66. Li JL, Harrison RJ, Reszka AP, Brosh RM Jr, Bohr VA, Neidle S, Hickson ID (2001) Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands. Biochemistry 40:15194–15202

    Article  CAS  PubMed  Google Scholar 

  67. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147

    Article  CAS  PubMed  Google Scholar 

  68. Lin H, Bondy ML, Langford LA, Hess KR, Delclos GL, Wu X, Chan W, Pershouse MA, Yung WK, Steck PA (1998) Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin Cancer Res 4:2447–2454

    CAS  PubMed  Google Scholar 

  69. Lin WC, Lin FT, Nevins JR (2001) Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 15:1833–1844

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079

    CAS  PubMed  Google Scholar 

  71. Loeb LA (2001) A mutator phenotype in cancer. Cancer Res 61:3230–3239

    CAS  PubMed  Google Scholar 

  72. Louis DN, Holland EC, Cairncross JG (2001) Glioma classification: a molecular reappraisal. Am J Pathol 159:779–786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Lundberg AS, Hahn WC, Gupta P, Weinberg RA (2000) Genes involved in senescence and immortalization. Curr Opin Cell Biol 12:705–709

    Article  CAS  PubMed  Google Scholar 

  74. Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M, Youssoufian H, Vogel H, Schultz RA, Bradley A (2000) Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 26:424–429

    Article  CAS  PubMed  Google Scholar 

  75. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378

    Article  CAS  PubMed  Google Scholar 

  76. Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9:125–128

    Article  CAS  PubMed  Google Scholar 

  77. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311–1333

    Article  CAS  PubMed  Google Scholar 

  78. Maier D, Jones G, Li X, Schonthal AH, Gratzl O, Van Meir EG, Merlo A (1999) The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells. Cancer Res 59:5479–5482

    CAS  PubMed  Google Scholar 

  79. Mao L, Merlo A, Bedi G, Shapiro GI, Edwards CD, Rollins BJ, Sidransky D (1995) A novel p16INK4A transcript. Cancer Res 55:2995–2997

    CAS  PubMed  Google Scholar 

  80. Maser RS, Mirzoeva OK, Wells J, Olivares H, Williams BR, Zinkel RA, Farnham PJ, Petrini JH (2001) Mre11 complex and DNA replication: linkage to E2F and sites of DNA synthesis. Mol Cell Biol 21:6006–6016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. McLean GW, Brown K, Arbuckle MI, Wyke AW, Pikkarainen T, Ruoslahti E, Frame MC (2001) Decreased focal adhesion kinase suppresses papilloma formation during experimental mouse skin carcinogenesis. Cancer Res 61:8385–8389

    CAS  PubMed  Google Scholar 

  82. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD (1998) The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94:363–374

    Article  CAS  PubMed  Google Scholar 

  83. Menoyo A, Alazzouzi H, Espin E, Armengol M, Yamamoto H, Schwartz S Jr (2001) Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. Cancer Res 61:7727–7730

    CAS  PubMed  Google Scholar 

  84. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D (1995) 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1:686–692

    Article  CAS  PubMed  Google Scholar 

  85. Merlo A, Rochlitz C, Scott R (1996) Survival of patients with Turcot's syndrome and glioblastoma. N Engl J Med 334:736–737

    Article  CAS  PubMed  Google Scholar 

  86. Mishima K, Johns TG, Luwor RB, Scott AM, Stockert E, Jungbluth AA, Ji XD, Suvarna P, Voland JR, Old LJ, Huang HJ, Cavenee WK (2001) Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 61:5349–5354

    CAS  PubMed  Google Scholar 

  87. Montagne J, Radimerski T, Thomas G (2001) Insulin signaling: lessons from the drosophila tuberous sclerosis complex, a tumor suppressor. Sci STKE 2001:E36

    Google Scholar 

  88. Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ (1998) Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci U S A 95:5724–5729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, Woods CG, Fryns JP, Hamel B, Hoefsloot LH, Peeters EA, Padberg GW (1999) Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet 7:267–273

    Article  CAS  PubMed  Google Scholar 

  90. Oumesmar BN, Vignais L, Baron-Van Evercooren A (1997) Developmental expression of platelet-derived growth factor alpha-receptor in neurons and glial cells of the mouse CNS. J Neurosci 17:125–139

    CAS  Google Scholar 

  91. Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I (2001) Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res 29:4378–4386

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 96:1563–1568

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Prives C, Hall PA (1999) The p53 pathway. J Pathol 187:112–126

    Article  CAS  PubMed  Google Scholar 

  94. Quelle DE, Ashmun RA, Hannon GJ, Rehberger PA, Trono D, Richter KH, Walker C, Beach D, Sherr CJ, Serrano M (1995) Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11:635–645

    CAS  PubMed  Google Scholar 

  95. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T (2000) Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26:109–113

    Article  CAS  PubMed  Google Scholar 

  96. Renan MJ (1993) How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog 7:139–146

    Article  CAS  PubMed  Google Scholar 

  97. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    Article  CAS  PubMed  Google Scholar 

  98. Ronnstrand L, Heldin CH (2001) Mechanisms of platelet-derived growth factor-induced chemotaxis. Int J Cancer 91:757–762

    Article  CAS  PubMed  Google Scholar 

  99. Rustia A, Wierzbicki V, Marrocco L, Tossini A, Zamponi C, Lista F (2001) Is exon 5 of the PTEN/MMAC1 gene a prognostic marker in anaplastic glioma? Neurosurg Rev 24:97–102

