| 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. © Springer Science+Business Media, LLC. 2009. |
| Keywords: |
signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; human tissue; protein expression; protein phosphorylation; unclassified drug; mutation; nonhuman; glioma; mutant protein; cell proliferation; animal cell; mouse; animals; cell survival; cell cycle; cell cycle progression; cell cycle s phase; gene overexpression; protein p16; stat3 protein; apoptosis; gene expression; epidermal growth factor receptor; nerve tissue proteins; gene product; cell fate; neural stem cell; cell differentiation; neurons; receptor, epidermal growth factor; cell line, tumor; transfection; wild type; time factors; viral gene delivery system; gene activation; gene expression regulation, neoplastic; messenger rna; enzyme inhibitors; glioblastoma; protein p27; cell migration; cell movement; cell cycle arrest; glia cell; stem cells; green fluorescent proteins; cell count; cell cycle m phase; down regulation; upregulation; oxidative stress; protein dephosphorylation; animals, newborn; egfr; cell clone; superoxide; thiazoles; protein p21; neural stem cells; nerve cell differentiation; nestin; cell cycle g1 phase; cell cycle g0 phase; stable expression; broxuridine; brain tumors; phospholipase c gamma; perinatal period; 4 (3 chloroanilino) 6,7 dimethoxyquinazoline; beta actin; protein bax; protein bid; protein tuj1; tetrazolium salts; tyrphostins
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