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High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant

Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitoch...

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Autores principales: Farnie, Gillian, Sotgia, Federica, Lisanti, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741545/
https://www.ncbi.nlm.nih.gov/pubmed/26421710
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author Farnie, Gillian
Sotgia, Federica
Lisanti, Michael P.
author_facet Farnie, Gillian
Sotgia, Federica
Lisanti, Michael P.
author_sort Farnie, Gillian
collection PubMed
description Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4–8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population.
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spelling pubmed-47415452016-03-03 High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant Farnie, Gillian Sotgia, Federica Lisanti, Michael P. Oncotarget Priority Research Paper Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4–8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population. Impact Journals LLC 2015-10-03 /pmc/articles/PMC4741545/ /pubmed/26421710 Text en Copyright: © 2015 Farnie et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Farnie, Gillian
Sotgia, Federica
Lisanti, Michael P.
High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title_full High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title_fullStr High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title_full_unstemmed High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title_short High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
title_sort high mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741545/
https://www.ncbi.nlm.nih.gov/pubmed/26421710
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