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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.

Original publication

DOI

10.18632/oncotarget.5401

Type

Journal article

Journal

Oncotarget

Publication Date

13/10/2015

Volume

6

Pages

30472 - 30486

Keywords

MitoTracker, cancer stem cells, mitochondria, tumor metabolism, Aldehyde Dehydrogenase, Animals, Antigens, CD24, Antigens, Neoplasm, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Cell Adhesion Molecules, Comet Assay, DNA Damage, Drug Resistance, Neoplasm, Epithelial Cell Adhesion Molecule, Female, Flow Cytometry, Humans, MCF-7 Cells, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Neoplasm Transplantation, Neoplastic Stem Cells, Paclitaxel, Spheroids, Cellular, Transplantation, Heterologous, Tumor Cells, Cultured