Abstract
BackgroundCisplatin 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.MethodsChemoresistant 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.ResultsLong-term cisplatin exposure resulted in seven-fold higher IC50 value in resistant cells, cross-resistance to oxaliplatin and carboplatin, and increased migratory capacity, invasiveness and tumorigenicity, associated with hypomethylation of differentially methylated genes/promotors. Resistant cells exhibited increased expression of prominin-1 (CD133), ATP binding cassette subfamily G member 2 (ABCG2), aldehyde dehydrogenase 3 isoform A1 (ALDH3A1), correlating with reduced gene and promoter methylation, as well as increased expression of ALDH1A3 and higher overall ALDH enzymatic activity, rendering them cross-resistant to DEAB, disulfiram and napabucasin. Salinomycin and tunicamycin were significantly more toxic to resistant cells. Pretreatment with napabucasin resensitized the cells to cisplatin and reduced their tumorigenicity in vivo.ConclusionsThe novel chemoresistant cells represent unique model of refractory oYST. CSC markers are associated with cisplatin resistance being possible targets in chemorefractory oYST.
Highlights
Cisplatin resistance of ovarian yolk sac tumors is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare
The present study extensively examines a newly derived cisplatin-resistant ovarian yolk sac tumors (oYST) cell line (NOY-1 CisR), including sensitivity to various platinum derivates, migratory abilities, gene expression
Cross-resistance to satraplatin and oxaliplatin was described previously and occurred in cisplatin-resistant testicular germ cell tumors (TGCTs) cell lines resulting in therapeutic failure in overcoming the resistance [42]
Summary
Cisplatin resistance of ovarian yolk sac tumors (oYST) is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare. Yolk sac tumor (YST), known as endodermal sinus tumor, is the second most prevalent histologic subtype of MOGCTs [4], showing a poorer prognosis [5]. Schmidtova et al Cancer Cell Int (2020) 20:364 alpha-fetoprotein (AFP) is a useful marker for YST, informative for monitoring response to chemotherapy and tumor recurrence [6, 7]. Treatment modalities for MOGCTs are based on those for testicular germ cell tumors (TGCTs) [8, 9], including surgery, possibly followed by platinum-based chemotherapy [10,11,12,13]. If occurring within 4–6 weeks of therapy, the cancers are considered platinum-resistant, with an extremely poor prognosis, of which data regarding further treatment is lacking [3]
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