Mouse Models in Preclinical Drug Development: Applications to CNS Models

  • Eletha Carbajal
  • Eric C. Holland


Primary tumors of the CNS can be divided into several groups; the most common in adults being the gliomas and in children the medulloblastomas (Kleihues et al. J Neuropathol Exp Neurol 61(3):215–225, 2002). Gliomas are thought to arise from cells at some point of differentiation along glial lineage leading to astrocytes and oligodendrocytes. In the normal brain, the primary function of astrocytes is to maintain homeostasis of neuronal extracellular milieu and protect the neurons by establishing the blood–brain barrier during development. Oligodendrocytes provide the CNS axons with myelin sheaths that insulate the neurons and thereby accelerating the action potential transduction. By contrast, medulloblastomas appear to arise from cells of the external granule layer in the developing cerebellum that give rise to the internal granule layer neurons. These tumors are the most common tumor found in children. Gliomas are relatively radiation-resistant and the clinical outcome for patients with the most aggressive and common of the gliomas, Glioblastoma Multiforme or GBM, has been poor and essentially unchanged in the last 50 years with the median survival averaging 12–14 months (CBTRUS. Statistical report: primary brain tumors in the USA). Medulloblastomas on the other hand are much more responsive than GBMs to radiation and chemotherapy with a 70% cure rate. An important step toward improving existing treatments and discovering new ones comes from creating genetically and histologically accurate mouse models that can be used as a representative system of human tumors in order to study the biological and mechanistic causes of brain cancer and the way that these tumor interact with their microenvironment. Furthermore, accurate mouse models of these tumors are helping us to identify novel targets and therapies for clinical testing (Hambardzumyan et al. Expert Opin 2(11):1435–1451, 2007).


Notch Signaling Preclinical Trial External Granular Layer Positron Emission Tomography Ligand External Granule Layer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760PubMedCrossRefGoogle Scholar
  2. Becher OJ, Holland EC (2006) Genetically engineered models have advantages over xenografts for preclinical studies. Cancer Res 66(7):3355–3358, discussion 3358–3359PubMedCrossRefGoogle Scholar
  3. Becher OJ, Hambardzumyan D, Fomchenko EI, Momota H, Mainwaring L, Bleau AM, Katz AM, Edgar MA, Kenney AM, Cordon-Cardo C, Blasberg RG, Holland EC (2008) Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res 68(7):2241–2249PubMedCrossRefGoogle Scholar
  4. Bradbury MS, Hambardzumyan D, Zanzonico PB, Schwartz J, Cai S, Burnazi EM, Longo V, Larson SM, Holland EC (2008) Dynamic small-animal pet imaging of tumor proliferation with 3′-deoxy-3′-18F-fluorothymidine in a genetically engineered mouse model of high-grade gliomas. J Nucl Med 49(3):422–429PubMedCrossRefGoogle Scholar
  5. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82PubMedCrossRefGoogle Scholar
  6. CBTRUS. Statistical report: primary brain tumors in the United States, 1997–2001 years data collected. Chicago: Central Brain Tumor Registry of the United States; 2004–2005.
