title: Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy.
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.
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Department of Biochemistry, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Guffanti
authors.affiliation: Department of Oncology, Laboratory of Methodology for Biomedical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Porcu
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Spriano
authors.affiliation: Obstetrics and Gynecology Clinic, San Gerardo Hospital, Monza, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Dell'Anna
authors.affiliation: Obstetrics and Gynecology Clinic, San Gerardo Hospital, Monza, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Fruscio
authors.affiliation: Department of Oncology, Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: cancer stem cells; cisplatinum resistance; epithelial-mesenchymal transition; ovarian carcinoma; patient-derived xenografts