Abstract
Even if ovarian cancer patients are very responsive to a cisplatinum-based therapy, most will relapse with a resistant disease. New experimental animal models are needed to explore the mechanisms of resistance, to better tailor treatment and improve patient prognosis. To address these aims, seven patient-derived high-grade serous/endometrioid ovarian cancer xenografts were characterized for the antitumor response after one and two cycles of cisplatinum and classified as Very Responsive, Responsive, and Low Responsive to drug treatment. Xenografts re-growing after the first drug cycle were much less responsive to the second one. The expression of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) genes was investigated in cisplatinum-treated and not-treated tumors. We found that different EMT (TCF3, CAMK2N1, EGFR, and IGFBP4) and CSCs (SMO, DLL1, STAT3, and ITGA6) genes were expressed at higher levels in Low Responsive than in Responsive and Very Responsive xenografts. The expression of STAT3 was found to be associated with lower survival (HR = 13.7; p = 0.013) in the TCGA patient data set. MMP9, CD44, DLL4, FOXP1, MERTK, and PTPRC genes were found more expressed in tumors re-growing after cisplatinum treatment than in untreated tumors. We here describe a new in vivo ovarian carcinoma experimental setting that will be instrumental for specific trials of combination therapy to counteract cisplatinum resistance in order to improve the prognosis of ovarian patients.
Highlights
Epithelial ovarian cancer (EOC) is a serious medical problem, with more than 100,000 women dying per year in western countries [1]
Epithelial ovarian cancer is highly responsive to a DDP-based front-line therapy, but in most cases patients relapse with a resistant disease
This work describes a new experimental in vivo setting of high grade serous/endometrioid ovarian patientderived xenografts (PDXs) to study the molecular determinants of platinum sensitivity and the development of its resistance
Summary
Epithelial ovarian cancer (EOC) is a serious medical problem, with more than 100,000 women dying per year in western countries [1]. Tumors are clinically classified as responsive or not to a platinum (DDP)-based therapy depending on the time to relapse from the end of adjuvant therapy They are classified as refractory if progressing during treatment, www.impactjournals.com/oncotarget resistant if relapsing within twelve months, and sensitive if relapsing after twelve months [2]. The molecular mechanisms of resistance to a DDP-based therapy are multifactorial, and include mechanisms interfering with drug transport, with the repair of the DDPinduced DNA damage, with DDP-induced signalling to the apoptotic machinery, up- and down-regulated expression of miRNAs, and others [3] Both the activation of the epithelial-mesenchymal transition (EMT) pathway and the existence of cancer stem cells (CSCs) have been advocated as possible mechanisms of relapse in different tumor types, including ovarian carcinomas [4,5]. More appropriate in vivo models are needed to recapitulate the primary and secondary/ acquired DDP resistance in ovarian cancer patients
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