Home LiteratureArticle Details
PMID: 22340591 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A mouse model of the most aggressive subgroup of human medulloblastoma.

Cancer cell ·Vol. 21 ·No. 2 ·2012-02-14 ·Pages 168-80

Kawauchi D, Robinson G, Uziel T, Gibson P, Rehg J, Gao C, Finkelstein D, Qu C, Pounds S, Ellison DW, Gilbertson RJ, Roussel MF

Abstract

Medulloblastomas that display a large cell/anaplastic morphology and overexpress the cellular c-MYC gene are highly aggressive and carry a very poor prognosis. This so-called MYC-subgroup differs in its histopathology, gene expression profile, and clinical behavior from other forms of medulloblastoma. We generated a mouse model of MYC-subgroup medulloblastoma by transducing Trp53-null cerebellar progenitor cells with Myc. The cardinal features of these mouse medulloblastomas closely mimic those of human MYC-subgroup tumors and significantly differ from mouse models of the Sonic-Hedgehog- and WNT-disease subgroups. This mouse model should significantly accelerate understanding and treatment of the most aggressive form of medulloblastoma and infers distinct roles for MYC and MYCN in tumorigenesis.

MeSH Terms
Animals Cell Proliferation/drug effects Cell Transformation, Neoplastic/drug effects Cerebellar Neoplasms/genetics,pathology Disease Models, Animal Gene Expression Regulation, Neoplastic Hedgehog Proteins/antagonists & inhibitors Humans Medulloblastoma/genetics,pathology Mice Salivary alpha-Amylases/genetics,metabolism,physiology Transcriptome Tumor Suppressor Protein p53/genetics Veratrum Alkaloids/pharmacology
Chemicals
Hedgehog Proteins Tumor Suppressor Protein p53 Veratrum Alkaloids Amy1 protein, mouse Salivary alpha-Amylases cyclopamine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kawauchi Daisuke
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Robinson Giles
Uziel Tamar
Gibson Paul
Rehg Jerold
Gao Cuilan
Finkelstein David
Qu Chunxu
Pounds Stanley
Ellison David W
Gilbertson Richard J
Roussel Martine F
References (60)
60 references, click to expand
  1. N-Myc and the cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 coordinately regulate cerebellar development.
    Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11579-83 PMID: 16864777
  2. Myc target genes.
    Trends Biochem Sci. 1997 May;22(5):177-81 PMID: 9175477
  3. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer.
    Stem Cells. 2009 Dec;27(12):2875-83 PMID: 19816957
  4. beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee.
    J Clin Oncol. 2005 Nov 1;23(31):7951-7 PMID: 16258095
  5. MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group.
    Arch Pathol Lab Med. 2002 May;126(5):540-4 PMID: 11958658
  6. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs.
    Cell. 2010 Oct 15;143(2):313-24 PMID: 20946988
  7. TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma.
    J Clin Oncol. 2010 Dec 10;28(35):5188-96 PMID: 21060032
  8. Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors.
    Cancer Res. 2007 Mar 15;67(6):2676-84 PMID: 17363588
  9. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization.
    Genes Dev. 1998 Aug 1;12(15):2424-33 PMID: 9694806
  10. The Myc/Max/Mad network and the transcriptional control of cell behavior.
    Annu Rev Cell Dev Biol. 2000;16:653-99 PMID: 11031250
  11. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice.
    Cancer Cell. 2004 Sep;6(3):229-40 PMID: 15380514
  12. Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling.
    Development. 2004 Jul;131(13):3159-68 PMID: 15197161
  13. Radial glia cells are candidate stem cells of ependymoma.
    Cancer Cell. 2005 Oct;8(4):323-35 PMID: 16226707
  14. Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development.
    Genes Dev. 2008 Mar 15;22(6):722-7 PMID: 18347090
  15. A molecular fingerprint for medulloblastoma.
    Cancer Res. 2003 Sep 1;63(17):5428-37 PMID: 14500378
  16. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
    Cell. 2006 Aug 25;126(4):663-76 PMID: 16904174
  17. Medulloblastoma comprises four distinct molecular variants.
    J Clin Oncol. 2011 Apr 10;29(11):1408-14 PMID: 20823417
  18. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables.
    J Clin Oncol. 2011 Apr 10;29(11):1400-7 PMID: 20921458
  19. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.
    Genes Dev. 1999 Oct 15;13(20):2658-69 PMID: 10541552
  20. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice.
    Genes Dev. 2005 Jun 15;19(12):1438-43 PMID: 15964995
  21. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1.
    Genes Dev. 1994 Dec 1;8(23):2817-30 PMID: 7995520
  22. Colon cancer stem cells: promise of targeted therapy.
    Gastroenterology. 2010 Jun;138(6):2151-62 PMID: 20420952
  23. Math1-driven GFP expression in the developing nervous system of transgenic mice.
    Gene Expr Patterns. 2003 Aug;3(4):389-95 PMID: 12915300
