Level of Notch activation determines the effect on growth and stem cell-like features in glioblastoma multiforme neurosphere cultures

Cancer Biol Ther. 2013 Jul;14(7):625-37. doi: 10.4161/cbt.24595. Epub 2013 May 10.

Abstract

Background: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in glioblastoma multiforme (GBM) and they are assigned a central role in tumor initiation, progression and relapse. The Notch pathway is important for maintenance and cell fate decisions in the normal NSC population. Notch signaling is often deregulated in GBM and recent results suggest that this pathway plays a significant role in bCSC as well. We therefore wished to further elucidate the role of Notch activation in GBM-derived bCSC.

Methods: Human-derived GBM xenograft cells were cultured as NSC-like neurosphere cultures. Notch modulation was accomplished either by blocking the pathway using the γ-secretase inhibitor DAPT or by activating it by transfecting the cells with the constitutive active Notch-1 receptor.

Results: GBM neurosphere cultures with high endogenous Notch activation displayed sensitivity toward Notch inhibition with regard to tumorigenic features as demonstrated by increased G0/G1 population and reduced colony formation capacity. Of the NSC-like characteristics, only the primary sphere forming potential was affected, while no effect was observed on self-renewal or differentiation. In contrast, when Notch signaling was activated a decrease in the G0/G1 population and an enhanced capability of colony formation was observed, along with increased self-renewal and de-differentiation.

Conclusion: Based on the presented results we propose that active Notch signaling plays a role for cell growth and stem cell-like features in GBM neurosphere cultures and that Notch-targeted anti-bCSC treatment could be feasible for GBM patients with high endogenous Notch pathway activation.

Keywords: DAPT; ICN-1; Notch activity; Notch signaling; brain cancer stem-like cells; glioblastoma multiforme; neurosphere cultures.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Differentiation / physiology
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Humans
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Receptors, Notch / metabolism*
  • Signal Transduction

Substances

  • Receptors, Notch