  7. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24(1):3–12PubMedCrossRefGoogle Scholar
  8. Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, Mischel P, Czernin J, Phelps ME, Silverman DH (2005) Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 46(6):945–952PubMedGoogle Scholar
  9. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL (2008) Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1):e8PubMedCrossRefGoogle Scholar
  10. Contag PR, Olomu IN, Stevenson DK, Contag CH (1998) Bioluminescent indicators in living mammals. Nat Med 4(2):245–247PubMedCrossRefGoogle Scholar
  11. Cuevas IC, Slocum AL, Jun P, Costello JF, Bollen AW, Riggins GJ, McDermott MW, Lal A (2005) Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res 65(12):5070–5075PubMedCrossRefGoogle Scholar
  12. Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126(14):3089–3100PubMedGoogle Scholar
  13. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC (2001) PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15(15):1913–1925PubMedCrossRefGoogle Scholar
  14. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398(6727):518–522PubMedCrossRefGoogle Scholar
  15. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284PubMedCrossRefGoogle Scholar
  16. Dinca EB, Sarkaria JN, Schroeder MA, Carlson BL, Voicu R, Gupta N, Berger MS, James CD (2007) Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy. J Neurosurg 107(3):610–616PubMedCrossRefGoogle Scholar
  17. Edinger M, Sweeney TJ, Tucker AA, Olomu AB, Negrin RS, Contag CH (1999) Noninvasive assessment of tumor cell proliferation in animal models. Neoplasia 1(4):303–310PubMedCrossRefGoogle Scholar
  18. Ekstrand AJ, Longo N, Hamid ML, Olson JJ, Liu L, Collins VP, James CD (1994) Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene 9(8):2313–2320PubMedGoogle Scholar
  19. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66(15):7445–7452PubMedCrossRefGoogle Scholar
  20. Federspiel MJ, Bates P, Young JA, Varmus HE, Hughes SH (1994) A system for tissue-specific gene targeting: transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors. Proc Natl Acad Sci USA 91(23):11241–11245PubMedCrossRefGoogle Scholar
  21. Finkelstein SD, Black P, Nowak TP, Hand CM, Christensen S, Finch PW (1994) Histological characteristics and expression of acidic and basic fibroblast growth factor genes in intracerebral xenogeneic transplants of human glioma cells. Neurosurgery 34(1):136–143PubMedCrossRefGoogle Scholar
  22. Fisher HW, Puck TT (1956) On the functions of X-irradiated “Feeder” cells in supporting growth of single mammalian cells. Proc Natl Acad Sci USA 42(12):900–906PubMedCrossRefGoogle Scholar
  23. Fitzgerald K, Harrington A, Leder P (2000) Ras pathway signals are required for notch-mediated oncogenesis. Oncogene 19(37):4191–4198PubMedCrossRefGoogle Scholar
  24. Fomchenko EI, Holland EC (2006) Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res 12(18):5288–5297PubMedCrossRefGoogle Scholar
  25. Gallia GL, Rand V, Siu IM, Eberhart CG, James CD, Marie SK, Oba-Shinjo SM, Carlotti CG, Caballero OL, Simpson AJ, Brock MV, Massion PP, Carson BS Sr, Riggins GJ (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4(10):709–714PubMedCrossRefGoogle Scholar
  26. Genoud S, Lappe-Siefke C, Goebbels S, Radtke F, Aguet M, Scherer SS, Suter U, Nave KA, Mantei N (2002) Notch1 control of oligodendrocyte differentiation in the spinal cord. J Cell Biol 158(4):709–718PubMedCrossRefGoogle Scholar
  27. Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E, Carlson BL, Schroeder MA, James CD (2005) Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 7(2):164–176PubMedCrossRefGoogle Scholar
  28. Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277(5329):1109–1113PubMedCrossRefGoogle Scholar
  29. Grisendi S, Pandolfi PP (2004) Germline modifications strategies. In: Holland EC (ed) Mouse models of human cancer. Wiley, p 43–65Google Scholar
  30. Guha A, Dashner K, Black PM, Wagner JA, Stiles CD (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60(2):168–173PubMedCrossRefGoogle Scholar
  31. Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA, Olson JM (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64(21):7794–7800PubMedCrossRefGoogle Scholar
  32. Hambardzumyan D, Becher OJ, Rosenblum M, Manova-Todorova K, Holland EC (2007a) P53 and PTEN dependent radiation response in medulloblastoma cell types in vivo. Genes Dev 22(4):436–448CrossRefGoogle Scholar
