Skip to main content

Advertisement

SpringerLink
Log in

What underlies the diversity of brain tumors?

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children, respectively. Recent genomic and transcriptional approaches present a complex group of diseases and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing, and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development and the potential for these animals to impact brain tumor research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lumsden, A., & Krumlauf, R. (1996). Patterning the vertebrate neuraxis. Science, 274(5290), 1109–1115.

    Article  PubMed  CAS  Google Scholar 

  2. Liu, A., & Niswander, L. A. (2005). Bone morphogenetic protein signalling and vertebrate nervous system development. Nature Reviews Neuroscience, 6(12), 945–954.

    Article  PubMed  CAS  Google Scholar 

  3. Rowitch, D. H., & Kriegstein, A. R. (2010). Developmental genetics of vertebrate glial-cell specification. Nature, 468(7321), 214–222.

    Article  PubMed  CAS  Google Scholar 

  4. Malatesta, P., Hartfuss, E., & Gotz, M. (2000). Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development, 127(24), 5253–5263.

    PubMed  CAS  Google Scholar 

  5. Hansen, D. V., Lui, J. H., Parker, P. R., & Kriegstein, A. R. (2010). Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature, 464(7288), 554–561.

    Article  PubMed  CAS  Google Scholar 

  6. Feng, L., Hatten, M. E., & Heintz, N. (1994). Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron, 12(4), 895–908.

    Article  PubMed  CAS  Google Scholar 

  7. Hartfuss, E., Galli, R., Heins, N., & Gotz, M. (2001). Characterization of CNS precursor subtypes and radial glia. Developmental Biology, 229(1), 15–30.

    Article  PubMed  CAS  Google Scholar 

  8. Kurtz, A., Zimmer, A., Schnutgen, F., Bruning, G., Spener, F., & Muller, T. (1994). The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. Development, 120(9), 2637–2649.

    PubMed  CAS  Google Scholar 

  9. Anthony, T. E., Klein, C., Fishell, G., & Heintz, N. (2004). Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron, 41(6), 881–890.

    Article  PubMed  CAS  Google Scholar 

  10. Noble, M. (2000). Precursor cell transitions in oligodendrocyte development. The Journal of Cell Biology, 148(5), 839–842.

    Article  PubMed  CAS  Google Scholar 

  11. Menn, B., Garcia-Verdugo, J. M., Yaschine, C., Gonzalez-Perez, O., Rowitch, D., & Alvarez-Buylla, A. (2006). Origin of oligodendrocytes in the subventricular zone of the adult brain. The Journal of Neuroscience, 26(30), 7907–7918.

    Article  PubMed  CAS  Google Scholar 

  12. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 97(6), 703–716.

    Article  PubMed  CAS  Google Scholar 

  13. Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., et al. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4(11), 1313–1317.

    Article  PubMed  CAS  Google Scholar 

  14. Kriegstein, A., & Alvarez-Buylla, A. (2009). The glial nature of embryonic and adult neural stem cells. Annual Review of Neuroscience, 32, 149–184.

    Article  PubMed  CAS  Google Scholar 

  15. Spassky, N., Merkle, F. T., Flames, N., Tramontin, A. D., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (2005). Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. The Journal of Neuroscience, 25(1), 10–18.

    Article  PubMed  CAS  Google Scholar 

  16. Sgaier, S. K., Millet, S., Villanueva, M. P., Berenshteyn, F., Song, C., & Joyner, A. L. (2005). Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping. Neuron, 45(1), 27–40.

    PubMed  CAS  Google Scholar 

  17. Simeone, A. (2000). Positioning the isthmic organizer where Otx2 and Gbx2meet. Trends in Genetics, 16(6), 237–240.

    Article  PubMed  CAS  Google Scholar 

  18. Joyner, A. L., Liu, A., & Millet, S. (2000). Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Current Opinion in Cell Biology, 12(6), 736–741.

    Article  PubMed  CAS  Google Scholar 

  19. Ito, M. (2008). Control of mental activities by internal models in the cerebellum. Nature Reviews Neuroscience, 9(4), 304–313.

    Article  PubMed  CAS  Google Scholar 

  20. Levisohn, L., Cronin-Golomb, A., & Schmahmann, J. D. (2000). Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain, 123(Pt 5), 1041–1050.

    Article  PubMed  Google Scholar 

  21. Hatten, M. E., & Heintz, N. (1995). Mechanisms of neural patterning and specification in the developing cerebellum. Annual Review of Neuroscience, 18, 385–408.

    Article  PubMed  CAS  Google Scholar 

  22. Hoshino, M., Nakamura, S., Mori, K., Kawauchi, T., Terao, M., Nishimura, Y. V., et al. (2005). Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron, 47(2), 201–213.

    Article  PubMed  CAS  Google Scholar 

  23. Pascual, M., Abasolo, I., Mingorance-Le Meur, A., Martinez, A., Del Rio, J. A., Wright, C. V., et al. (2007). Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Proceedings of the National Academy of Sciences of the United States of America, 104(12), 5193–5198.

    Article  PubMed  CAS  Google Scholar 

  24. Edwards, M. A., Yamamoto, M., & Caviness, V. S., Jr. (1990). Organization of radial glia and related cells in the developing murine CNS. An analysis based upon a new monoclonal antibody marker. Neuroscience, 36(1), 121–144.

    Article  PubMed  CAS  Google Scholar 

  25. Morales, D., & Hatten, M. E. (2006). Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. The Journal of Neuroscience, 26(47), 12226–12236.

    Article  PubMed  CAS  Google Scholar 

  26. Hevner, R. F., Hodge, R. D., Daza, R. A., & Englund, C. (2006). Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neuroscience Research, 55(3), 223–233.

    Article  PubMed  CAS  Google Scholar 

  27. Akazawa, C., Ishibashi, M., Shimizu, C., Nakanishi, S., & Kageyama, R. (1995). A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. The Journal of Biological Chemistry, 270(15), 8730–8738.

