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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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.
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.
Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34 , 333–351 (1938).
Jensen, R. Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg. Neurol. 49, 189– 195 (1998).
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).
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.
Lee, J. C., Mayer-Proschel, M. & Rao, M. S. Gliogenesis in the central nervous system. Glia 30, 105–121 ( 2000).
Mi, H. & Barres, B. Purification and characterization of astrocyte precursor cells in the developing rat optic nerve. J. Neurosci. 19, 1049–1061 (1999).
Cameron, H. A., Hazel, T. G. & McKay, R. D. Regulation of neurogenesis by growth factors and transmitters. J. Neurobiol. 36, 287– 309 (1998).
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).
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).
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).
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).
Rajan, P. & McKay, R. D. Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 18, 3620– 3629 (1998).
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.
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).
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).
Weis, J. et al. CNTF and its receptor subunits in human gliomas. J. Neurooncol. 44, 243–253 (1999).
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).
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).
Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80, 225– 236 (1995).
Martin-Blanco, E. p38 MAPK signalling cascades: ancient roles and new functions. Bioessays 22, 637–645 ( 2000).
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).
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).
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).
Thomas, G. & Hall, M. N. TOR signaling and control of cell growth. Curr. Opin. Cell Biol. 9, 782– 787 (1997).
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).
Sano, T. et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res. 59, 1820–1824 (1999).
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
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.
Jen, J. et al. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 54, 6353–6358 (1994).
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).
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
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).
Haber, D. A. Splicing into senescence: the curious case of p16 and p19ARF. Cell 91, 555–558 ( 1997).
Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94–99 (2000).
Liggett, W. H. Jr & Sidransky, D. Role of the p16 tumor suppressor gene in cancer. J. Clin. Oncol. 16, 1197–1206 ( 1998).
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).
Louis, D. N. The p53 gene and protein in human brain tumors. J. Neuropath. Exp. Neurol. 53, 11–21 ( 1994).
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).
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).
von Deimling, A. et al. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Path. 3, 19– 23 (1993).
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).
Marutani, M. et al. Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastomamultiforme. Cancer Res. 59, 4765–4769 (1999).
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).
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
Teng, D. H. et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 57, 5221– 5225 (1997).
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).
Hass, R. Retrodifferentiation and cell death. Crit. Rev. Oncol. 5, 359–371 (1994). PubMed
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).
Prados, M. D. & Levin, V. Biology and treatment of malignant glioma. Semin. Oncol. 27, S1– S10 (2000).
Castro, M. G. et al. Gene therapy strategies for intracranial tumours: glioma and pituitary adenomas. Histol. Histopathol. 15, 1233–1252 (2000).
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).
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).
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).
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.
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.
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).
Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 ( 1999).
Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).
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).
Wessenberger, J. et al. Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 14, 2005–2013 (1997).
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).
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.
Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27– 37 (1996).
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).
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).
Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).
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).
Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).
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).
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).
Lal, A. et al. A public database for gene expression in human cancers. Cancer Res. 59, 5403–5407 (1999).
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.
ENCYCLOPEDIA OF LIFE SCIENCES
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.
- BRAIN PARENCHYMA
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.
- GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP).
An intermediate filament protein. The expression of its gene is limited to astrocytes.
- PLATELET-DERIVED GROWTH FACTOR (PDGF).
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.
- FIBROBLAST GROWTH FACTOR 2 (FGF2).
This ligand binds to the FGF2 receptor, promotes the proliferation of undifferentiated cells and stimulates angiogenesis.
- CILLIARY NEUROTROPHIC FACTOR (CNTF).
This ligand binds to the CNTF receptor and promotes oligodendrocyte and astrocyte differentiation.
- EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
This receptor is bound by epidermal growth factor and the transforming growth factor-α.
- GLYCOGEN SYNTHASE KINASE 3 (GSK3).
A kinase involved in several biological processes, including glucose metabolism and signalling through the Wnt pathway. GSK3 also functions downstream of AKT.
- MAMMALIAN TARGET OF RAPAMYCIN (mTOR).
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.
- FORKHEAD TRANSCRIPTION FACTOR (FKHR).
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.
- POLYOMA VIRUS MIDDLE T ANTIGEN
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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