Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells

BMC Cancer

Research Article

Gang Cheng¹  Liang Li¹  Luo-An Fu¹  Fang Gao²  Ya-Ning Wei²  Hua Han²  Yi-Yang Hu²  Min-Hua Zheng²  Liang Liang² 

[1] Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, 710032, Xi'an, P.R. China;State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, 710032, Xi'an, P.R. China;

关键词: Tumor Sphere;    Brain Tumor Stem Cell;    Human Glial Cell;    Inhibit Notch Signaling;    Normal Neural Stem Cell;   

DOI  :  10.1186/1471-2407-11-82

 received in 2010-10-22, accepted in 2011-02-22,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Hu et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.