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.
Highlights
It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties
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
Summary
It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Low CD10 expression was consistent with a specific set of ovarian cancer patient samples 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. Tumour-initiating cells within the heterogeneous tumour are referred to as ‘cancer stem cells’ (CSCs) owing to their stem cell-like properties of self-renewal, differentiation and (malignant) tissue genesis.[1,2,3] Many studies have shown that CSCs from different malignancies are chemoresistant.[4] CSCs are potential clinical targets, for the treatment of refractory disease, but CSC targeting has not been efficiently translated to the clinic.[1,5] This may be due to the complex organisation of CSCs as stem-progenitor-differentiated cell hierarchies.
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