    Google Scholar 

  100. Scolding NJ, Rayner PJ, Compston DA (1999) Identification of A2B5-positive putative oligodendrocyte progenitor cells and A2B5-positive astrocytes in adult human white matter. Neuroscience 89:1–4

    Article  CAS  PubMed  Google Scholar 

  101. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37

    Article  CAS  PubMed  Google Scholar 

  102. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413:86–91

    Article  CAS  PubMed  Google Scholar 

  103. Shaw RJ, Paez JG, Curto M, Yaktine A, Pruitt WM, Saotome I, O'Bryan JP, Gupta V, Ratner N, Der CJ, Jacks T, McClatchey AI (2001) The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell 1:63–72

    Article  CAS  PubMed  Google Scholar 

  104. Shen JC, Loeb LA (2000) The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases. Trends Genet 16:213–220

    Article  CAS  PubMed  Google Scholar 

  105. Sherr CJ, Weber JD (2000) The ARF/p53 pathway. Curr Opin Genet Dev 10:94–99

    Article  CAS  PubMed  Google Scholar 

  106. Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD (2000) FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2:249–256

    Article  CAS  PubMed  Google Scholar 

  107. Silber JR, Blank A, Bobola MS, Mueller BA, Kolstoe DD, Ojemann GA, Berger MS (1996) Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. Proc Natl Acad Sci U S A 93:6941–6946

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Silber JR, Bobola MS, Ghatan S, Blank A, Kolstoe DD, Berger MS (1998) O6-methylguanine-DNA methyltransferase activity in adult gliomas: relation to patient and tumor characteristics. Cancer Res 58:1068–1073

    CAS  PubMed  Google Scholar 

  109. Simpson L, Parsons R (2001) PTEN: life as a tumor suppressor. Exp Cell Res 264:29–41

    Article  CAS  PubMed  Google Scholar 

  110. Simpson PB, Armstrong RC (1999) Intracellular signals and cytoskeletal elements involved in oligodendrocyte progenitor migration. Glia 26:22–35

    Article  CAS  PubMed  Google Scholar 

  111. Smith JS, Wang XY, Qian J, Hosek SM, Scheithauer BW, Jenkins RB, James CD (2000) Amplification of the platelet-derived growth factor receptor-A (PDGFRA) gene occurs in oligodendrogliomas with grade IV anaplastic features. J Neuropathol Exp Neurol 59:495–503

    CAS  PubMed  Google Scholar 

  112. Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T (2000) Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 275:16309–16315

    Article  CAS  PubMed  Google Scholar 

  113. Soriano E, Alvarado-Mallart RM, Dumesnil N, Del Rio JA, Sotelo C (1997) Cajal-Retzius cells regulate the radial glia phenotype in the adult and developing cerebellum and alter granule cell migration. Neuron 18:563–577

    Article  CAS  PubMed  Google Scholar 

  114. 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 (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362

    Article  CAS  PubMed  Google Scholar 

  115. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8:1169–1178

    Article  CAS  PubMed  Google Scholar 

  116. Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M (2001) Glutamate release promotes growth of malignant gliomas. Nat Med 7:1010–1015

    Article  CAS  PubMed  Google Scholar 

  117. Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 274:20693–20703

    Article  CAS  PubMed  Google Scholar 

  118. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM (1998) Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280:1614–1617

    Article  CAS  PubMed  Google Scholar 

  119. Uhrbom L, Hesselager G, Nister M, Westermark B (1998) Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res 58:5275–5279

    CAS  PubMed  Google Scholar 

  120. Uhrbom L, Hesselager G, Ostman A, Nister M, Westermark B (2000) Dependence of autocrine growth factor stimulation in platelet-derived growth factor-B-induced mouse brain tumor cells. Int J Cancer 85:398–406

    Article  CAS  PubMed  Google Scholar 

  121. Vogt PK (2001) PI 3-kinase, mTOR, protein synthesis and cancer. Trends Mol Med 7:482–484

    Article  CAS  PubMed  Google Scholar 

  122. Yeh HJ, Silos-Santiago I, Wang YX, George RJ, Snider WD, Deuel TF (1993) Developmental expression of the platelet-derived growth factor alpha-receptor gene in mammalian central nervous system. Proc Natl Acad Sci U S A 90:1952–1956

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Zhang H, Marra G, Jiricny J, Maher VM, McCormick JJ (2000) Mismatch repair is required for O(6)-methylguanine-induced homologous recombination in human fibroblasts. Carcinogenesis 21:1639–1646

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work of A.M. is supported by the Swiss National Science Foundation, the Regional Cancer League of both Basel Land and Basel City, and the Novartis Stiftung.

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  1. Departments of Surgery and Research, Neurosurgery and Molecular Neuro-Oncology Laboratory, University Hospitals, Spitalstrasse 21, 4031, Basel, Switzerland

    Adrian Merlo

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Correspondence to Adrian Merlo.

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Commentaries on this paper are available at http://dx.doi.org/10.1007/s10143-003-0268-7 and http://dx.doi.org/10.1007/s10143-003-0269-6

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Merlo, A. Genes and pathways driving glioblastomas in humans and murine disease models. Neurosurg Rev 26, 145–158 (2003). https://doi.org/10.1007/s10143-003-0267-8

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