Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents

• Published in: PloS one 2015-05, Vol.10 (5), p.e0119549
• Main Authors: Pasdar, Elham Alizadeh, Smits, Michael, Stapelberg, Michael, Bajzikova, Martina, Stantic, Marina, Goodwin, Jacob, Yan, Bing, Stursa, Jan, Kovarova, Jaromira, Sachaphibulkij, Karishma, Bezawork-Geleta, Ayenachew, Sobol, Margaryta, Filimonenko, Anatoly, Tomasetti, Marco, Zobalova, Renata, Hozak, Pavel, Dong, Lan-Feng, Neuzil, Jiri
• Format: Article
• Language: English
• Subjects: Adherent cells; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Asbestos; Biomarkers; Biomarkers, Tumor - metabolism; Biotechnology; Cancer; CD24 Antigen - metabolism; Cell Adhesion - drug effects; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; Drug resistance; Gene Knockdown Techniques; Genetics; Humans; Immunodeficiency; Inhibitory Concentration 50; Laboratory animals; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mesothelioma; Mesothelioma - metabolism; Mesothelioma - pathology; Mesothelioma, Malignant; Metabolism; Mice, Nude; Microscopy; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oct-4 protein; Phenotype; Science; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Stem cell transplantation; Stem cells; Tocopherol; Tocopherols - pharmacology; Transplantation; Tumorigenicity; Tumors; Vitamin E
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119549

Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM.