Therapeutically Targeting Epigenetic Regulation of Cancer Stem Cells

Ffrench, Brendan; O’Leary, John; Gallagher, Michael

doi:10.1016/b978-0-12-800206-3.00027-6

Cited by 2 publications

(1 citation statement)

References 111 publications

(124 reference statements)

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“…Tumour-initiation is a property of self-renewing CSCs such as hECCs, which is lost during differentiation. 42 In the developing tumour, CSCs that persist in the SR state while other CSCs differentiate are, therefore, clear clinical targets. Global targeting of CSCs via forced-differentiation treatments using drugs such as RA has been largely inefficient in the clinic, apart from in specific patients with specific malignancies, [43][44][45] which indicates the importance of better understanding CSC differentiation resistance.…”

Section: Discussionmentioning

confidence: 99%

MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells

et al. 2017

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We have previously reported that myeloid differentiation primary response gene 88 (MyD88) is downregulated during all-trans retinoic acid (RA)-induced differentiation of pluripotent NTera2 human embryonal carcinoma cells (hECCs), whereas its maintained expression is associated with RA differentiation resistance in nullipotent 2102Ep hECCs. MyD88 is the main adapter for toll-like receptor (TLR) signalling, where it determines the secretion of chemokines and cytokines in response to pathogens. In this study, we report that loss of MyD88 is essential for RA-facilitated differentiation of hECCs. Functional analysis using a specific MyD88 peptide inhibitor (PepInh) demonstrated that high MyD88 expression in the self-renewal state inhibits the expression of a specific set of HOX genes. In NTera2 cells, MyD88 is downregulated during RA-induced differentiation, a mechanism that could be broadly replicated by MyD88 PepInh treatment of 2102Ep cells. Notably, MyD88 inhibition transitioned 2102Ep cells into a stable, self-renewing state that appears to be primed for differentiation upon addition of RA. At a molecular level, MyD88 inhibition combined with RA treatment upregulated HOX, RA signalling and TLR signalling genes. These events permit differentiation through a standard downregulation of Oct4-Sox2-Nanog mechanism. In line with its role in regulating secretion of specific proteins, conditioned media experiments demonstrated that differentiated (MyD88 low) NTera2 cell media was sufficient to differentiate NTera2 cells. Protein array analysis indicated that this was owing to secretion of factors known to regulate angiogenesis, neurogenesis and all three branches of TGF-β Superfamily signalling. Collectively, these data offer new insights into RA controlled differentiation of pluripotent cells, with notable parallels to the ground state model of embryonic stem cell self-renewal. These data may provide insights to facilitate improved differentiation protocols for regenerative medicine and differentiation-therapies in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells

et al. 2017

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CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy

et al. 2017

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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.

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Therapeutically Targeting Epigenetic Regulation of Cancer Stem Cells

Cited by 2 publications

References 111 publications

MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells

MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells

CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy

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