EGFR signaling is differentially activated in patient-derived glioblastoma stem cells Journal Article

Authors: Howard, B. M.; Gursel, D. B.; Bleau, A. M.; Beyene, R. T.; Holland, E. C.; Boockvar, J. A.
Article Title: EGFR signaling is differentially activated in patient-derived glioblastoma stem cells
Abstract: Evidence suggests that stem-like cells are responsible for initiation, maintenance and recurrence of solid tumors, including Glioblastoma Multiforme (GBM). GBM is an intractable, highly lethal tumor of the central nervous system. Although epidermal growth factor receptor (EGFR) is highly expressed in many GBMs, anti-EGFR therapies have been unsuccessful as treatment. Few studies have examined EGFR activation in GBM stem cells (GSCs) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically. We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy. Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478. Second messenger pathways operative in these processes were elucidated by immunoblotting. EGFR activated AKT and inactivated GSK3β in EGFR+/PTEN+ GSCs. AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR +/PTEN+ GSCs generated and the rate of sphere formation. Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis, likely via inhibition of AKT and activation of GSK3β. Sphere formation by EGFR-/PTEN- GSCs was independent of EGF stimulation, but dependant on B27 growth supplement. Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro. © 2010 Old City Publishing, Inc.
Keywords: signal transduction; protein kinase b; controlled study; protein expression; protein phosphorylation; human cell; single nucleotide polymorphism; missense mutation; erlotinib; nonhuman; animal cell; mouse; cell cycle; apoptosis; enzyme inhibition; protein protein interaction; epidermal growth factor receptor; animal experiment; animal model; receptor, epidermal growth factor; enzyme activation; cell line, tumor; protein kinase inhibitors; amino acid sequence; immunocytochemistry; neoplastic stem cells; glioblastoma; glycogen synthase kinase 3beta; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cancer stem cell; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; dna sequence; senescence; egfr; akt; quinazolines; glycogen synthase kinase 3; 4 (3 chloroanilino) 6,7 dimethoxyquinazoline; tyrphostins; brain tumor stem cells; gsk3β
Journal Title: Journal of Experimental Therapeutics and Oncology
Volume: 8
Issue: 3
ISSN: 1359-4117
Publisher: Old City Publishing, Inc  
Date Published: 2010-01-01
Start Page: 247
End Page: 260
Language: English
PUBMED: 20734923
PROVIDER: scopus
Notes: --- - "Export Date: 20 April 2011" - "CODEN: JETOF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Anne-Marie Bleau
    11 Bleau
  2. Eric Holland
    224 Holland
  3. Robel Beyene
    1 Beyene