CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy
Article
Ffrench, B., Gasch, C., Hokamp, K., Spillane, C., Blackshields, G., Mahgoub, T., Bates, M., Kehoe, L., Mooney, A., Doyle, R., Doyle, B., O'Donnell, D., Gleeson, N., Hennessy, B., Stordal, B., O'Riain, C., Lambkin, H., O'Toole, S., O'Leary, J. and Gallagher, M. 2017. CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy. Cell Death & Disease. 8 (10). https://doi.org/10.1038/cddis.2017.379
Type | Article |
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Title | CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy |
Authors | Ffrench, B., Gasch, C., Hokamp, K., Spillane, C., Blackshields, G., Mahgoub, T., Bates, M., Kehoe, L., Mooney, A., Doyle, R., Doyle, B., O'Donnell, D., Gleeson, N., Hennessy, B., Stordal, B., O'Riain, C., Lambkin, H., O'Toole, S., O'Leary, J. and Gallagher, M. |
Abstract | It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CSC hierarchies and chemoresistance in an ovarian cancer model. Using a single cell-based approach to CSC discovery and validation, we report a novel, four-component CSC hierarchy based around the markers cluster of differentiation 10 (CD10) and aldehyde dehydrogenase (ALDH). In a change to our understanding of CSC biology, resistance to chemotherapy drug cisplatin was found to be the sole property of CD10−/ALDH− CSCs, while all four CSC types were sensitive to chemotherapy drug paclitaxel. Cisplatin treatment quickly altered the hierarchy, resulting in a three-component hierarchy dominated by the cisplatin-resistant CD10−/ALDH− CSC. This organisation was found to be hard-wired in a long-term cisplatin-adapted model, where again CD10−/ALDH− CSCs were the sole cisplatin-resistant component, and all CSC types remained paclitaxel-sensitive. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Clinically, low CD10 expression was consistent with a specific set of ovarian cancer patient samples. Collectively, these data advance our understanding of the relationship between CSC hierarchies and chemoresistance, which was shown to be CSC- and drug-type specific, and facilitated by specific and synergistic inherent and adaptive mechanisms. Furthermore, our data indicate that primary stage targeting of CD10−/ALDH− CSCs in specific ovarian cancer patients in future may facilitate targeting of recurrent disease, before it ever develops. |
Keywords | Cancer stem cells; Cancer therapeutic resistance; Chemotherapy; Ovarian cancer |
Sustainable Development Goals | 3 Good health and well-being |
Middlesex University Theme | Health & Wellbeing |
Research Group | Biomarkers for Cancer group |
Publisher | Springer |
Journal | Cell Death & Disease |
ISSN | |
Electronic | 2041-4889 |
Publication dates | |
Online | 19 Oct 2017 |
Oct 2017 | |
Publication process dates | |
Accepted | 15 Jun 2017 |
Submitted | 16 Mar 2017 |
Deposited | 10 May 2024 |
Output status | Published |
Publisher's version | License File Access Level Open |
Copyright Statement | Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Digital Object Identifier (DOI) | https://doi.org/10.1038/cddis.2017.379 |
PubMed ID | 29048400 |
PubMed Central ID | 5680566 |
Web of Science identifier | WOS:000414022900031 |
Related Output | |
Is supplemented by | https://www.nature.com/articles/cddis2017379#Sec15 |
Language | English |
https://repository.mdx.ac.uk/item/1378qy
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