Laboratory Investigation - Human/Animal Tissue

Journal of Neuro-Oncology

, Volume 97, Issue 3, pp 323-337

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

  • Angel Ayuso-SacidoAffiliated withNeurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell UniversityDepartment of Cell Morphology, Centro de Investigación Principe Felipe and RETICS-CIBERNED Email author 
  • , Jennifer A. MoliternoAffiliated withNeurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell University
  • , Sebila KratovacAffiliated withNeurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell University
  • , Gurpreet S. KapoorAffiliated withDepartment of Neurological Surgery, University of Pennsylvania School of Medicine
  • , Donald M. O’RourkeAffiliated withDepartment of Neurological Surgery, University of Pennsylvania School of Medicine
  • , Eric C. HollandAffiliated withDepartment of Neurological Surgery, Memorial Sloan-Kettering Cancer Center
  • , Jose Manuel García-VerdugoAffiliated withDepartment of Cell Morphology, Centro de Investigación Principe Felipe and RETICS-CIBERNED
  • , Neeta S. RoyAffiliated withDepartment of Neurology and Neuroscience, Weill Cornell Medical College of Cornell University
  • , John A. BoockvarAffiliated withNeurosurgical Laboratory for Translational Stem Cell Research, Department of Neurosurgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell UniversityDepartment of Neurological Surgery, Weill Cornell Medical College of Cornell University Email author 

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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