Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

Hussein, D.; Punjaruk, W.; Storer, L. C. D.; Shaw, L.; Othman, R. T.; Peet, A.; Miller, S.; Bandopadhyay, G.; Heath, R.; Kumari, R.; Bowman, K. J.; Braker, P.; Rahman, R.; Jones, G. D. D.; Watson, S.; Lowe, J.; Kerr, I. D.; Grundy, R. G.; Coyle, B.

Abstract

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neu-roectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3– 4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neuro-sphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xeno-graft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Citation

Hussein, D., Punjaruk, W., Storer, L. C. D., Shaw, L., Othman, R. T., Peet, A., …Coyle, B. (2011). Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion. Neuro-Oncology, 13(1), 70-83. https://doi.org/10.1093/neuonc/noq144

• Journal Article Type: Article
• Acceptance Date: Jul 22, 2010
• Online Publication Date: Oct 25, 2010
• Publication Date: Jan 1, 2011
• Deposit Date: Dec 5, 2018
• Publicly Available Date: Dec 12, 2018
• Journal: Neuro-Oncology
• Print ISSN: 1522-8517
• Electronic ISSN: 1523-5866
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 1
• Pages: 70-83
• DOI: https://doi.org/10.1093/neuonc/noq144
• Keywords: cancer stem cells; drug resistance; etoposide; pediatric
• Public URL: https://nottingham-repository.worktribe.com/output/1370605
• Publisher URL: https://academic.oup.com/neuro-oncology/article/13/1/70/1023033
• Additional Information: A correction has been published: ; Neuro-Oncology, Volume 14, Issue 12, 1 December 2012, Pages 1528, https://doi.org/10.1093/neuonc/nos297