A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes

Cancer Cell. 2015 Dec 14;28(6):730-742. doi: 10.1016/j.ccell.2015.10.008. Epub 2015 Dec 5.

Abstract

In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP-Jκ and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumors.

Keywords: Hes5; Notch signaling; brain tumor; glioma; primitive neuroectodermal tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Cell Proliferation
  • Databases, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Transfer Techniques
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / mortality
  • Glioma / pathology
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Infusions, Intraventricular
  • Kaplan-Meier Estimate
  • Mice, Knockout
  • Neoplasm Grading
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Phenotype
  • Platelet-Derived Growth Factor / administration & dosage
  • Prosencephalon / metabolism*
  • Prosencephalon / pathology
  • Proto-Oncogene Proteins c-sis / genetics
  • Proto-Oncogene Proteins c-sis / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Recombinant Proteins / administration & dosage
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • Time Factors
  • Tumor Burden
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hes5 protein, mouse
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Notch1 protein, mouse
  • Notch2 protein, mouse
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Rbpj protein, mouse
  • Receptor, Notch1
  • Receptor, Notch2
  • Receptors, Notch
  • Recombinant Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • platelet-derived growth factor A

Associated data

  • GEO/GSE64230