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Gliomagenesis: genetic alterations and mouse models

Key Points

  • Gliomas are primary tumours that arise from glial cells in the brain and spinal cord. The most malignant gliomas — glioblastoma multiforme (GBM) — are nearly always fatal. Treatment strategies for this disease have remained unchanged for many years and most are based on a limited understanding of the biology of the disease.

  • Chromosomal instability and the deletion and amplification of certain genes are a hallmark of the more severe clinical grades of human glioma.

  • The cells of malignant gliomas share certain characteristics with undifferentiated glial progenitor cells. Mutations found in GBMs frequently activate the signalling pathways that control the differentiation and proliferation of these progenitors or disrupt cell-cycle arrest pathways.

  • Recapitulating the genetic alterations found in human gliomas in mouse models gives rise to tumours that histologically resemble human gliomas. These mouse models have given clues as to the molecular origins of gliomas, and should contribute to the design and testing of new rational therapies.


Glioblastoma multiforme is the most malignant of the primary brain tumours and is almost always fatal. The treatment strategies for this disease have not changed appreciably for many years and most are based on a limited understanding of the biology of the disease. However, in the past decade, characteristic genetic alterations have been identified in gliomas that might underlie the initiation or progression of the disease. Recent modelling experiments in mice are helping to delineate the molecular aetiology of this disease and are providing systems to identify and test novel and rational therapeutic strategies.

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Figure 1: Cellular differentiation in the central nervous system.
Figure 2: Signalling pathways altered by mutations in human gliomas.
Figure 3: INK4A-initiated cell-cycle arrest pathways.
Figure 4: Pathways to gliomagenesis.
Figure 5: Mouse glioma histology.


  1. 1

    Kleihues, P. & Cavenee, W. Pathology and genetics of tumors of the nervous system. (IARC Press, Lyon, 2000). An excellent overview of the molecular and histological characteristics of brain tumours.

  2. 2

    Russel, D. S. & Rubenstein, L. J. Pathology of tumors of the nervous system. (Williams & Wilkins, Baltimore, 1989).Classic in-depth text on tumour pathology in the central nervous system.

  3. 3

    Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34 , 333–351 (1938).

    Google Scholar 

  4. 4

    Jensen, R. Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg. Neurol. 49, 189– 195 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Uhm, J. H., Dooley, N. P., Villemure, J. G. & Yong, V. W. Mechanisms of glioma invasion: role of matrix-metalloproteinases. Can. J. Neurol. Sci. 24, 3–15 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000). Review of cell lineage specification in the central nervous system during development and in adulthood.

    CAS  Article  Google Scholar 

  7. 7

    Lee, J. C., Mayer-Proschel, M. & Rao, M. S. Gliogenesis in the central nervous system. Glia 30, 105–121 ( 2000).

    CAS  Article  Google Scholar 

  8. 8

    Mi, H. & Barres, B. Purification and characterization of astrocyte precursor cells in the developing rat optic nerve. J. Neurosci. 19, 1049–1061 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Cameron, H. A., Hazel, T. G. & McKay, R. D. Regulation of neurogenesis by growth factors and transmitters. J. Neurobiol. 36, 287– 309 (1998).

    CAS  Article  Google Scholar 

  10. 10

    McKinnon, R. D., Matsui, T., Dubois-Dalcq, M. & Aaronson, S. A. FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron 5, 603–614 ( 1990).

    CAS  Article  Google Scholar 

  11. 11

    Mayer, M., Bogler, O. & Nobel, M. The inhibition of oligodendrocytic differentiation of O2A progenitors caused by basic fibroblast growth factor is overridden by astrocytes. Glia 8, 12– 19 (1993).

    CAS  Article  Google Scholar 

  12. 12

    Bogler, O., Wren, D., Barnett, S., Land, H. & Nobel, M. Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type 2 astrocyte (O2A) progenitor cells. Proc. Natl Acad. Sci. USA 87, 6368 –6372 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Mayer, M., Bhakoo, K. & Nobel, M. Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120, 143– 153 (1994).

    CAS  PubMed  Google Scholar 

  14. 14

    Rajan, P. & McKay, R. D. Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 18, 3620– 3629 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Nobel, M. & Mayer-Proschel, M. Growth factors, glia and gliomas. J. Neurooncol. 35, 193– 209 (1997).Review of the connections between glial cell differentiation and gliomagenesis.