    Article  PubMed  CAS  Google Scholar 

  28. Ben-Arie, N., Bellen, H. J., Armstrong, D. L., McCall, A. E., Gordadze, P. R., Guo, Q., et al. (1997). Math1 is essential for genesis of cerebellar granule neurons. Nature, 390(6656), 169–172.

    Article  PubMed  CAS  Google Scholar 

  29. Altman, J., & Bayer, S. A. (1997). Development of the cerebellar system: In relation to its evolution, structure and functions. Boca Raton: CRC Press.

    Google Scholar 

  30. Wechsler-Reya, R. J., & Scott, M. P. (1999). Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron, 22(1), 103–114.

    Article  PubMed  CAS  Google Scholar 

  31. Dahmane, N., & Ruiz i Altaba, A. (1999). Sonic hedgehog regulates the growth and patterning of the cerebellum. Development, 126(14), 3089–3100.

    PubMed  Google Scholar 

  32. Huang, X., Liu, J., Ketova, T., Fleming, J. T., Grover, V. K., Cooper, M. K., et al. (2010). Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development. Proceedings of the National Academy of Sciences of the United States of America, 107(18), 8422–8427.

    Article  PubMed  CAS  Google Scholar 

  33. Machold, R., & Fishell, G. (2005). Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron, 48(1), 17–24.

    Article  PubMed  CAS  Google Scholar 

  34. Wang, V. Y., Rose, M. F., & Zoghbi, H. Y. (2005). Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron, 48(1), 31–43.

    Article  PubMed  CAS  Google Scholar 

  35. Zhuo, L., Theis, M., Alvarez-Maya, I., Brenner, M., Willecke, K., & Messing, A. (2001). hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis, 31(2), 85–94.

    Article  PubMed  CAS  Google Scholar 

  36. Schuller, U., Heine, V. M., Mao, J., Kho, A. T., Dillon, A. K., Han, Y. G., et al. (2008). Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell, 14(2), 123–134.

    Article  PubMed  CAS  Google Scholar 

  37. Yang, Z. J., Ellis, T., Markant, S. L., Read, T. A., Kessler, J. D., Bourboulas, M., et al. (2008). Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell, 14(2), 135–145.

    Article  PubMed  CAS  Google Scholar 

  38. Aldinger, K. A., & Elsen, G. E. (2008). Ptf1a is a molecular determinant for both glutamatergic and GABAergic neurons in the hindbrain. The Journal of Neuroscience, 28(2), 338–339.

    Article  PubMed  CAS  Google Scholar 

  39. Raaf, J., & Kernohan, J. (1944). A study of the external granular layer in the cerebellum. The American Journal of Anatomy, 75, 151–172.

    Article  Google Scholar 

  40. Chizhikov, V. V., Lindgren, A. G., Currle, D. S., Rose, M. F., Monuki, E. S., & Millen, K. J. (2006). The roof plate regulates cerebellar cell-type specification and proliferation. Development, 133(15), 2793–2804.

    Article  PubMed  CAS  Google Scholar 

  41. Machold, R. P., Kittell, D. J., & Fishell, G. J. (2007). Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Development, 2, 5.

    Article  PubMed  CAS  Google Scholar 

  42. Alder, J., Lee, K. J., Jessell, T. M., & Hatten, M. E. (1999). Generation of cerebellar granule neurons in vivo by transplantation of BMP-treated neural progenitor cells. Nature Neuroscience, 2(6), 535–540.

    Article  PubMed  CAS  Google Scholar 

  43. Rios, I., Alvarez-Rodriguez, R., Marti, E., & Pons, S. (2004). Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development, 131(13), 3159–3168.

    Article  PubMed  CAS  Google Scholar 

  44. Zhao, H., Ayrault, O., Zindy, F., Kim, J. H., & Roussel, M. F. (2008). Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes & Development, 22(6), 722–727.

    Article  CAS  Google Scholar 

  45. Lutolf, S., Radtke, F., Aguet, M., Suter, U., & Taylor, V. (2002). Notch1 is required for neuronal and glial differentiation in the cerebellum. Development, 129(2), 373–385.

    PubMed  CAS  Google Scholar 

  46. Solecki, D. J., Liu, X. L., Tomoda, T., Fang, Y., & Hatten, M. E. (2001). Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron, 31(4), 557–568.

    Article  PubMed  CAS  Google Scholar 

  47. Stupp, R., Hegi, M. E., Mason, W. P., van den Bent, M. J., Taphoorn, M. J., Janzer, R. C., et al. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology, 10(5), 459–466.

    Article  PubMed  CAS  Google Scholar 

  48. Cairncross, J. G., Ueki, K., Zlatescu, M. C., Lisle, D. K., Finkelstein, D. M., Hammond, R. R., et al. (1998). Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. Journal of the National Cancer Institute, 90(19), 1473–1479.

    Article  PubMed  CAS  Google Scholar 

  49. Cancer Genome Atlas Research Network. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216), 1061–1068.

    Article  CAS  Google Scholar 

  50. Phillips, H. S., Kharbanda, S., Chen, R., Forrest, W. F., Soriano, R. H., Wu, T. D., et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9(3), 157–173.

    Article  PubMed  CAS  Google Scholar 

  51. Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1), 98–110.

    Article  PubMed  CAS  Google Scholar 

  52. Lai, A., Kharbanda, S., Pope, W. B., Tran, A., Solis, O. E., Peale, F., et al. (2011). Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. Journal of Clinical Oncology, 29(34), 4482–4490.

    Article  PubMed  CAS  Google Scholar 

  53. Pfister, S., Janzarik, W. G., Remke, M., Ernst, A., Werft, W., Becker, N., et al. (2008). BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. The Journal of Clinical Investigation, 118(5), 1739–1749.

    Article  PubMed  CAS  Google Scholar 

  54. Jones, D. T., Kocialkowski, S., Liu, L., Pearson, D. M., Backlund, L. M., Ichimura, K., et al. (2008). Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Research, 68(21), 8673–8677.

