ABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0119549.].
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.
Subject(s)
Antineoplastic Agents/pharmacology , Lung Neoplasms/pathology , Mesothelioma/pathology , Neoplastic Stem Cells/pathology , Animals , Biomarkers, Tumor/metabolism , CD24 Antigen/metabolism , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Progression , Gene Knockdown Techniques , Humans , Inhibitory Concentration 50 , Lung Neoplasms/metabolism , Mesothelioma/metabolism , Mesothelioma, Malignant , Mice, Nude , Mitochondria/drug effects , Mitochondria/metabolism , Neoplasm Invasiveness , Neoplasm Transplantation , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Phenotype , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Tocopherols/pharmacologyABSTRACT
Tumor-initiating cells (TICs) often survive therapy and give rise to second-line tumors. We tested the plausibility of sphere cultures as models of TICs. Microarray data and microRNA data analysis confirmed the validity of spheres as models of TICs for breast and prostate cancer as well as mesothelioma cell lines. Microarray data analysis revealed the Trp pathway as the only pathway upregulated significantly in all types of studied TICs, with increased levels of indoleamine-2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme of Trp metabolism along the kynurenine pathway. All types of TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. IDO1 expression was regulated via both transcriptional and posttranscriptional mechanisms, depending on the cancer type. Serial transplantation of TICs in mice resulted in gradually increased IDO1. Mitocans, represented by α-tocopheryl succinate and mitochondrially targeted vitamin E succinate (MitoVES), suppressed IDO1 in TICs. MitoVES suppressed IDO1 in TICs with functional mitochondrial complex II, involving transcriptional and posttranscriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work indicates that IDO1 is increased in TICs and that mitocans suppress the protein.