  33. Hambardzumyan D, Lyustikman Y, Holland EC (2007b) An update on mouse brain tumor models in cancer drug advice. Expert Opin 2(11):1435–1451Google Scholar
  34. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22(4):436–448PubMedCrossRefGoogle Scholar
  35. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52(11):3213–3219PubMedGoogle Scholar
  36. 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 Res 63(15):4305–4309PubMedGoogle Scholar
  37. Holland EC, Hively WP, DePinho RA, Varmus HE (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 Dev 12(23):3675–3685PubMedCrossRefGoogle Scholar
  38. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25(1):55–57PubMedCrossRefGoogle Scholar
  39. Hormigo A, Gu B, Karimi S, Riedel E, Panageas KS, Edgar MA, Tanwar MK, Rao JS, Fleisher M, DeAngelis LM, Holland EC (2006) YKL-40 and matrix metalloproteinase-9 as potential serum biomarkers for patients with high-grade gliomas. Clin Cancer Res 12(19):5698–5704PubMedCrossRefGoogle Scholar
  40. Hornsey S (1973) The radiosensitivity of the intestine. Strahlenschutz Forsch Prax 13:78–88PubMedGoogle Scholar
  41. Hu X, Holland EC (2005) Applications of mouse glioma models in preclinical trials. Mutat Res 576(1–2):54–65PubMedGoogle Scholar
  42. Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M, Holland EC (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7(4):356–368PubMedCrossRefGoogle Scholar
  43. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272(5268):1668–1671PubMedCrossRefGoogle Scholar
  44. Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O’Brien SJ, Wong AJ, Vogelstein B (1987) Identification of an amplified, highly expressed gene in a human glioma. Science 236(4797):70–73PubMedCrossRefGoogle Scholar
  45. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61(3):215–225, discussion 226–219PubMedGoogle Scholar
  46. Koutcher JA, Hu X, Xu S, Gade TP, Leeds N, Zhou XJ, Zagzag D, Holland EC (2002) MRI of mouse models for gliomas shows similarities to humans and can be used to identify mice for preclinical trials. Neoplasia 4(6):480–485PubMedCrossRefGoogle Scholar
  47. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947PubMedCrossRefGoogle Scholar
  48. Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11(1):17–22PubMedCrossRefGoogle Scholar
  49. Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. Bioessays 24(1):91–98PubMedCrossRefGoogle Scholar
  50. Mayer EG, Boone ML, Aristizabal SA (1976) Role of radiation therapy in the management of neoplasms of the central nervous system. Adv Neurol 15:201–220PubMedGoogle Scholar
  51. McConville P, Hambardzumyan D, Moody JB, Leopold WR, Kreger AR, Woolliscroft MJ, Rehemtulla A, Ross BD, Holland EC (2007) Magnetic resonance imaging determination of tumor grade and early response to temozolomide in a genetically engineered mouse model of glioma. Clin Cancer Res 13(10):2897–2904PubMedCrossRefGoogle Scholar
  52. Momota H, Holland EC (2005) Bioluminescence technology for imaging cell proliferation. Curr Opin Biotechnol 16(6):681–686PubMedCrossRefGoogle Scholar
  53. Momota H, Nerio E, Holland EC (2005) Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65(16):7429–7435PubMedCrossRefGoogle Scholar
  54. Momota H, Shih AH, Edgar MA, Holland EC (2008) c-Myc and β-catenin cooperate with loss of p53 to generate multiple members of the primitive neuroectodermal tumor (PTEN) family in mice. Oncogene 27(32):4392–4401PubMedCrossRefGoogle Scholar
  55. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, Anderson DJ (2000) Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101(5):499–510PubMedCrossRefGoogle Scholar
  56. Nery S, Wichterle H, Fishell G (2001) Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 128(4):527–540PubMedGoogle Scholar
  57. Nister M, Libermann TA, Betsholtz C, Pettersson M, Claesson-Welsh L, Heldin CH, Schlessinger J, Westermark B (1988) 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 48(14):3910–3918PubMedGoogle Scholar
  58. Nye JS, Kopan R, Axel R (1994) An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. Development 120(9):2421–2430PubMedGoogle Scholar
  59. Ohgaki H, Kita D, Favereaux A, Huang H, Homma T, Dessen P, Weiss WA, Kleihues P, Heppner FL (2006) Brain tumors in S100beta-v-erbB transgenic rats. J Neuropathol Exp Neurol 65(12):1111–1117PubMedCrossRefGoogle Scholar