    Article  PubMed  CAS  Google Scholar 

  55. Lewis, R. A., Gerson, L. P., Axelson, K. A., Riccardi, V. M., & Whitford, R. P. (1984). von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology, 91(8), 929–935.

    PubMed  CAS  Google Scholar 

  56. Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., et al. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226–231.

    Article  PubMed  CAS  Google Scholar 

  57. Johnson, R. A., Wright, K. D., Poppleton, H., Mohankumar, K. M., Finkelstein, D., Pounds, S. B., et al. (2010). Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature, 466(7306), 632–636.

    Article  PubMed  CAS  Google Scholar 

  58. Wong, A. J., Ruppert, J. M., Bigner, S. H., Grzeschik, C. H., Humphrey, P. A., Bigner, D. S., et al. (1992). Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proceedings of the National Academy of Sciences of the United States of America, 89(7), 2965–2969.

    Article  PubMed  CAS  Google Scholar 

  59. Ekstrand, A. J., Longo, N., Hamid, M. L., Olson, J. J., Liu, L., Collins, V. P., et al. (1994). Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene, 9(8), 2313–2320.

    PubMed  CAS  Google Scholar 

  60. Holland, E. C., Hively, W. P., DePinho, R. A., & Varmus, H. E. (1998). A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes & Development, 12(23), 3675–3685.

    Article  CAS  Google Scholar 

  61. Weiss, W. A., Burns, M. J., Hackett, C., Aldape, K., Hill, J. R., Kuriyama, H., et al. (2003). Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Research, 63(7), 1589–1595.

    PubMed  CAS  Google Scholar 

  62. Ding, H., Shannon, P., Lau, N., Wu, X., Roncari, L., Baldwin, R. L., et al. (2003). Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Research, 63(5), 1106–1113.

    PubMed  CAS  Google Scholar 

  63. Persson, A. I., Petritsch, C., Swartling, F. J., Itsara, M., Sim, F. J., Auvergne, R., et al. (2010). Non-stem cell origin for oligodendroglioma. Cancer Cell, 18(6), 669–682.

    Article  PubMed  CAS  Google Scholar 

  64. Bachoo, R. M., Maher, E. A., Ligon, K. L., Sharpless, N. E., Chan, S. S., You, M. J., et al. (2002). Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell, 1(3), 269–277.

    Article  PubMed  CAS  Google Scholar 

  65. Zhu, H., Acquaviva, J., Ramachandran, P., Boskovitz, A., Woolfenden, S., Pfannl, R., et al. (2009). Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2712–2716.

    Article  PubMed  CAS  Google Scholar 

  66. Acquaviva, J., Jun, H. J., Lessard, J., Ruiz, R., Zhu, H., Donovan, M., et al. (2011). Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation. Cancer Research, 71(23), 7198–7206.

    Article  PubMed  CAS  Google Scholar 

  67. Fleming, T. P., Saxena, A., Clark, W. C., Robertson, J. T., Oldfield, E. H., Aaronson, S. A., et al. (1992). Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Research, 52(16), 4550–4553.

    PubMed  CAS  Google Scholar 

  68. Hermanson, M., Funa, K., Hartman, M., Claesson-Welsh, L., Heldin, C. H., Westermark, B., et al. (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 Research, 52(11), 3213–3219.

    PubMed  CAS  Google Scholar 

  69. Calzolari, F., Appolloni, I., Tutucci, E., Caviglia, S., Terrile, M., Corte, G., et al. (2008). Tumor progression and oncogene addiction in a PDGF-B-induced model of gliomagenesis. Neoplasia, 10(12), 1373–1382. following 1382.

    PubMed  CAS  Google Scholar 

  70. 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 Research, 58(23), 5275–5279.

    PubMed  CAS  Google Scholar 

  71. Assanah, M. C., Bruce, J. N., Suzuki, S. O., Chen, A., Goldman, J. E., & Canoll, P. (2009). PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain. Glia, 57(16), 1835–1847.

    Article  PubMed  CAS  Google Scholar 

  72. Dai, C., Celestino, J. C., Okada, Y., Louis, D. N., Fuller, G. N., & Holland, E. C. (2001). PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes & Development, 15(15), 1913–1925.

    Article  CAS  Google Scholar 

  73. Lindberg, N., Kastemar, M., Olofsson, T., Smits, A., & Uhrbom, L. (2009). Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene, 28(23), 2266–2275.

    Article  PubMed  CAS  Google Scholar 

  74. Hesselager, G., Uhrbom, L., Westermark, B., & Nister, M. (2003). Complementary effects of platelet-derived growth factor autocrine stimulation and p53 or Ink4a-Arf deletion in a mouse glioma model. Cancer Research, 63(15), 4305–4309.

    PubMed  CAS  Google Scholar 

  75. Tchougounova, E., Kastemar, M., Brasater, D., Holland, E. C., Westermark, B., & Uhrbom, L. (2007). Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma. Oncogene, 26(43), 6289–6296.

    Article  PubMed  CAS  Google Scholar 

  76. Hede, S. M., Hansson, I., Afink, G. B., Eriksson, A., Nazarenko, I., Andrae, J., et al. (2009). GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background. Glia, 57(11), 1143–1153.

    Article  PubMed  Google Scholar 

  77. Nazarenko, I., Hedren, A., Sjodin, H., Orrego, A., Andrae, J., Afink, G. B., et al. (2011). Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells. PloS One, 6(4), e18303.

    Article  PubMed  CAS  Google Scholar 

  78. Lei, L., Sonabend, A. M., Guarnieri, P., Soderquist, C., Ludwig, T., Rosenfeld, S., et al. (2011). Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype. PloS One, 6(5), e20041.

    Article  PubMed  CAS  Google Scholar 

  79. Ding, H., Roncari, L., Shannon, P., Wu, X., Lau, N., Karaskova, J., et al. (2001). Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Research, 61(9), 3826–3836.

    PubMed  CAS  Google Scholar 

  80. Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. E., & Fuller, G. N. (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics, 25(1), 55–57.

