Characterisation of mesothelioma-initiating cells and their susceptibility to anti-cancer agents.
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.
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Elham Alizadeh
EA
Pasdar
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Michael
M
Smits
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Michael
M
Stapelberg
Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Martina
M
Bajzikova
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Marina
M
Stantic
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Jacob
J
Goodwin
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Bing
B
Yan
Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
Jan
J
Stursa
Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Jaromira
J
Kovarova
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Karishma
K
Sachaphibulkij
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Ayenachew
A
Bezawork-Geleta
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Margaryta
M
Sobol
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Anatoly
A
Filimonenko
Department of Molecular and Clinical Sciences, Polytechnic University of Marche, Ancona, Italy.
Marco
M
Tomasetti
School of Medical Science, Griffith University, Southport, Queensland, Australia; Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Renata
R
Zobalova
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Pavel
P
Hozak
School of Medical Science, Griffith University, Southport, Queensland, Australia.
Lan-Feng
LF
Dong
School of Medical Science, Griffith University, Southport, Queensland, Australia; Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Jiri
J
Neuzil
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D024505:Tocopherols / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D024505:Tocopherols