  60. Petropoulos CJ, Hughes SH (1991) Replication-competent retrovirus vectors for the transfer and expression of gene cassettes in avian cells. J Virol 65(7):3728–3737PubMedGoogle Scholar
  61. Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW (2003) c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestinexpressing neural progenitors in mice. Neoplasia 5(3):198–204PubMedGoogle Scholar
  62. Romer J, Curran T (2005) Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res 65(12):4975–4978PubMedCrossRefGoogle Scholar
  63. Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H, Connelly M, Stewart CF, Gould S, Rubin LL, Curran T (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 6(3):229–240PubMedCrossRefGoogle Scholar
  64. Ross BD, Chenevert TL, Moffat BA, Rehemtulla A, Hall DE (2004) Use of magnetic resonance imaging for evaluation of treatment response. In: Holland EC (ed) Mouse models of human cancer. WileyGoogle Scholar
  65. Rowitch DH, St. Jacques B, Lee SM, Flax JD, Snyder EY, McMahon AP (1999) Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci 19(20):8954–8965PubMedGoogle Scholar
  66. Sara VR, Prisell P, Sjogren B, Persson L, Boethius J, Enberg G (1986) Enhancement of insulin-like growth factor 2 receptors in glioblastoma. Cancer Lett 32(3):229–234PubMedCrossRefGoogle Scholar
  67. Sausville EA, Burger AM (2006) Contributions of human tumor xenografts to anticancer drug development. Cancer Res 66(7):3351–3354, discussion 3354PubMedCrossRefGoogle Scholar
  68. Shannon P, Sabha N, Lau N, Kamnasaran D, Gutmann DH, Guha A (2005) Pathological and molecular progression of astrocytomas in a GFAP:12 VHa-Ras mouse astrocytoma model. Am J Pathol 167(3):859–867PubMedCrossRefGoogle Scholar
  69. Shih AH, Holland EC (2006a) Notch signaling enhances nestin expression in gliomas. Neoplasia 8(12):1072–1082PubMedCrossRefGoogle Scholar
  70. Shih AH, Holland EC (2006b) Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett 232(2):139–147PubMedCrossRefGoogle Scholar
  71. Shih AH, Dai C, Hu X, Rosenblum MK, Koutcher JA, Holland EC (2004) Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis. Cancer Res 64(14):4783–4789PubMedCrossRefGoogle Scholar
  72. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedCrossRefGoogle Scholar
  73. Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5(3):219–234PubMedCrossRefGoogle Scholar
  74. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31(3):306–310PubMedCrossRefGoogle Scholar
  75. Tekki-Kessaris N, Woodruff R, Hall AC, Gaffield W, Kimura S, Stiles CD, Rowitch DH, Richardson WD (2001) Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 128(13):2545–2554PubMedGoogle Scholar
  76. Trojan J, Blossey BK, Johnson TR, Rudin SD, Tykocinski M, Ilan J, Ilan J (1992) Loss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I. Proc Natl Acad Sci USA 89(11):4874–4878PubMedCrossRefGoogle Scholar
  77. Uhrbom L, Hesselager G, Nister M, Westermark B (1998) Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res 58(23):5275–5279PubMedGoogle Scholar
  78. Uhrbom L, Nerio E, Holland EC (2004) Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nat Med 10(11):1257–1260PubMedCrossRefGoogle Scholar
  79. Uhrbom L, Kastemar M, Johansson FK, Westermark B, Holland EC (2005) Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis. Cancer Res 65(6):2065–2069PubMedCrossRefGoogle Scholar
  80. Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA (1998) Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21(1):63–75PubMedCrossRefGoogle Scholar
  81. Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22(1):103–114PubMedCrossRefGoogle Scholar
  82. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM, Miele L (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8(9):979–986PubMedCrossRefGoogle Scholar
  83. Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61(2):513–516PubMedGoogle Scholar
  84. Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296(5569):920–922PubMedCrossRefGoogle Scholar
  85. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF (2005) Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8(2):119–130PubMedCrossRefGoogle Scholar
  86. Zindy F, Uziel T, Ayrault O, Calabrese C, Valentine M, Rehg JE, Gilbertson RJ, Sherr CJ, Roussel MF (2007) Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors. Cancer Res 67(6):2676–2684PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Program in Cancer Biology and GeneticsMemorial Sloan Kettering Cancer CenterNew YorkUSA

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