    Article  PubMed  CAS  Google Scholar 

  81. Uhrbom, L., Dai, C., Celestino, J. C., Rosenblum, M. K., Fuller, G. N., & Holland, E. C. (2002). Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Research, 62(19), 5551–5558.

    PubMed  CAS  Google Scholar 

  82. Marumoto, T., Tashiro, A., Friedmann-Morvinski, D., Scadeng, M., Soda, Y., Gage, F. H., et al. (2009). Development of a novel mouse glioma model using lentiviral vectors. Nature Medicine, 15(1), 110–116.

    Article  PubMed  CAS  Google Scholar 

  83. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E., & Jacks, T. (2000). Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genetics, 26(1), 109–113.

    Article  PubMed  CAS  Google Scholar 

  84. Wang, Y., Yang, J., Zheng, H., Tomasek, G. J., Zhang, P., McKeever, P. E., et al. (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell, 15(6), 514–526.

    Article  PubMed  CAS  Google Scholar 

  85. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., et al. (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell, 8(2), 119–130.

    Article  PubMed  CAS  Google Scholar 

  86. von Deimling, A., Eibl, R. H., Ohgaki, H., Louis, D. N., von Ammon, K., Petersen, I., et al. (1992). p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Research, 52(10), 2987–2990.

    Google Scholar 

  87. Kwon, C. H., Zhao, D., Chen, J., Alcantara, S., Li, Y., Burns, D. K., et al. (2008). Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Research, 68(9), 3286–3294.

    Article  PubMed  CAS  Google Scholar 

  88. Alcantara Llaguno, S., Chen, J., Kwon, C. H., Jackson, E. L., Li, Y., Burns, D. K., et al. (2009). Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell, 15(1), 45–56.

    Article  PubMed  CAS  Google Scholar 

  89. Jacques, T. S., Swales, A., Brzozowski, M. J., Henriquez, N. V., Linehan, J. M., Mirzadeh, Z., et al. (2010). Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. The EMBO Journal, 29(1), 222–235.

    Article  PubMed  CAS  Google Scholar 

  90. Chow, L. M., Endersby, R., Zhu, X., Rankin, S., Qu, C., Zhang, J., et al. (2011). Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain. Cancer Cell, 19(3), 305–316.

    Article  PubMed  CAS  Google Scholar 

  91. Gronych, J., Korshunov, A., Bageritz, J., Milde, T., Jugold, M., Hambardzumyan, D., et al. (2011). An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice. The Journal of Clinical Investigation, 121(4), 1344–1348.

    Article  PubMed  CAS  Google Scholar 

  92. Becher, O. J., Hambardzumyan, D., Walker, T. R., Helmy, K., Nazarian, J., Albrecht, S., et al. (2010). Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Research, 70(6), 2548–2557.

    Article  PubMed  CAS  Google Scholar 

  93. Hitoshi, Y., Harris, B. T., Liu, H., Popko, B., & Israel, M. A. (2008). Spinal glioma: platelet-derived growth factor B-mediated oncogenesis in the spinal cord. Cancer Research, 68(20), 8507–8515.

    Article  PubMed  CAS  Google Scholar 

  94. Liu, C., Sage, J. C., Miller, M. R., Verhaak, R. G., Hippenmeyer, S., Vogel, H., et al. (2011). Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell, 146(2), 209–221.

    Article  PubMed  CAS  Google Scholar 

  95. Hambardzumyan, D., Amankulor, N. M., Helmy, K. Y., Becher, O. J., & Holland, E. C. (2009). Modeling adult gliomas using RCAS/t-va technology. Translational Oncology, 2(2), 89–95.

    PubMed  Google Scholar 

  96. Taylor, M. D., Poppleton, H., Fuller, C., Su, X., Liu, Y., Jensen, P., et al. (2005). Radial glia cells are candidate stem cells of ependymoma. Cancer Cell, 8(4), 323–335.

    Article  PubMed  CAS  Google Scholar 

  97. Saran, A. (2009). Medulloblastoma: role of developmental pathways, DNA repair signaling, and other players. Current Molecular Medicine, 9(9), 1046–1057.

    Article  PubMed  CAS  Google Scholar 

  98. Schmidt, A. L., Brunetto, A. L., Schwartsmann, G., Roesler, R., & Abujamra, A. L. (2010). Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets. CNS & Neurological Disorders Drug Targets, 9(3), 335–348.

    Article  CAS  Google Scholar 

  99. Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., et al. (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica, 114(2), 97–109.

    Article  PubMed  Google Scholar 

  100. Eberhart, C. G., Brat, D. J., Cohen, K. J., & Burger, P. C. (2000). Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatric and Developmental Pathology, 3(4), 346–352.

    Article  PubMed  CAS  Google Scholar 

  101. Taylor, M. D., Northcott, P. A., Korshunov, A., Remke, M., Cho, Y. J., Clifford, S. C., et al. (2011). Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathology, 123(4), 465–472.

    Article  CAS  Google Scholar 

  102. Thompson, M. C., Fuller, C., Hogg, T. L., Dalton, J., Finkelstein, D., Lau, C. C., et al. (2006). Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. Journal of Clinical Oncology, 24(12), 1924–1931.

    Article  PubMed  CAS  Google Scholar 

  103. Kool, M., Koster, J., Bunt, J., Hasselt, N. E., Lakeman, A., van Sluis, P., et al. (2008). Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PloS One, 3(8), e3088.

    Article  PubMed  CAS  Google Scholar 

  104. Cho, Y. J., Tsherniak, A., Tamayo, P., Santagata, S., Ligon, A., Greulich, H., et al. (2011). Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. Journal of Clinical Oncology, 29(11), 1424–1430.

    Article  PubMed  Google Scholar 

  105. Northcott, P. A., Korshunov, A., Witt, H., Hielscher, T., Eberhart, C. G., Mack, S., et al. (2011). Medulloblastoma comprises four distinct molecular variants. Journal of Clinical Oncology, 29(11), 1408–1414.

    Article  PubMed  Google Scholar 

  106. Kool, M., Korshunov, A., Remke, M., Jones, D. T., Schlanstein, M., Northcott, P. A., et al. (2012). Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, group 3, and group 4 medulloblastomas. Acta Neuropathologica, 123(4), 473–484.

