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  • Characterization of Mesothelioma Stem Cells, Their Metabolic Signature and Susceptibility to Selected Mitocans

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    Pasdar_2015_02Thesis.pdf (3.068Mb)
    Author(s)
    Alizadeh Pasdar, Elham
    Primary Supervisor
    Neuzil, Jiri
    Other Supervisors
    Morrison, Nigel
    Year published
    2015
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    Abstract
    Populations of tumor cells display a remarkable diversity in their phenotypic traits, including their drug resistance and ability to form metastases. This heterogeneity has recently been explained by the cancer stem cell (CSC) model. In this study, we investigated the presence of CSCs in established malignant mesothelioma (MM) cell lines and characterized their molecular and metabolic features. Mesothelioma cells successfully formed mesospheres as a model of cancer stem cells. Mesospheres had the capacity to initiate tumours in immunodeficient mice and maintained this capacity through serial transplantation. We identified ...
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    Populations of tumor cells display a remarkable diversity in their phenotypic traits, including their drug resistance and ability to form metastases. This heterogeneity has recently been explained by the cancer stem cell (CSC) model. In this study, we investigated the presence of CSCs in established malignant mesothelioma (MM) cell lines and characterized their molecular and metabolic features. Mesothelioma cells successfully formed mesospheres as a model of cancer stem cells. Mesospheres had the capacity to initiate tumours in immunodeficient mice and maintained this capacity through serial transplantation. We identified CD24, ABCG2 and Oct4 as potential markers of mesothelioma stem cells and showed that CD24 knockdown cells exhibit loss of sphere formation capacity, change of morphology, decrease in the rate of proliferation and lower tumorigenicity. Subjecting mesospheres to serial transplantation resulted in more aggressive tumors, which expressed consistently higher levels of stem cell markers. CSCs have distinct molecular and biological signature, but little is known about their mitochondrial and metabolic features. Our data reveal that like somatic stem cells, MM CSCs exhibit lower levels of normalised oxidative phosphorylation and mtDNA, and use glycolysis as their main source of energy production, thus have increased levels of lactate formation and glucose uptake and lower levels of ATP and mitochondrial proteins. They also feature enhanced mitochondrial membrane potential (ΔΨm) and ROS generation.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Medical Science
    DOI
    https://doi.org/10.25904/1912/352
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Item Access Status
    Public
    Note
    In order to comply with copyright the following figures and tables have not been published here. Figure 1.1, Table 1.1, Figure 1.2, Figure 1.3, Figure 1.4.
    Subject
    Tumor cells
    Cancer stem cell (CSC) model
    Mesothelioma cells
    Mesothelioma Stem Cells
    Publication URI
    http://hdl.handle.net/10072/367990
    Collection
    • Theses - Higher Degree by Research

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