    Article  Google Scholar 

  16. 16

    Takahashi, J. et al. Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas. J. Neurosurg. 76, 792–798 (1992).

    CAS  Article  Google Scholar 

  17. 17

    Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).

    CAS  PubMed  Google Scholar 

  18. 18

    Weis, J. et al. CNTF and its receptor subunits in human gliomas. J. Neurooncol. 44, 243–253 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Guha, A., Dashner, K., Black, P. M., Wagner, J. A. & Stiles, C. D. Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int. J. Cancer 60, 168– 173 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Wong, A. J. et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc. Natl Acad. Sci. USA 89 , 2965–2969 (1992).

    CAS  Article  Google Scholar 

  21. 21

    Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80, 225– 236 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Martin-Blanco, E. p38 MAPK signalling cascades: ancient roles and new functions. Bioessays 22, 637–645 ( 2000).

    CAS  Article  Google Scholar 

  23. 23

    Xu, G. F. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835–841 ( 1990).

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Jiang, B. H., Aoki, M., Zheng, J. Z., Li, J. & Vogt, P. K. Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. Proc. Natl Acad. Sci. USA 96, 2077–2081 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Thomas, G. & Hall, M. N. TOR signaling and control of cell growth. Curr. Opin. Cell Biol. 9, 782– 787 (1997).

    CAS  Article  Google Scholar 

  27. 27

    Fujisawa, H. et al. Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25-qter. Am. J. Pathol. 155, 387–394 (1999).

    CAS  Article  Google Scholar 

  28. 28

    Sano, T. et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res. 59, 1820–1824 (1999).

    CAS  PubMed  Google Scholar 

  29. 29

    Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 12, 55–57 (2000).This study demonstrated the cooperation between the Ras and Akt signalling pathways in the formation of GBMs in a mouse model. PubMed

    Article  Google Scholar 

  30. 30

    Ichimura, K., Schmidt, E. E., Goike, H. M. & Collins, V. P. Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13, 1065–1072 ( 1996).A large series of gliomas were analysed for mutations in this study, illustrating the importance of cell-cycle arrest pathways in GBM formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Jen, J. et al. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 54, 6353–6358 (1994).

    CAS  PubMed  Google Scholar 

  32. 32

    Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    CAS  Article  Google Scholar 

  33. 33

    Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19Arf. Cell 91, 649–659 (1993). PubMed

    Article  Google Scholar 

  34. 34

    Pomerantz, J. et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 . Cell 92, 713–723 (1998).

    CAS  Article  Google Scholar 

  35. 35

    Haber, D. A. Splicing into senescence: the curious case of p16 and p19ARF. Cell 91, 555–558 ( 1997).

    CAS  Article  Google Scholar 

  36. 36

    Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94–99 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Liggett, W. H. Jr & Sidransky, D. Role of the p16 tumor suppressor gene in cancer. J. Clin. Oncol. 16, 1197–1206 ( 1998).

    CAS  Article  Google Scholar 

  38. 38

    Fulci, G. et al. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 19, 3816–3822 ( 2000).

    CAS  Article  Google Scholar 

  39. 39

    Louis, D. N. The p53 gene and protein in human brain tumors. J. Neuropath. Exp. Neurol. 53, 11–21 ( 1994).

    CAS  Article  Google Scholar 

  40. 40

    Costello, J. F. et al. Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. Cancer Res. 57, 1250–1254 ( 1997).

    CAS  Google Scholar 

  41. 41

    He, J., Reifenberger, G., Liu, L., Collins, V. P. & James, C. D. Analysis of glioma cell lines for amplification and overexpression of MDM2. Genes Chromosomes Cancer 11, 91–96 ( 1994).

    CAS  Article  Google Scholar 

  42. 42

    von Deimling, A. et al. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Path. 3, 19– 23 (1993).

    CAS  Article  Google Scholar 

  43. 43

    van Meyel, D. J. et al. p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J. Natl Cancer Inst. 86, 1011–1017 ( 1994).

    CAS  Article  Google Scholar 

  44. 44

    Marutani, M. et al. Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastomamultiforme. Cancer Res. 59, 4765–4769 (1999).

    CAS  PubMed  Google Scholar 

  45. 45

    Watanabe, K. et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 6, 217–223 (1996).

