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

Brian M. Howard, Demirkan B. Gursel, Anne Marie Bleau, Robel T. Beyene, Eric C. Holland, John A. Boockvar

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)247-260
Number of pages14
JournalJournal of Experimental Therapeutics and Oncology
Volume8
Issue number3
StatePublished - Jul 13 2010

Keywords

  • AKT
  • Brain tumor stem cells
  • EGFR
  • Glioblastoma
  • GSK3β

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Cancer Research

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  • Cite this

    Howard, B. M., Gursel, D. B., Bleau, A. M., Beyene, R. T., Holland, E. C., & Boockvar, J. A. (2010). EGFR signaling is differentially activated in patient-derived glioblastoma stem cells. Journal of Experimental Therapeutics and Oncology, 8(3), 247-260.