Journal of Neuro-Oncology

, Volume 97, Issue 3, pp 323–337 | Cite as

Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells

  • Angel Ayuso-Sacido
  • Jennifer A. Moliterno
  • Sebila Kratovac
  • Gurpreet S. Kapoor
  • Donald M. O’Rourke
  • Eric C. Holland
  • Jose Manuel García-Verdugo
  • Neeta S. Roy
  • John A. Boockvar
Laboratory Investigation - Human/Animal Tissue

Abstract

Recent evidence supports the notion that transformation of undifferentiated neural stem cell (NSC) precursors may contribute to the development of glioblastoma multiforme (GBM). The over-expression and mutation of the epidermal growth factor receptor (EGFR), along with other cellular pathway mutations, plays a significant role in GBM maintenance progression. Though EGFR signaling is important in determining neural cell fate and conferring astrocyte differentiation, there is a limited understanding of its role in NSC and tumor stem cell (TSC) biology. We hypothesized that EGFR expression and mutation in post-natal NSCs may contribute to cellular aggressiveness including enhanced cellular proliferation, survival and migration. Stable subclones of C17.2 murine NSCs were transfected to over-express either the wild-type EGFR (wtEGFR) or its most common mutated variant EGFRvIII. Activated EGFR signaling in these cells induced behaviors characteristic of GBM TSCs, including enhanced proliferation, survival and migration, even in the absence of EGF ligand. wtEGFR activation was also found to block neuronal differentiation and was associated with a dramatic increase in chemotaxis in the presence of EGF. EGFRvIII expression lead to an increase in NSC proliferation and survival, while it simultaneously blocked neuronal differentiation and promoted glial fate. Our findings suggest that activated EGFR signaling enhances the aggressiveness of NSCs. Understanding the regulatory mechanisms of NSCs may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment modalities.

Keywords

EGFR Neural stem cells Glioma Brain tumors 

Supplementary material

11060_2009_35_MOESM1_ESM.pdf (636 kb)
Supplementary material 1 (PDF 635 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Angel Ayuso-Sacido
    • 1
    • 5
  • Jennifer A. Moliterno
    • 1
  • Sebila Kratovac
    • 1
  • Gurpreet S. Kapoor
    • 3
  • Donald M. O’Rourke
    • 3
  • Eric C. Holland
    • 4
  • Jose Manuel García-Verdugo
    • 5
  • Neeta S. Roy
    • 2
  • John A. Boockvar
    • 1
    • 6
  1. 1.Neurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor CenterWeill Cornell Medical College of Cornell UniversityNew YorkUSA
  2. 2.Department of Neurology and NeuroscienceWeill Cornell Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of Neurological SurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Department of Neurological SurgeryMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Department of Cell MorphologyCentro de Investigación Principe Felipe and RETICS-CIBERNEDValenciaSpain
  6. 6.Department of Neurological SurgeryWeill Cornell Medical College of Cornell UniversityNew YorkUSA

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