    Article  PubMed  CAS  Google Scholar 

  107. Nusslein-Volhard, C., & Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287(5785), 795–801.

    Article  PubMed  CAS  Google Scholar 

  108. Espinosa, J. S., & Luo, L. (2008). Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells. The Journal of Neuroscience, 28(10), 2301–2312.

    Article  PubMed  CAS  Google Scholar 

  109. Hahn, H., Wicking, C., Zaphiropoulous, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., et al. (1996). Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell, 85(6), 841–851.

    Article  PubMed  CAS  Google Scholar 

  110. Goodrich, L. V., Milenkovic, L., Higgins, K. M., & Scott, M. P. (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science, 277(5329), 1109–1113.

    Article  PubMed  CAS  Google Scholar 

  111. Pazzaglia, S., Mancuso, M., Atkinson, M. J., Tanori, M., Rebessi, S., Majo, V. D., et al. (2002). High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene, 21(49), 7580–7584.

    Article  PubMed  CAS  Google Scholar 

  112. Wetmore, C., Eberhart, D. E., & Curran, T. (2001). Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Research, 61(2), 513–516.

    PubMed  CAS  Google Scholar 

  113. Hallahan, A. R., Pritchard, J. I., Hansen, S., Benson, M., Stoeck, J., Hatton, B. A., et al. (2004). The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Research, 64(21), 7794–7800.

    Article  PubMed  CAS  Google Scholar 

  114. Hatton, B. A., Villavicencio, E. H., Tsuchiya, K. D., Pritchard, J. I., Ditzler, S., Pullar, B., et al. (2008). The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Research, 68(6), 1768–1776.

    Article  PubMed  CAS  Google Scholar 

  115. Mao, J., Ligon, K. L., Rakhlin, E. Y., Thayer, S. P., Bronson, R. T., Rowitch, D., et al. (2006). A novel somatic mouse model to survey tumorigenic potential applied to the hedgehog pathway. Cancer Research, 66(20), 10171–10178.

    Article  PubMed  CAS  Google Scholar 

  116. Huangfu, D., & Anderson, K. V. (2005). Cilia and hedgehog responsiveness in the mouse. Proceedings of the National Academy of Sciences of the United States of America, 102(32), 11325–11330.

    Article  PubMed  CAS  Google Scholar 

  117. Rohatgi, R., Milenkovic, L., & Scott, M. P. (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836), 372–376.

    Article  PubMed  CAS  Google Scholar 

  118. Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y., & Reiter, J. F. (2005). Vertebrate smoothened functions at the primary cilium. Nature, 437(7061), 1018–1021.

    Article  PubMed  CAS  Google Scholar 

  119. Han, Y. G., Kim, H. J., Dlugosz, A. A., Ellison, D. W., Gilbertson, R. J., & Alvarez-Buylla, A. (2009). Dual and opposing roles of primary cilia in medulloblastoma development. Nature Medicine, 15(9), 1062–1065.

    Article  PubMed  CAS  Google Scholar 

  120. Weiner, H. L., Bakst, R., Hurlbert, M. S., Ruggiero, J., Ahn, E., Lee, W. S., et al. (2002). Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Research, 62(22), 6385–6389.

    PubMed  CAS  Google Scholar 

  121. Rao, G., Pedone, C. A., Coffin, C. M., Holland, E. C., & Fults, D. W. (2003). c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia, 5(3), 198–204.

    PubMed  CAS  Google Scholar 

  122. Rao, G., Pedone, C. A., Del Valle, L., Reiss, K., Holland, E. C., & Fults, D. W. (2004). Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene, 23(36), 6156–6162.

    Article  PubMed  CAS  Google Scholar 

  123. Browd, S. R., Kenney, A. M., Gottfried, O. N., Yoon, J. W., Walterhouse, D., Pedone, C. A., et al. (2006). N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma. Cancer Research, 66(5), 2666–2672.

    Article  PubMed  CAS  Google Scholar 

  124. Kenney, A. M., Cole, M. D., & Rowitch, D. H. (2003). Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development, 130(1), 15–28.

    Article  PubMed  CAS  Google Scholar 

  125. Kessler, J. D., Hasegawa, H., Brun, S. N., Yang, Z. J., Dutton, J. W., Wang, F., et al. (2009). N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma. Genes & Development, 23(2), 157–170.

    Article  CAS  Google Scholar 

  126. Stecca, B., & Ruiz i Altaba, A. (2009). A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. The EMBO Journal, 28(6), 663–676.

    Article  PubMed  CAS  Google Scholar 

  127. Flora, A., Klisch, T. J., Schuster, G., & Zoghbi, H. Y. (2009). Deletion of Atoh1 disrupts sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science, 326(5958), 1424–1427.

    Article  PubMed  CAS  Google Scholar 

  128. Lee, Y., Kawagoe, R., Sasai, K., Li, Y., Russell, H. R., Curran, T., et al. (2007). Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene, 26(44), 6442–6447.

    Article  PubMed  CAS  Google Scholar 

  129. Rausch, T., Jones, D. T., Zapatka, M., Stutz, A. M., Zichner, T., Weischenfeldt, J., et al. (2012). Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell, 148(1–2), 59–71.

    Article  PubMed  CAS  Google Scholar 

  130. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J., & Berns, A. (2000). Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes & Development, 14(8), 994–1004.

    CAS  Google Scholar 

  131. Tong, W. M., Ohgaki, H., Huang, H., Granier, C., Kleihues, P., & Wang, Z. Q. (2003). Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(−/−) mice. The American Journal of Pathology, 162(1), 343–352.

    Article  PubMed  CAS  Google Scholar 

  132. Lee, Y., & McKinnon, P. J. (2002). DNA ligase IV suppresses medulloblastoma formation. Cancer Research, 62(22), 6395–6399.

