Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells.
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.
Ayuso-Sacido
Angel
A
Department of Neurosurgery, Neurosurgical Laboratory for Translational Stem Cell Research, Weill Cornell Brain Tumor Center, Weill Cornell Medical College of Cornell University, New York, NY, USA. aayuso@cipf.es
Moliterno
Jennifer A
JA
Kratovac
Sebila
S
Kapoor
Gurpreet S
GS
O'Rourke
Donald M
DM
Holland
Eric C
EC
García-Verdugo
Jose Manuel
JM
Roy
Neeta S
NS
Boockvar
John A
JA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D011799:Quinazolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D020032:Tyrphostins; D049452:Green Fluorescent Proteins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; C022616:thiazolyl blue