Cancer Stem-Like Phenotype of Mitochondria Dysfunctional Hep3B Hepatocellular Carcinoma Cell Line (original) (raw)
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Mitochondrial biology in cancer stem cells
Seminars in cancer biology, 2017
Cancer stem cells (CSCs) have been suggested to be responsible for tumor re-growth and relapse. Physiological and morphological knowledge of CSCs may be essential for the development of new therapeutic strategies targeting cancer development, progression, and recurrence. Current research is focused on a deeper understanding of CSCs metabolic profiles, taking into consideration their energy demands. Energy metabolism and mitochondrial function are important factors operating on stemness maintenance and cell fate specification. Due to the role of mitochondria as central hubs in the overall cell metabolism and death and survival pathways, research on their physiology in CSCs is of paramount importance to decipher mechanisms underlying their therapy-resistant phenotype. In this review, we focus on CSCs mitochondrial biology and mitochondria-related signaling pathways that contribute to CSCs survival and maintenance, thereby representing possible therapeutic targets.
Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells
2014
The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies.
Medical Hypotheses, 2013
Cancer development is an evolutionary process that has been highly conserved among centuries within organisms. Based on this, the interest in cancer research focuses on cells, organelles and genes that possess a genetic conservatism from yeasts to human. Towards this thought, mitochondria, the highly conserved and responsible for the cellular bioenergetic activity organelles, might play crucial role in carcinogenesis. Interestingly, tumors with low bioenergetic signature have worse prognosis and show a decreased expression of ATPase protein. Furthermore, according to the stem-cell theory of carcinogenesis, aggressive tumors are characterized by an increase number of malignant stem-like cell population and their resistance to chemotherapy has been found to be mitochondrially driven. The above considerations triggered us to hypothesize that mitochondrial bioenergetic processes in stem-like cancer cells plays a crucial role in the highly conserved process of carcinogenesis. Specifically, we support that mitochondrial and/or nuclear DNA alterations that control stem cells' ATP production drive stem cells to ''immortalization'' (Otto Warburg theory) that mediates cancer initiation and progression. Substantiation of our hypothesis requires evidence that: (1) alterations in mitochondria bioenergetic metabolites and enzymes encoded either from the mtDNA or the nuclear DNA are linked to human cancer and (2) mitochondrial functions are regulated by highly conserved genes involved in cancer-related cellular processes such as apoptosis, aging and autophagy. Experimental approach on how this hypothesis might be tested and promising strategies in cancer therapeutics are also discussed. In case the hypothesis of stem-cell bioenergetic malformations' related carcinogenesis proves to be correct, it would contribute to the development of new prognostic, diagnostic and even more effective therapeutic interventions against various types of cancer.
Mitochondrial DNA Deficiency in Ovarian Cancer Cells and Cancer Stem Cell-like Properties
Anticancer research, 2015
A low quantity of mitochondrial DNA (mtDNA) is a risk factor in a variety of tumor types. However, it is unclear how mtDNA reduction influences tumor behavior. mtDNA-deficient ovarian cancer cells were established by ethidium bromide (EtBr) treatment with additive combination of pyruvate and uridine. The mtDNA-deficient cells had a low growth and colony-forming efficiency compared to the control cells. RNA sequencing revealed down-regulation of mitochondrion-related genes and up-regulation of genes related to cell proliferation and anti-apoptosis. The expression of genes involved in cancer metastasis, proliferation, angiogenesis, drug resistance and cancer cell stemness were also up-regulated. Intriguingly, cancer stem cell markers CD90 and CD117 were both up-regulated by EtBr dose-dependently in both cell lines. MtDNA deficiency may induce ovarian cancer stem cell-like properties through different ways in vitro, therefore contributing to different tumor behaviors.
Oncotarget, 2015
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 mitohigh 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 overcoming drug resistance, by therapeutically targeting the mito-high CSC population.
Oncotarget, 2015
Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of cancer stem-like cells (CSCs). More specifically, we used the drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that XCT790 efficiently blocks both the survival and propagation of tumor initiating stem-like cells (TICs), using the MCF7 cell line as a model system. Mechanistically, we show that XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by Acetyl-L-Carnitine (ALCAR), a mitochondrial fuel. Consistent with our ...
