“Energetic” Cancer Stem Cells (e-CSCs): A New Hyper-Metabolic and Proliferative Tumor Cell Phenotype, Driven by Mitochondrial Energy
Here, we provide the necessary evidence that mitochondrial metabolism drives the anchorage-independent proliferation of CSCs. Two human breast cancer cell lines, MCF7 [ER(+)] and MDA-MB-468 (triple-negative), were used as model systems. To directly address the issue of metabolic heterogeneity in can...
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| Published in: | Frontiers in oncology Vol. 8; p. 677 |
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| Main Authors: | , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Switzerland
Frontiers Media S.A
05.02.2019
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| Subjects: | |
| ISSN: | 2234-943X, 2234-943X |
| Online Access: | Get full text |
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| Summary: | Here, we provide the necessary evidence that mitochondrial metabolism drives the anchorage-independent proliferation of CSCs. Two human breast cancer cell lines, MCF7 [ER(+)] and MDA-MB-468 (triple-negative), were used as model systems. To directly address the issue of metabolic heterogeneity in cancer, we purified a new distinct sub-population of CSCs, based solely on their energetic profile. We propose the term "energetic" cancer stem cells (e-CSCs), to better describe this novel cellular phenotype. In a single step, we first isolated an auto-fluorescent cell sub-population, based on their high flavin-content, using flow-cytometry. Then, these cells were further subjected to a detailed phenotypic characterization. More specifically, e-CSCs were more glycolytic, with higher mitochondrial mass and showed significantly elevated oxidative metabolism. e-CSCs also demonstrated an increased capacity to undergo cell cycle progression, as well as enhanced anchorage-independent growth and ALDH-positivity. Most importantly, these e-CSCs could be effectively targeted by treatments with either (i) OXPHOS inhibitors (DPI) or (ii) a CDK4/6 inhibitor (Ribociclib). Finally, we were able to distinguish two distinct phenotypic sub-types of e-CSCs, depending on whether they were grown as 2D-monolayers or as 3D-spheroids. Remarkably, under 3D anchorage-independent growth conditions, e-CSCs were strictly dependent on oxidative mitochondrial metabolism. Unbiased proteomics analysis demonstrated the up-regulation of gene products specifically related to the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Therefore, mitochondrial inhibitors should be further developed as promising anti-cancer agents, to directly target and eliminate the "fittest" e-CSCs. Our results have important implications for using e-CSCs, especially those derived from 3D-spheroids, (i) in tumor tissue bio-banking and (ii) as a new cellular platform for drug development. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Francesco De Francesco, Azienda Ospedaliero Universitaria Ospedali Riuniti, Italy; Cesar Cardenas, Universidad Mayor, Chile Edited by: Massimo Bonora, Albert Einstein College of Medicine, United States This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology |
| ISSN: | 2234-943X 2234-943X |
| DOI: | 10.3389/fonc.2018.00677 |