  24. Cerebellum development and medulloblastoma.
    Curr Top Dev Biol. 2011;94:235-82 PMID: 21295689
  25. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations.
    J Clin Oncol. 2006 Apr 20;24(12):1924-31 PMID: 16567768
  26. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation.
    Genes Dev. 2002 Oct 15;16(20):2699-712 PMID: 12381668
  27. Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells.
    Cancer Res. 2010 Jul 1;70(13):5618-27 PMID: 20516124
  28. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells.
    Cancer Cell. 2008 Aug 12;14(2):135-45 PMID: 18691548
  29. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation.
    Nature. 2009 Jan 29;457(7229):603-7 PMID: 19092805
  30. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.
    PLoS One. 2008 Aug 28;3(8):e3088 PMID: 18769486
  31. Cross-species genomics matches driver mutations and cell compartments to model ependymoma.
    Nature. 2010 Jul 29;466(7306):632-6 PMID: 20639864
  32. Apoptotic signaling by c-MYC.
    Oncogene. 2008 Oct 27;27(50):6462-72 PMID: 18955973
  33. Identification of human brain tumour initiating cells.
    Nature. 2004 Nov 18;432(7015):396-401 PMID: 15549107
  34. 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.
    Lancet Oncol. 2006 Oct;7(10):813-20 PMID: 17012043
  35. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched.
    Cancer Res. 2001 Jan 15;61(2):513-6 PMID: 11212243
  36. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.
    Cancer Cell. 2008 Aug 12;14(2):123-34 PMID: 18691547
  37. Pleiotropic role for MYCN in medulloblastoma.
    Genes Dev. 2010 May 15;24(10):1059-72 PMID: 20478998
  38. Capturing pluripotency.
    Cell. 2008 Feb 22;132(4):532-6 PMID: 18295569
  39. N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation.
    Genes Dev. 2000 Jun 1;14(11):1390-9 PMID: 10837031
  40. The TP53-ARF tumor suppressor pathway is frequently disrupted in large/cell anaplastic medulloblastoma.
    Brain Res Mol Brain Res. 2004 Feb 5;121(1-2):137-40 PMID: 14969745
  41. A frequent activated smoothened mutation in sporadic basal cell carcinomas.
    Oncogene. 1999 Jan 21;18(3):833-6 PMID: 9989836
  42. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups.
    Acta Neuropathol. 2011 Mar;121(3):381-96 PMID: 21267586
  43. Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas.
    J Neuropathol Exp Neurol. 2003 Jun;62(6):627-32 PMID: 12834107
  44. Medulloblastoma growth inhibition by hedgehog pathway blockade.
    Science. 2002 Aug 30;297(5586):1559-61 PMID: 12202832
  45. Mouse models of medulloblastoma.
    Chin J Cancer. 2011 Jul;30(7):442-9 PMID: 21718590
  46. Mediation of c-Myc-induced apoptosis by p53.
    Science. 1994 Sep 30;265(5181):2091-3 PMID: 8091232
  47. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.
    Cell. 1997 Nov 28;91(5):649-59 PMID: 9393858
  48. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.
    Nature. 2005 Aug 11;436(7052):807-11 PMID: 16094360
  49. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma.
    Cancer Cell. 2009 Feb 3;15(2):135-47 PMID: 19185848
  50. Isolation of neural stem cells from the postnatal cerebellum.
    Nat Neurosci. 2005 Jun;8(6):723-9 PMID: 15908947
  51. Identification of stem cells in small intestine and colon by marker gene Lgr5.
    Nature. 2007 Oct 25;449(7165):1003-7 PMID: 17934449
  52. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  53. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci.
    J Clin Oncol. 2009 Apr 1;27(10):1627-36 PMID: 19255330
  54. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.
    Nat Genet. 2008 May;40(5):499-507 PMID: 18443585
  55. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors.
    Development. 2003 Jan;130(1):15-28 PMID: 12441288
  56. The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation.
    Genes Dev. 2005 Nov 15;19(22):2656-67 PMID: 16260494
  57. Sporadic medulloblastomas contain PTCH mutations.
    Cancer Res. 1997 Mar 1;57(5):842-5 PMID: 9041183
  58. Subtypes of medulloblastoma have distinct developmental origins.
    Nature. 2010 Dec 23;468(7327):1095-9 PMID: 21150899
  59. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.
    J Clin Oncol. 2011 Apr 10;29(11):1424-30 PMID: 21098324
  60. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc.
    Science. 1991 Mar 8;251(4998):1211-7 PMID: 2006410
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.12.023
Published
2012-02-14
Pages
168-80
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3285412
Subset
IM
Grants
NCI NIH HHS · R01 CA129541 · United States
NCI NIH HHS · P01 CA096832-08 · United States
NCI NIH HHS · CA-21765 · United States
NCI NIH HHS · P30 CA021765 · United States
NCI NIH HHS · P01 CA096832 · United States
NCI NIH HHS · CA-096832 · United States
Corrections
CommentIn
PMID: 22340583
External Links
PubMed source DOI: 10.1016/j.ccr.2011.12.023 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2