    PubMed  CAS  Google Scholar 

  133. Frappart, P. O., Lee, Y., Russell, H. R., Chalhoub, N., Wang, Y. D., Orii, K. E., et al. (2009). Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proceedings of the National Academy of Sciences of the United States of America, 106(6), 1880–1885.

    Article  PubMed  CAS  Google Scholar 

  134. Yan, C. T., Kaushal, D., Murphy, M., Zhang, Y., Datta, A., Chen, C., et al. (2006). XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 103(19), 7378–7383.

    Article  PubMed  CAS  Google Scholar 

  135. Nusse, R., van Ooyen, A., Cox, D., Fung, Y. K., & Varmus, H. (1984). Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature, 307(5947), 131–136.

    Article  PubMed  CAS  Google Scholar 

  136. Ellison, D. W., Dalton, J., Kocak, M., Nicholson, S. L., Fraga, C., Neale, G., et al. (2011). Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathologica, 121(3), 381–396.

    Article  PubMed  CAS  Google Scholar 

  137. Gibson, P., Tong, Y., Robinson, G., Thompson, M. C., Currle, D. S., Eden, C., et al. (2010). Subtypes of medulloblastoma have distinct developmental origins. Nature, 468(7327), 1095–1099.

    Article  PubMed  CAS  Google Scholar 

  138. Korshunov, A., Remke, M., Kool, M., Hielscher, T., Northcott, P. A., Williamson, D., et al. (2011). Biological and clinical heterogeneity of MYCN-amplified medulloblastoma. Acta Neuropathology, 123(4), 515–527.

    Article  CAS  Google Scholar 

  139. Swartling, F. J., Grimmer, M. R., Hackett, C. S., Northcott, P. A., Fan, Q. W., Goldenberg, D. D., et al. (2010). Pleiotropic role for MYCN in medulloblastoma. Genes & Development, 24(10), 1059–1072.

    Article  CAS  Google Scholar 

  140. Pei, Y., Moore, C. E., Wang, J., Tewari, A. K., Eroshkin, A., Cho, Y. J., et al. (2012). An animal model of MYC-driven medulloblastoma. Cancer Cell, 21(2), 155–167.

    Article  PubMed  CAS  Google Scholar 

  141. Kawauchi, D., Robinson, G., Uziel, T., Gibson, P., Rehg, J., Gao, C., et al. (2012). A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell, 21(2), 168–180.

    Article  PubMed  CAS  Google Scholar 

  142. Swartling, F. J., Savov, V., Persson, A. I., Chen, J., Hackett, C. S., Grimmer, M. R., et al. (2012). Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. Cancer Cell, 25(5), 601–613.

    Article  CAS  Google Scholar 

  143. Gajjar, A., Chintagumpala, M., Ashley, D., Kellie, S., Kun, L. E., Merchant, T. E., et al. (2006). Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. The Lancet Oncology, 7(10), 813–820.

    Article  PubMed  Google Scholar 

  144. von Hoff, K., Hinkes, B., Gerber, N. U., Deinlein, F., Mittler, U., Urban, C., et al. (2009). Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91. European Journal of Cancer, 45(7), 1209–1217.

    Article  Google Scholar 

  145. Wu, X., Northcott, P. A., Dubuc, A., Dupuy, A. J., Shih, D. J., Witt, H., et al. (2012). Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature, 482(7386), 529–533.

    Article  PubMed  CAS  Google Scholar 

  146. MacDonald, T. J., Brown, K. M., LaFleur, B., Peterson, K., Lawlor, C., Chen, Y., et al. (2001). Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nature Genetics, 29(2), 143–152.

    Article  PubMed  CAS  Google Scholar 

  147. Eibl, R. H., Kleihues, P., Jat, P. S., & Wiestler, O. D. (1994). A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen. The American Journal of Pathology, 144(3), 556–564.

    PubMed  CAS  Google Scholar 

  148. Theuring, F., Gotz, W., Balling, R., Korf, H. W., Schulze, F., Herken, R., et al. (1990). Tumorigenesis and eye abnormalities in transgenic mice expressing MSV-SV40 large T-antigen. Oncogene, 5(2), 225–232.

    PubMed  CAS  Google Scholar 

  149. al-Ubaidi, M. R., Font, R. L., Quiambao, A. B., Keener, M. J., Liou, G. I., Overbeek, P. A., et al. (1992). Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter. The Journal of Cell Biology, 119(6), 1681–1687.

    Article  PubMed  CAS  Google Scholar 

  150. Momota, H., Shih, A. H., Edgar, M. A., & Holland, E. C. (2008). c-Myc and beta-catenin cooperate with loss of p53 to generate multiple members of the primitive neuroectodermal tumor family in mice. Oncogene, 27(32), 4392–4401.

    Article  PubMed  CAS  Google Scholar 

  151. Perry, A., Miller, C. R., Gujrati, M., Scheithauer, B. W., Zambrano, S. C., Jost, S. C., et al. (2009). Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. Brain Pathology, 19(1), 81–90.

    Article  PubMed  Google Scholar 

  152. Biegel, J. A., Tan, L., Zhang, F., Wainwright, L., Russo, P., & Rorke, L. B. (2002). Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clinical Cancer Research, 8(11), 3461–3467.

    PubMed  CAS  Google Scholar 

  153. Jagani, Z., Mora-Blanco, E. L., Sansam, C. G., McKenna, E. S., Wilson, B., Chen, D., et al. (2010). Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nature Medicine, 16(12), 1429–1433.

    Article  PubMed  CAS  Google Scholar 

  154. Guidi, C. J., Sands, A. T., Zambrowicz, B. P., Turner, T. K., Demers, D. A., Webster, W., et al. (2001). Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Molecular and Cellular Biology, 21(10), 3598–3603.

    Article  PubMed  CAS  Google Scholar 

  155. Roberts, C. W., Galusha, S. A., McMenamin, M. E., Fletcher, C. D., & Orkin, S. H. (2000). Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proceedings of the National Academy of Sciences of the United States of America, 97(25), 13796–13800.

