Animal Models for Low-Grade Gliomas

  • Rolf Bjerkvig
  • Sébastien Bougnaud
  • Simone P. Niclou
Chapter
First Online:

Abstract

The establishment of animal models for human brain tumors is based on the realization that clear mechanistic information with a functional focus is difficult to obtain in human studies and from the fact that in vitro tumor models do not reflect the physiological complexity of tumors grown in vivo. Animal models for low-grade gliomas have mainly appeared during the last two decades with the development of genetically engineered mice where in particular the platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) systems seem to be important in tumor formation. Also, with the advent of neurosphere culture techniques used to propagate neural stem cells, recent developments indicate that low-grade gliomas can be initiated as xenografts in immunodeficient animals. A major challenge of these models is the time required to tumor development. Nevertheless, it is expected that animal modeling for low-grade gliomas will provide important new insight into the etiology of low-grade tumor development in the years to come.

Keywords

Genetically modified mice Xenografts Oligodendroglioma PDGF EGFR IDH1 IDH2 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Pilkington GJ, Lantos PL. Pathology of experimental brain tumours. In: Thomas DGT, editor. Primary ­malignant brain tumours. London: Hodder Arnold; 1990. p. 51–76.Google Scholar
  2. 2.
    Ausman JI, Shapiro WR, Rall DP. Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res. 1970;30(9):2394–400.PubMedGoogle Scholar
  3. 3.
    Berens ME, et al. Allogeneic astrocytoma in immune competent dogs. Neoplasia. 1999;1(2):107–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Ernestus RI, Wilmes LJ, Hoehn-Berlage M. Identification of intracranial liqor metastases of experimental stereotactically implanted brain tumors by the tumor-selective MRI contrast agent MnTPPS. Clin Exp Metastasis. 1992;10(5):345–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Lantos PL, Pilkington GJ. Neuroblasts in cerebral tumors induced by ethylnitrosourea in rats. A fine structural study. Virchows Arch B Cell Pathol. 1977;25(3):243–59.PubMedGoogle Scholar
  6. 6.
    Hambardzumyan D, et al. Genetic modeling of gliomas in mice: new tools to tackle old problems. Glia. 2011;59(8):1155–68.PubMedCrossRefGoogle Scholar
  7. 7.
    Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 2006;66(7):3351–4, discussion 4.PubMedCrossRefGoogle Scholar
  8. 8.
    Fomchenko EI, Holland EC. Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res. 2006;12(18):5288–97.PubMedCrossRefGoogle Scholar
  9. 9.
    Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10(5):319–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Noble M, et al. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature. 1988;333(6173):560–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Raff MC, Miller RH, Noble M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature. 1983;303(5916):390–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Richardson WD, et al. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell. 1988;53(2):309–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Fruttiger M, et al. PDGF mediates a neuron-astrocyte interaction in the developing retina. Neuron. 1996;17(6):1117–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Hutchins JB. Platelet-derived growth factor receptors of mouse central nervous system cells in vitro. J Comp Neurol. 1995;360(1):59–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Di Rocco F, et al. Platelet-derived growth factor and its receptor expression in human oligodendrogliomas. Neurosurgery. 1998;42(2):341–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Robinson S, et al. Constitutive expression of growth-related oncogene and its receptor in oligodendrogliomas. Neurosurgery. 2001;48(4):864–73; discussion 873–4.PubMedGoogle Scholar
  17. 17.
    Shoshan Y, et al. Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors. Proc Natl Acad Sci USA. 1999;96(18):10361–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Smith JS, et al. Amplification of the platelet-derived growth factor receptor-A (PDGFRA) gene occurs in oligodendrogliomas with grade IV anaplastic features. J Neuropathol Exp Neurol. 2000;59(6):495–503.PubMedGoogle Scholar
  19. 19.
    Guha A, et al. Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer. 1995;60(2):168–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Nister M, et al. Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res. 1988;48(14):3910–8.PubMedGoogle Scholar
  21. 21.
    Uhrbom L, et al. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 1998;58(23):5275–9.PubMedGoogle Scholar
  22. 22.
    Federspiel MJ, et al. A system for tissue-specific gene targeting: transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors. Proc Natl Acad Sci USA. 1994;91(23):11241–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Fisher GH, et al. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene. 1999;18(38):5253–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Holland EC, et al. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998;12(23):3675–85.PubMedCrossRefGoogle Scholar
  25. 25.
    Holland EC, Varmus HE. Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc Natl Acad Sci USA. 1998;95(3):1218–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Dai C, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 2001;15(15):1913–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Tchougounova E, et al. Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma. Oncogene. 2007;26(43):6289–96.PubMedCrossRefGoogle Scholar
  28. 28.
    Lindberg N, et al. Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene. 2009;28(23):2266–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Hambardzumyan D, et al. Modeling adult gliomas using RCAS/t-va technology. Transl Oncol. 2009;2(2):89–95.PubMedGoogle Scholar
