Abstract
BackgroundCancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma. Notch signaling, an evolutionarily conserved pathway mediating direct cell-cell interaction, has been shown to regulate neural stem cells (NSCs) and glioma stem cells (GSCs) in normal neurogenesis and pathological carcinogenesis, respectively. However, how Notch signaling regulates the proliferation and differentiation of GSCs has not been well elucidated.MethodsWe isolated and cultivate human GSCs from glioma patient specimens. Then on parallel comparison with NSCs, we inhibited Notch signaling using γ-secretase inhibitors (GSI) and assessed the potential functions of Notch signaling in human GSCs.ResultsSimilar to the GSI-treated NSCs, the number of the primary and secondary tumor spheres from GSI-treated GSCs decreased significantly, suggesting that the proliferation and self-renewal ability of GSI-treated GSCs were attenuated. GSI-treated GSCs showed increased differentiation into mature neural cell types in differentiation medium, similar to GSI-treated NSCs. Next, we found that GSI-treated tumor spheres were composed of more intermediate progenitors instead of CSCs, compared with the controls. Interestingly, although inhibition of Notch signaling decreased the ratio of proliferating NSCs in long term culture, we found that the ratio of G2+M phase-GSCs were almost undisturbed on GSI treatment within 72 h.ConclusionsThese data indicate that like NSCs, Notch signaling maintains the patient-derived GSCs by promoting their self-renewal and inhibiting their differentiation, and support that Notch signal inhibitor GSI might be a prosperous candidate of the treatment targeting CSCs for gliomas, however, with GSI-resistance at the early stage of GSCs cell cycle.
Highlights
Cancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma
We explore the roles of Notch signaling in patient-derived glioma stem cells (GSCs) with parallel analysis of normal neural stem cells (NSCs) by using g-secretase inhibitors (GSI)-mediated inhibition of Notch signaling in vitro
Our results suggested that Notch signaling maintained GSCs by promoting their selfrenewal and inhibiting their differentiation into intermediate neural progenitors (INPs)-like cells, and supported that Notch signal inhibitors might be prosperous candidates of the treatments targeting CSCs for gliomas
Summary
Cancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma. Recent researches highlight the importance of cancerinitiating cells in the malignancy of gliomas [1,2,3] These cells have been referred to as glioma stem cells (GSC), as they share similarities to normal neural stem cells (NSCs) in the brain. There is increasing evidence that malignant gliomas arise from and contain these minority tumor cells with stem cell-like properties. This subpopulation of tumor cells with the potential for self-renewal and multi-lineage differentiation that recapitulates the phenotype of the original glioma [4,5,6,7,8], plays an important role in glioma initiation, growth, and recurrence.
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