title: Exosome-derived miRNAs and ovarian carcinoma progression.
abstract: The objective of this study was to analyze the expression, biological role and clinical relevance of exosomal microRNAs (miRNAs) from ovarian carcinoma (OC) effusion supernatants. Exosomal miRNA expression profiling was performed using miRNA Taqman arrays. Selected miRNAs were validated using quantitative PCR in 86 OC effusion supernatants. The role of exosomal miRNA in this cancer was further studied using in vitro and in vivo models. miRNA profiling identified 99 miRNAs with high expression levels in exosomes from OC effusion supernatants. Quantitative PCR validation of 11 miRNAs showed significant associations with effusion site (peritoneum versus pleura) and International Federation of Gynecology and Obstetrics stage. In univariate survival analysis, high levels of miRNAs 21, 23b and 29a were associated with poor progression-free survival (P = 0.01, P = 0.015 and P = 0.009, respectively), whereas high expression of miRNA 21 correlated with poor overall survival (P = 0.017). The latter association was retained in Cox multivariate analysis (P = 0.001). Exposure of LP9 mesothelial cells and ES2 OC cells to OC effusion-derived exosomes inhibited tumor spheroid expansion and reduced mesothelial clearance area. Treatment of severe combined immunodeficiency mice with exosomes from OC effusions prior to injection of tumor cells was associated with larger tumor load, more infiltrative tumors and shorter survival. Patient-derived OC effusion exosomes contain multiple miRNAs, of which some may have clinical relevance. In experimental models, OC exosomes affect both tumor cells and cells in the tumor microenvironment and induce more aggressive disease. Collectively, these data demonstrate the central role of miRNAs and their content in the biology of this cancer.
authors.affiliation: Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Vaksman
authors.affiliation: Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Claes
authors.initials: C
authors.lastname: Tropé
authors.affiliation: Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, N-0316 Oslo, Norway, Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway and.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Department of Gynecologic Oncology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway, David R. Bloom Center for Pharmacy and Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics, Hebrew University of Jerusalem, Jerusalem 91120, Israel reich@cc.huji.ac.il.
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009368:Neoplasm Transplantation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000378:metabolism; D016016:Proportional Hazards Models; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: D035683:MicroRNAs