Abstract
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.
Highlights
Malignant mesothelioma (MM), the primary tumour of the pleura, is highly aggressive, with very little if any therapeutic options
We report on the existence of tumour-initiating cells (TICs) in mesothelioma by characterising spheres derived from different mesothelioma cell lines as a previously established model for culturing stem cells and TICs [16,17,18]
To verify that MM cells comprise a sub-population with distinctive self-renewal capacity, established MM cell lines including Ist-Mes-2, Meso-2 and MM-BI cells, as well as murine AE17 MM cells were cultured under conditions established for enriching cell populations in TICs
Summary
Malignant mesothelioma (MM), the primary tumour of the pleura, is highly aggressive, with very little if any therapeutic options. Being diagnosed 20 to 40 years after exposure to asbestos, the main carcinogen of MM, this neoplastic disease is very aggressive and the mortality rate is exceedingly high with a few months survival after diagnosis [1, 2], the relapse of the tumour occurring shortly after the initiation of treatment [3]. Despite the current ban of PLOS ONE | DOI:10.1371/journal.pone.0119549. Douglas Francis Green PhD Scholarship provided by the Queensland Asbestos-Related Disease Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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