    CAS  Article  Google Scholar 

  46. 46

    Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 257, 1943–1947 (1997). PubMed

    Article  Google Scholar 

  47. 47

    Teng, D. H. et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 57, 5221– 5225 (1997).

    CAS  PubMed  Google Scholar 

  48. 48

    Paramio, J. M., Segrelles, C., Casanova, M. L. & Jorcano, J. L. Opposite functions for E2F1 and E2F4 in human epidermal keratinocyte differentiation . J. Biol. Chem. 275, 41219– 41226 (2000).

    CAS  Article  Google Scholar 

  49. 49

    Hass, R. Retrodifferentiation and cell death. Crit. Rev. Oncol. 5, 359–371 (1994). PubMed

    CAS  Article  Google Scholar 

  50. 50

    Hoshimaru, M., Ray, J., Sah, D. W. & Gage, F. H. Dedifferentiation of the immortalized adult neuronal progenitor cell line HC2S2 into neurons by regulatable suppression of the v-myc oncogene. Proc. Natl Acad. Sci. USA 93, 1518–1523 (1996).

    CAS  Article  Google Scholar 

  51. 51

    Prados, M. D. & Levin, V. Biology and treatment of malignant glioma. Semin. Oncol. 27, S1– S10 (2000).

    Google Scholar 

  52. 52

    Castro, M. G. et al. Gene therapy strategies for intracranial tumours: glioma and pituitary adenomas. Histol. Histopathol. 15, 1233–1252 (2000).

    CAS  PubMed  Google Scholar 

  53. 53

    Pollack, I. F., Okada, H. & Chambers, W. H. Exploitation of immune mechanisms in the treatment of central nervous system cancer. Semin. Pediatr. Neurol. 7, 131–143 (2000).

    CAS  Article  Google Scholar 

  54. 54

    Finkelstein, S. D. et al. Histological characteristics and expression of acidic and basic fibroblast growth factor genes in intracerebral xenogeneic transplants of human glioma cells. Neurosurgery 34, 136–143 (1994).

    CAS  PubMed  Google Scholar 

  55. 55

    Aguzzi, A., Brandner, S., Isenmann, S., Steoinbach, J. P. & Sure, U. Transgenic and gene disrupution techniques in the study of neurocarcinogenesis. Glia 15, 348–364 (1995).

    CAS  Article  Google Scholar 

  56. 56

    Macleod, K. F. & Jacks, T. Insights into cancer from transgenic mouse models. J. Pathol. 187, 43–60 (1999).A review of the uses of germline-modification strategies in mice for studying human cancers.

    CAS  Article  Google Scholar 

  57. 57

    Fisher, G. H. et al. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 18, 5253–5260 (1999). A review of the somatic-cell gene-transfer approach to modelling cancer in mice.

    CAS  Article  Google Scholar 

  58. 58

    Holland, E. C. et al. Astrocytes can give rise to oligodendrocytomas and astrocytomas after transfer of middle T antigen in mice. Am. J. Pathol. 157, 1031–1037 (2000).

    CAS  Article  Google Scholar 

  59. 59

    Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 ( 1999).

    CAS  Article  Google Scholar 

  60. 60

    Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).

    CAS  Article  Google Scholar 

  61. 61

    Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3 , 565–577 (1999).

    CAS  Article  Google Scholar 

  62. 62

    Wessenberger, J. et al. Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 14, 2005–2013 (1997).

    Article  Google Scholar 

  63. 63

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

    CAS  Google Scholar 

  64. 64

    Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E. & Jacks, T. Nf1; Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genet. 26, 109–113 (2000).This paper reported cooperation between signalling pathways and cell-cycle arrest pathways in the formation of gliomas in a mouse model.

    CAS  Article  Google Scholar 

  65. 65

    Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27– 37 (1996).

    CAS  Article  Google Scholar 

  66. 66

    Holland, E. C., Hively, W.P., Gallo, V. & Varmus, H. E. Overexpression of cdk4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes, modeling mutations in the G1 arrest pathway in human gliomas . Genes Dev. 12, 3644–3649 (1998).

    CAS  Article  Google Scholar 

  67. 67

    Kamijo, T., Bodner, S., van de Kamp, E., Randle, D. H. & Sherr, C. J. Tumor spectrum in ARF-deficient mice. Cancer Res. 59, 2217– 2222 (1999).

    CAS  Google Scholar 

  68. 68

    Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    CAS  Article  Google Scholar 

  69. 69

    Yahanda, A. M., Bruner, J. M., Donehower, L. A. & Morrison, R. S. Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas. Mol. Cell. Biol. 15, 4249–5259 ( 1995).

    CAS  Article  Google Scholar 

  70. 70

    Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    CAS  Article  Google Scholar 

  71. 71

    Wiliams, B. O. et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13, 4251–4259 ( 1994).

    Article  Google Scholar 

  72. 72

    Holland, E. C., Hively, W. P., DePinho, R. A. & Aarmus, H. E. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell cycle arrest pathways to induce gliomas in mice. Genes Dev. 12, 3675–3685 ( 1998).

    CAS  Article  Google Scholar 

  73. 73

    Lal, A. et al. A public database for gene expression in human cancers. Cancer Res. 59, 5403–5407 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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I would like to thank Greg Fuller and Joseph Celestino for help with the pathology, Chengkai Dai for help with the cell-lineage discussion, and V. K. Rajasekhar for help with the signal-transduction discussion.

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The specialized connective tissue of the central nervous system. It is made up of glial cells such as astrocytes, oligodendrocytes and ependymal cells.


One of the three main cell types in the brain, the others being neurons and oligodendrocytes. Astrocytes act as the scaffold that maintains the brain structure and that supports the functions of both neurons and oligodendrocytes.


One of the three main cell types that make up the brain parenchyma, the other two being neurons and astrocytes. Oligodendrocytes produce myelin, which insulates axons to alter the conduction properties of neurons.


A pathological increase in the size of cells or the structure that they form.


The inner substance of the brain that is composed primarily of neurons, oligodendrocytes, astrocytes and blood vessels.


The region directly below the pia, the membrane that forms the limiting edge of the brain. Invading glioma cells tend to accumulate in this region to generate one of the classic secondary structures of human gliomas.


When cells or tissues revert to a more embryonic or undifferentiated form and have an increased capacity to multiply.


An intermediate filament protein. The expression of its gene is limited to astrocytes.


A growth factor that exists as a homodimer or heterodimer of PDGFA and PDGFB chains. This growth factor binds to and activates the PDGF receptor PDGFRA or PDGFRB.


This ligand binds to the FGF2 receptor, promotes the proliferation of undifferentiated cells and stimulates angiogenesis.


This ligand binds to the CNTF receptor and promotes oligodendrocyte and astrocyte differentiation.


This receptor is bound by epidermal growth factor and the transforming growth factor-α.


A kinase involved in several biological processes, including glucose metabolism and signalling through the Wnt pathway. GSK3 also functions downstream of AKT.


A protein that is activated by AKT and which activates ribosomal protein S6 kinase. S6 kinase alters the ability of the ribosome to translate specific mRNAs.


BAD promotes apoptosis by dimerizing with and inhibiting BCL-2.


BCL-2 inhibits apoptosis by inhibiting caspase activation.


One of a family of proteases that are activated specifically in apoptotic cells.


This protein activates cell death. It is inactivated by AKT-dependent phosphorylation, which relocalizes it from the nucleus to the cytoplasm.


DNA content similar to that of a diploid cell.


A transcription factor that is bound to RB during G1 cell-cycle arrest and is released after phosphorylation of RB by CDK2 or CDK4. Free E2F1 then alters gene expression to lead to cell-cycle progression.


Cells derived from one species that are implanted into a host of another species; for example, human tumour cells implanted into a mouse.


Cells implanted into a host that are derived from another individual of the same species.


Viral gene product that activates many signalling pathways that are activated by the PDGF receptors.


Harvey Ras. Activated Ras allele initially isolated from Moloney mouse leukaemia virus.


A virally encoded oncogene originally isolated from the Rous sarcoma virus. This gene encodes a deleted and activated version of the cellular Src gene. Expression of this gene activates multiple signalling pathways.


A virally encoded oncogene originally isolated from the chicken erythroblastosis virus. This gene encodes an activated variant of the EGFR.


A virally encoded oncogene originally isolated from the simian sarcoma virus. This gene encodes the complete sequence of the PDGFB chain. Overexpression results in autocrine stimulation of the PDGF receptor.


Kirsten Ras. Activated Ras allele initially isolated from Kirsten mouse leukaemia virus.

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Holland, E. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2, 120–129 (2001).

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