  30. 30.
    Hitoshi Y, et al. Spinal glioma: platelet-derived growth factor B-mediated oncogenesis in the spinal cord. Cancer Res. 2008;68(20):8507–15.PubMedCrossRefGoogle Scholar
  31. 31.
    Hede SM, et al. GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background. Glia. 2009;57(11):1143–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Weiss WA, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res. 2003;63(7):1589–95.PubMedGoogle Scholar
  33. 33.
    Persson AI, et al. Non-stem cell origin for oligodendroglioma. Cancer Cell. 2010;18(6):669–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Ding H, et al. Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Res. 2003;63(5):1106–13.PubMedGoogle Scholar
  35. 35.
    Ohgaki H, et al. Brain tumors in S100beta-v-erbB transgenic rats. J Neuropathol Exp Neurol. 2006;65(12):1111–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Copeland NG, Jenkins NA. Deciphering the genetic landscape of cancer – from genes to pathways. Trends Genet. 2009;25(10):455–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Cancer Genome Atlas Research Network (TCGA). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.CrossRefGoogle Scholar
  39. 39.
    Parsons DW, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Hartmann C, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120(6):707–18.PubMedCrossRefGoogle Scholar
  41. 41.
    Yan H, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.PubMedCrossRefGoogle Scholar
  42. 42.
    Verhaak RG, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhao S, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Dang L, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Noushmehr H, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Stieber D, Abdul Rahim SA, Niclou SP. Novel ways to target brain tumour metabolism. Expert Opin Ther Targets. 2011;15(10):1227–39.PubMedCrossRefGoogle Scholar
  48. 48.
    Clark MJ, et al. U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line. PLoS Genet. 2010;6(1):e1000832.PubMedCrossRefGoogle Scholar
  49. 49.
    Claes A, et al. Phenotypic and genotypic characterization of orthotopic human glioma models and its relevance for the study of anti-glioma therapy. Brain Pathol. 2008;18(3):423–33.PubMedCrossRefGoogle Scholar
  50. 50.
    Sakariassen PO, et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA. 2006;103(44):16466–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Wang J, et al. A reproducible brain tumour model established from human glioblastoma biopsies. BMC Cancer. 2009;9:465.PubMedCrossRefGoogle Scholar
  52. 52.
    Pandita A, et al. Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR. Genes Chromosomes Cancer. 2004;39(1):29–36.PubMedCrossRefGoogle Scholar
  53. 53.
    Taillandier L, Antunes L, Angioi-Duprez KS. Models for neuro-oncological preclinical studies: solid orthotopic and heterotopic grafts of human gliomas into nude mice. J Neurosci Methods. 2003;125(1–2):147–57.PubMedCrossRefGoogle Scholar
  54. 54.
    Giannini C, et al. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol. 2005;7(2):164–76.PubMedCrossRefGoogle Scholar
  55. 55.
    Keunen O, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA. 2011;108(9):3749–54.PubMedCrossRefGoogle Scholar
  56. 56.
    Boveri T, editor. Zur Frage der Enstehung maligner Tumoren. Jena: Gustav Fisher Verlag; 1914.Google Scholar
  57. 57.
    Hansemann D. Ueber asymmetrische Zelltheilung in Epithelkrebsen und deren bologische Bedeutung. Virchows Arch Pathol Anat. 1890;119:299–326.CrossRefGoogle Scholar
  58. 58.
    Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992;12(11):4565–74.PubMedGoogle Scholar
  59. 59.
    Vescovi AL, et al. bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron. 1993;11(5):951–66.PubMedCrossRefGoogle Scholar
  60. 60.
    Galli R, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.PubMedCrossRefGoogle Scholar
  61. 61.
    Hemmati HD, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA. 2003;100(25):15178–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Ignatova TN, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia. 2002;39(3):193–206.PubMedCrossRefGoogle Scholar
  63. 63.
    Kelly JJ, et al. Oligodendroglioma cell lines containing t(1;19)(q10;p10). Neuro Oncol. 2010;12(7):745–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Tunici P, et al. Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma. Mol Cancer. 2004;3:25.PubMedCrossRefGoogle Scholar
  65. 65.
    Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992;255(5052):1707–10.PubMedCrossRefGoogle Scholar
  66. 66.
    Wan F, et al. The utility and limitations of neurosphere assay, CD133 immunophenotyping and side population assay in glioma stem cell research. Brain Pathol. 2010;20(5):877–89.PubMedGoogle Scholar
  67. 67.
    Luchman HA, et al. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro Oncol. 2012;14(2):184–91.PubMedCrossRefGoogle Scholar
  68. 68.
    Briancon-Marjollet A, et al. NG2-expressing glial precursor cells are a new potential oligodendroglioma cell initiating population in N-ethyl-N-nitrosourea-induced gliomagenesis. Carcinogenesis. 2010;31(10):1718–25.PubMedCrossRefGoogle Scholar
  69. 69.
    Assanah M, et al. Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci. 2006;26(25):6781–90.PubMedCrossRefGoogle Scholar
  70. 70.
    Ding H, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 2001;61(9):3826–36.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • Rolf Bjerkvig
    • 1
    • 2
  • Sébastien Bougnaud
    • 1
  • Simone P. Niclou
    • 1
  1. 1.NorLux Neuro-Oncology Laboratory, Department of OncologyCentre de Recherche Public de la Santé (CRP-Santé)Luxembourg CityLuxembourg
  2. 2.NorLux Neuro-Oncology Laboratory, Department of BiomedicineUniversity of BergenBergenNorway

Personalised recommendations