Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness.

Aldehyde dehydrogenase Cancer stem cells Cisplatin Yolk sac tumor

Journal

Cancer cell international
ISSN: 1475-2867
Titre abrégé: Cancer Cell Int
Pays: England
ID NLM: 101139795

Informations de publication

Date de publication:
2020
Historique:
received: 05 05 2020
accepted: 25 07 2020
entrez: 11 8 2020
pubmed: 11 8 2020
medline: 11 8 2020
Statut: epublish

Résumé

Cisplatin resistance of ovarian yolk sac tumors (oYST) is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare. We investigated potential association between cisplatin resistance and cancer stem cell (CSC) markers in chemoresistant oYST cells and targeting strategies to overcome resistance in oYST. Chemoresistant cells were derived from chemosensitive human oYST cells by cultivation in cisplatin in vitro. Derivative cells were characterized by chemoresistance, functional assays, flow cytometry, gene expression and protein arrays focused on CSC markers. RNAseq, methylation and microRNA profiling were performed. Quail chorioallantoic membranes (CAM) with implanted oYST cells were used to analyze the micro-tumor extent and interconnection with the CAM. Tumorigenicity in vivo was determined on immunodeficient mouse model. Chemoresistant cells were treated by inhibitors intefering with the CSC properties to examine the chemosensitization to cisplatin. Long-term cisplatin exposure resulted in seven-fold higher IC The novel chemoresistant cells represent unique model of refractory oYST. CSC markers are associated with cisplatin resistance being possible targets in chemorefractory oYST.

Sections du résumé

BACKGROUND BACKGROUND
Cisplatin resistance of ovarian yolk sac tumors (oYST) is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare. We investigated potential association between cisplatin resistance and cancer stem cell (CSC) markers in chemoresistant oYST cells and targeting strategies to overcome resistance in oYST.
METHODS METHODS
Chemoresistant cells were derived from chemosensitive human oYST cells by cultivation in cisplatin in vitro. Derivative cells were characterized by chemoresistance, functional assays, flow cytometry, gene expression and protein arrays focused on CSC markers. RNAseq, methylation and microRNA profiling were performed. Quail chorioallantoic membranes (CAM) with implanted oYST cells were used to analyze the micro-tumor extent and interconnection with the CAM. Tumorigenicity in vivo was determined on immunodeficient mouse model. Chemoresistant cells were treated by inhibitors intefering with the CSC properties to examine the chemosensitization to cisplatin.
RESULTS RESULTS
Long-term cisplatin exposure resulted in seven-fold higher IC
CONCLUSIONS CONCLUSIONS
The novel chemoresistant cells represent unique model of refractory oYST. CSC markers are associated with cisplatin resistance being possible targets in chemorefractory oYST.

Identifiants

DOI: 10.1186/s12935-020-01458-7 PMID: 32774158 PMC: PMC7397611
pubmed: 32774158
doi: 10.1186/s12935-020-01458-7
pii: 1458
pmc: PMC7397611
doi:

Types de publication

Journal Article

Langues

eng

Pagination

364

Informations de copyright

© The Author(s) 2020.

Déclaration de conflit d'intérêts

Competing interestsAll authors read and approved the final manuscript, and declare that they have no competing interest. A patent application has been filed covering the finding of using the presence of 3p amplification as a molecular marker to predict cisplatin resistance in germ cell tumors, and the possibility of alternative treatment options.

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Auteurs

Silvia Schmidtova (S)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
Translational Research Unit, Faculty of Medicine, Comenius University, Klenova 1, 833 10 Bratislava, Slovakia.
ORCID: 0000-0003-4537-2062

Lambert C J Dorssers (LCJ)

Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.

Katarina Kalavska (K)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
Translational Research Unit, Faculty of Medicine, Comenius University, Klenova 1, 833 10 Bratislava, Slovakia.
2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia.

Ad J M Gillis (AJM)

Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.

J Wolter Oosterhuis (JW)

Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.

Hans Stoop (H)

Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.

Svetlana Miklikova (S)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Zuzana Kozovska (Z)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Monika Burikova (M)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Katarina Gercakova (K)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Erika Durinikova (E)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Michal Chovanec (M)

Translational Research Unit, Faculty of Medicine, Comenius University, Klenova 1, 833 10 Bratislava, Slovakia.
2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia.

Michal Mego (M)

Translational Research Unit, Faculty of Medicine, Comenius University, Klenova 1, 833 10 Bratislava, Slovakia.
2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia.

Lucia Kucerova (L)

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Leendert H J Looijenga (LHJ)

Department of Pathology, Laboratory for Experimental Patho-Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.

Classifications MeSH