Effects of differentiation of embryonal carcinoma cells (P19) on mitochondrial DNA content in vitro
in Vitro Cellular & Developmental Biology-animal, 1991
The embryonal carcinoma cell line P19 is derived from mouse teratocarcinomas. These pluripotent cells can be induced to differentiate into a variety of cell types by exposure to various drugs. We used retinoic acid to induce embryonal carcinoma cells to differentiate into neuronlike cells. In this study, we show that changes occur in mitochondria during differentiation of embryonal carcinoma cells to neuronlike cells. We found that various morphologic parameters such as mitochondrial fractional area and mitochondrial size decrease as embryonal carcinoma cells differentiate into neuronlike cells. Similar changes were also observed in mitochondrial DNA content. Stereologic analysis of cell preparations provided a measure of mitochondrial fractional area per cell and mtDNA content was assessed by radiolabeled mtDNA probe. This study establishes that mitochondria are regulated as cells differentiate.
Scientific Reports, 2015
Mitochondrial activity is central to tissue homeostasis. Mitochondria dysfunction constitutes a hallmark of many genetic diseases and plays a key role in tumor progression. The essential role of mitochondria, added to their recently documented capacity to transfer from cell to cell, obviously contributes to their current interest. However, determining the proper role of mitochondria in defined biological contexts was hampered by the lack of suitable experimental tools. We designed a protocol (MitoCeption) to directly and quantitatively transfer mitochondria, isolated from cell type A, to recipient cell type B. We validated and quantified the effective mitochondria transfer by imaging, fluorescence-activated cell sorting (FACS) and mitochondrial DNA analysis. We show that the transfer of minute amounts of mesenchymal stem/stromal cell (MSC) mitochondria to cancer cells, a process otherwise occurring naturally in coculture, results in cancer cell enhanced oxidative phosphorylation (OXPHOS) activity and favors cancer cell proliferation and invasion. The MitoCeption technique, which can be applied to different cell systems, will therefore be a method of choice to analyze the metabolic modifications induced by exogenous mitochondria in host cells. M itochondria are involved in the central cell tasks of nutrient uptake and energy production. They are therefore at the core of a number of essential biological functions and corresponding disorders 1-4. Mitochondria are also actively involved in cancer progression, including metastasis, and in acquired resistance to therapy 5-8. These biological functions associated with a better understanding of the mitochondria dynamics and signaling have triggered a renewed interest in the field 2,4,9. Interestingly, in the past few years, several laboratories have reported the capacity of mitochondria to be transferred between cells, through nanotube formation, leading to cellular reprogramming and to phenotypes as diverse as protection against tissue injury and resistance to therapeutic agents 10-17. These first in vitro observations of the mitochondria transfer were confirmed in vivo and factors involved in the trafficking of mitochondria through nanotubes, notably the connexin 43 and the mitochondrial Ca 21-binding GTPase Miro1 (RHOT1), were identified 10,18. A number of these mitochondria transfers were shown to originate, through the formation of nanotube structures, from mesenchymal stem/ stromal cells (MSCs) and to target various tissues, leading to the transfer of MSC mitochondria to cardiomyocytes, endothelial cells, pulmonary alveolar epithelial cells, renal tubular cells and cancer cells 10-12,14,19-21. These various studies clearly showed that MSC mitochondria could convey new properties to the recipient cells. MSCs are identified by a panel of receptors, notably CD711, CD901, CD1051, CD45-, CD34-, and characterized by their immunosuppressive properties and their capacity to differentiate to different lineages 22,23. MSCs are recruited to inflammatory sites where they can contribute to tissue repair. They are also recruited to tumor sites where they can modify cancer cell growth and metastatic potential as well as response to therapy 24-37. In
Oxidative Medicine and Cellular Longevity, 2016
Cancer stem cells (CSCs) are highly resistant to conventional chemo- and radiotherapeutic regimes. Therefore, the multiple drug resistance (MDR) of cancer is most likely due to the resistance of CSCs. Such resistance can be attributed to some bypassing pathways including detoxification mechanisms of reactive oxygen and nitrogen species (RO/NS) formation or enhanced autophagy. Unlike in normal cells, where RO/NS concentration is maintained at certain threshold required for signal transduction or immune response mechanisms, CSCs may develop alternative pathways to diminish RO/NS levels leading to cancer survival. In this minireview, we will focus on elaborated mechanisms developed by CSCs to attenuate high RO/NS levels. Gaining a better insight into the mechanisms of stem cell resistance to chemo- or radiotherapy may lead to new therapeutic targets thus serving for better anticancer strategies.