    Article  PubMed  CAS  Google Scholar 

  156. Remke, M., Hielscher, T., Northcott, P. A., Witt, H., Ryzhova, M., Wittmann, A., et al. (2011). Adult medulloblastoma comprises three major molecular variants. Journal of Clinical Oncology, 29(19), 2717–2723.

    Article  PubMed  Google Scholar 

  157. Grammel, D., Warmuth-Metz, M., von Bueren, A. O., Kool, M., Pietsch, T., Kretzschmar, H. A., et al. (2012). Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathologica, 123(4), 601–614.

    Article  PubMed  CAS  Google Scholar 

  158. Wen, P. Y., & Kesari, S. (2008). Malignant gliomas in adults. The New England Journal of Medicine, 359(5), 492–507.

    Article  PubMed  CAS  Google Scholar 

  159. Gilbertson, R. J., & Ellison, D. W. (2008). The origins of medulloblastoma subtypes. Annual Review of Pathology, 3, 341–365.

    Article  PubMed  CAS  Google Scholar 

  160. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321(5897), 1807–1812.

    Article  PubMed  CAS  Google Scholar 

  161. Parsons, D. W., Li, M., Zhang, X., Jones, S., Leary, R. J., Lin, J. C., et al. (2011). The genetic landscape of the childhood cancer medulloblastoma. Science, 331(6016), 435–439.

    Article  PubMed  CAS  Google Scholar 

  162. Hudson, T. J., Anderson, W., Artez, A., Barker, A. D., Bell, C., Bernabe, R. R., et al. (2010). International network of cancer genome projects. Nature, 464(7291), 993–998.

    Article  PubMed  CAS  Google Scholar 

  163. Johansson, F. K., Brodd, J., Eklof, C., Ferletta, M., Hesselager, G., Tiger, C. F., et al. (2004). Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging. Proceedings of the National Academy of Sciences of the United States of America, 101(31), 11334–11337.

    Article  PubMed  CAS  Google Scholar 

  164. Johansson, F. K., Goransson, H., & Westermark, B. (2005). Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. Oncogene, 24(24), 3896–3905.

    Article  PubMed  CAS  Google Scholar 

  165. Johansson Swartling, F. (2008). Identifying candidate genes involved in brain tumor formation. Upsala Journal of Medical Sciences, 113(1), 1–38.

    Article  PubMed  Google Scholar 

  166. Swartling, F. J., Ferletta, M., Kastemar, M., Weiss, W. A., & Westermark, B. (2009). Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines. Oncogene, 28(35), 3121–3131.

    Article  PubMed  CAS  Google Scholar 

  167. Phillips, J. J., Huillard, E., Robinson, A. E., Ward, A., Lum, D. H., Polley, M. Y., et al. (2012). Heparan sulfate sulfatase SULF2 regulates PDGFRalpha signaling and growth in human and mouse malignant glioma. The Journal of Clinical Investigation, 122(3), 911–922.

    Article  PubMed  CAS  Google Scholar 

  168. Tchougounova, E., Jiang, Y., Brasater, D., Lindberg, N., Kastemar, M., Asplund, A., et al. (2009). Sox5 can suppress platelet-derived growth factor B-induced glioma development in Ink4a-deficient mice through induction of acute cellular senescence. Oncogene, 28(12), 1537–1548.

    Article  PubMed  CAS  Google Scholar 

  169. Ferletta, M., Uhrbom, L., Olofsson, T., Ponten, F., & Westermark, B. (2007). Sox10 has a broad expression pattern in gliomas and enhances platelet-derived growth factor-B-induced gliomagenesis. Molecular Cancer Research, 5(9), 891–897.

    Article  PubMed  CAS  Google Scholar 

  170. Wolf, R. M., Draghi, N., Liang, X., Dai, C., Uhrbom, L., Eklof, C., et al. (2003). p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes & Development, 17(4), 476–487.

    Article  CAS  Google Scholar 

  171. Wiesner, S. M., Decker, S. A., Larson, J. D., Ericson, K., Forster, C., Gallardo, J. L., et al. (2009). De novo induction of genetically engineered brain tumors in mice using plasmid DNA. Cancer Research, 69(2), 431–439.

    Article  PubMed  CAS  Google Scholar 

  172. Collier, L. S., Adams, D. J., Hackett, C. S., Bendzick, L. E., Akagi, K., Davies, M. N., et al. (2009). Whole-body sleeping beauty mutagenesis can cause penetrant leukemia/lymphoma and rare high-grade glioma without associated embryonic lethality. Cancer Research, 69(21), 8429–8437.

    Article  PubMed  CAS  Google Scholar 

  173. Bender, A. M., Collier, L. S., Rodriguez, F. J., Tieu, C., Larson, J. D., Halder, C., et al. (2010). Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas. Cancer Research, 70(9), 3557–3565.

    Article  PubMed  CAS  Google Scholar 

  174. Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G., & Jenkins, N. A. (2005). Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature, 436(7048), 221–226.

    Article  PubMed  CAS  Google Scholar 

  175. Weissenberger, J., Steinbach, J. P., Malin, G., Spada, S., Rulicke, T., & Aguzzi, A. (1997). Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene, 14(17), 2005–2013.

    Article  PubMed  CAS  Google Scholar 

  176. Kamijo, T., Bodner, S., van de Kamp, E., Randle, D. H., & Sherr, C. J. (1999). Tumor spectrum in ARF-deficient mice. Cancer Research, 59(9), 2217–2222.

    PubMed  CAS  Google Scholar 

  177. Jensen, N. A., Pedersen, K. M., Lihme, F., Rask, L., Nielsen, J. V., Rasmussen, T. E., et al. (2003). Astroglial c-Myc overexpression predisposes mice to primary malignant gliomas. The Journal of Biological Chemistry, 278(10), 8300–8308.

    Article  PubMed  CAS  Google Scholar 

  178. Abel, T. W., Clark, C., Bierie, B., Chytil, A., Aakre, M., Gorska, A., et al. (2009). GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma. Molecular Cancer Research, 7(5), 645–653.

