CD10 − /ALDH − Cells are the Sole Cisplatin-Resistant Component of a Novel Ovarian Cancer Stem Cell Hierarchy
| Autor: | Aoibhinn Mooney, Cathy Spillane, Bryan T. Hennessy, Karsten Hokamp, Louise Kehoe, Noreen Gleeson, Claudia Gasch, Ronan Doyle, Britta K. Stordal, Brendan Ffrench, Sharon O'Toole, John J. O'Leary, Dearbhaile M. O'Donnell, Thamir Mahmoud Mahgoub, Michael Gallagher, Brendan Doyle, Ciaran O'Riain, Helen Lambkin, Gordon Blackshields, Mark Bates |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Immunology Cell sole cisplatin-resistant Aldehyde dehydrogenase Bioinformatics 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Cancer stem cell medicine Cisplatin biology Cluster of differentiation Cell Biology medicine.disease 030104 developmental biology medicine.anatomical_structure Paclitaxel chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Tumour-initiating Earth Sciences cells Stem cell Ovarian cancer medicine.drug |
| Zdroj: | Articles |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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