c-Myc and β-catenin cooperate with loss of p53 to generate multiple members of the primitive neuroectodermal tumor family in mice

H. Momota, A. H. Shih, M. A. Edgar, E. C. Holland

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Primitive neuroectodermal tumors (PNETs) are a family of primary malignant brain tumors that include medulloblastomas. Although genetic models of a subset of medulloblastomas are documented over the past decade, the molecular basis of other subclasses of PNET remains unclear. As elevated c-Myc expression, activation of Wnt/β-catenin signaling and dysfunction of p53 are seen in human PNETs, we investigated what role these abnormalities have in the formation of PNETs. Incorporating these abnormalities, we generated supratentorial PNET (sPNET) in mice using somatic cell gene transfer. We show that sPNETs arise from GFAP-expressing cells by forced c-Myc expression combined with p53 inactivation. β-catenin activation promotes tumor progression and induces divergent differentiation. These c-Myc+β-catenin-induced PNETs are histologically similar to large cell/anaplastic medulloblastomas and can occur in both cerebrum and cerebellum. Furthermore, we have obtained one PNET with marked epithelial differentiation having histological resemblance to choroid plexus carcinoma in this series. Our results in mice suggest that sPNET with varied differentiation and large cell/anaplastic medulloblastomas may be two tumor groups with similar genetic foundations. These data provide insights into the biology and classification of human PNETs and suggest that multiple tumor types or variants can be generated from a fixed set of genetic abnormalities.

Original languageEnglish
Pages (from-to)4392-4401
Number of pages10
JournalOncogene
Volume27
Issue number32
DOIs
StatePublished - 24 Jul 2008
Externally publishedYes

Keywords

  • B-catenin
  • Mouse model
  • Primitive neuroectodermal tumor
  • c-Myc
  • p53

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