    Article  PubMed  CAS  Google Scholar 

  179. Shannon, P., Sabha, N., Lau, N., Kamnasaran, D., Gutmann, D. H., & Guha, A. (2005). Pathological and molecular progression of astrocytomas in a GFAP:12 V-Ha-Ras mouse astrocytoma model. The American Journal of Pathology, 167(3), 859–867.

    Article  PubMed  CAS  Google Scholar 

  180. Wei, Q., Clarke, L., Scheidenhelm, D. K., Qian, B., Tong, A., Sabha, N., et al. (2006). High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Research, 66(15), 7429–7437.

    Article  PubMed  CAS  Google Scholar 

  181. Xiao, A., Wu, H., Pandolfi, P. P., Louis, D. N., & Van Dyke, T. (2002). Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell, 1(2), 157–168.

    Article  PubMed  CAS  Google Scholar 

  182. 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. International Journal of Cancer, 85(3), 398–406.

    Article  CAS  Google Scholar 

  183. Dai, C., Lyustikman, Y., Shih, A., Hu, X., Fuller, G. N., Rosenblum, M., et al. (2005). The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia, 7(4), 397–406.

    Article  PubMed  CAS  Google Scholar 

  184. Shih, A. H., Dai, C., Hu, X., Rosenblum, M. K., Koutcher, J. A., & Holland, E. C. (2004). Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis. Cancer Research, 64(14), 4783–4789.

    Article  PubMed  CAS  Google Scholar 

  185. Hu, X., Pandolfi, P. P., Li, Y., Koutcher, J. A., Rosenblum, M., & Holland, E. C. (2005). mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia, 7(4), 356–368.

    Article  PubMed  CAS  Google Scholar 

  186. Zheng, H., Ying, H., Yan, H., Kimmelman, A. C., Hiller, D. J., Chen, A. J., et al. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature, 455(7216), 1129–1133.

    Article  PubMed  CAS  Google Scholar 

  187. Gil-Perotin, S., Marin-Husstege, M., Li, J., Soriano-Navarro, M., Zindy, F., Roussel, M. F., et al. (2006). Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. The Journal of Neuroscience, 26(4), 1107–1116.

    Article  PubMed  CAS  Google Scholar 

  188. Uziel, T., Zindy, F., Xie, S., Lee, Y., Forget, A., Magdaleno, S., et al. (2005). The tumor suppressors Ink4c and p53 collaborate independently with patched to suppress medulloblastoma formation. Genes & Development, 19(22), 2656–2667.

    Article  CAS  Google Scholar 

  189. Lee, Y., Miller, H. L., Russell, H. R., Boyd, K., Curran, T., & McKinnon, P. J. (2006). Patched2 modulates tumorigenesis in patched1 heterozygous mice. Cancer Research, 66(14), 6964–6971.

    Article  PubMed  CAS  Google Scholar 

  190. Ayrault, O., Zindy, F., Rehg, J., Sherr, C. J., & Roussel, M. F. (2009). Two tumor suppressors, p27Kip1 and patched-1, collaborate to prevent medulloblastoma. Molecular Cancer Research, 7(1), 33–40.

    Article  PubMed  CAS  Google Scholar 

  191. Briggs, K. J., Corcoran-Schwartz, I. M., Zhang, W., Harcke, T., Devereux, W. L., Baylin, S. B., et al. (2008). Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes & Development, 22(6), 770–785.

    Article  CAS  Google Scholar 

  192. Sutter, R., Shakhova, O., Bhagat, H., Behesti, H., Sutter, C., Penkar, S., et al. (2010). Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas. Oncogene, 29(12), 1845–1856.

    Article  PubMed  CAS  Google Scholar 

  193. Hatton, B. A., Villavicencio, E. H., Pritchard, J., LeBlanc, M., Hansen, S., Ulrich, M., et al. (2010). Notch signaling is not essential in sonic hedgehog-activated medulloblastoma. Oncogene, 29(26), 3865–3872.

    Article  PubMed  CAS  Google Scholar 

  194. McCall, T. D., Pedone, C. A., & Fults, D. W. (2007). Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic hedgehog-dependent medulloblastoma formation in mice. Cancer Research, 67(11), 5179–5185.

    Article  PubMed  CAS  Google Scholar 

  195. Frappart, P. O., Lee, Y., Lamont, J., & McKinnon, P. J. (2007). BRCA2 is required for neurogenesis and suppression of medulloblastoma. The EMBO Journal, 26(11), 2732–2742.

    Article  PubMed  CAS  Google Scholar 

  196. Rakic, P. (1972). Mode of cell migration to the superficial layers of fetal monkey neocortex. The Journal of Comparative Neurology, 145(1), 61–83.

    Article  PubMed  CAS  Google Scholar 

  197. Hatten, M. E. (1990). Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain. Trends in Neurosciences, 13(5), 179–184.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Pediatric Brain Tumor Foundation, the Swedish Research Council, Åke Wibergs stiftelse, Lions Cancerforskningsfond and Stiftelsen Lars Hiertas Minne, NIH grants CA133091, NS055750, CA102321, CA128583, CA148699, CA163155, CA081403, Burroughs Wellcome Fund, Alex’s Lemonade Stand, Katie Dougherty, Pediatric Brain Tumor, Samuel G. Waxman, and V Foundations. We apologize to authors whose work we did not cite due to space restrictions in this review. Authors further declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, SE-75185, Sweden

    Fredrik J. Swartling & Sanna-Maria Hede

  2. Department of Neurology, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

  3. Department of Pathology, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

  4. Department of Pediatrics, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

  5. Department Neurosurgery, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

  6. Brain Tumor Research Center, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

  7. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, USA

    William A. Weiss

Authors
  1. Fredrik J. Swartling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanna-Maria Hede
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William A. Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fredrik J. Swartling or William A. Weiss.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swartling, F.J., Hede, SM. & Weiss, W.A. What underlies the diversity of brain tumors?. Cancer Metastasis Rev 32, 5–24 (2013). https://doi.org/10.1007/s10555-012-9407-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-012-9407-3

Keywords

Search

Navigation