Abstract 3052: Ovarian carcinoma derived exosomes: miRNA signatures and role in cancer progression .

Abstract

Abstract Ovarian cancer (OC) is the leading cause of death from gynecological cancer in Western countries. The disease is asymptomatic in the early stages, and is usually diagnosed at an advance stage, leading to an extremely poor prognosis. Primary solid tumor, solid metastases, and effusions to the peritoneal and pleural cavities characterize the tumor as it progresses. MicroRNAs (miRNAs, miRs) are small, non-coding RNAs. They regulate gene expression by binding to the 3′UTR of a target mRNA, and decrease protein levels by inhibition of protein translation. In the recent years, miRNAs were found to play an important role in cancer, both as oncogenes and as tumor suppressor genes, depending on the target mRNA and the type of cancer. In addition to cells, miRNAs are present in body fluids in exosomes, 30-90 nm vesicles secreted by cells. Exosomes contain proteins, mRNA and miRNA. Exosomal RNA content can be shuttled from one cell to another, affecting the recipient cell. It has been implicated that an "exosomal messenger system" exhibits paracrine bioactivities that facilitate tumor communication within the local tumor microenvironment. We compared the expression of miRNAs present in effusion fluid-derived exosomes from 50 pre-chemo and 50 post-chemo patients of which 37 were chemo-resistant and 31chemo-sensitive, respectively. The patient cohort was in addition divided into 28 long and 72 short survivors, respectively. TaqMan miRNA arrays were used to identify miRNA profiles, and the qPCR miScript system for validation of the obtained results. Web-based algorithms were used for further bioinformatics analysis. We identified differentially expressed miRNAs in OC effusion-derived exosomes compared to exosomal miRNAs from sera, malignant mesothelioma effusions and reactive effusions. Fifty-seven miRNAs were differentially expressed in specimens from patients with long vs. short survival and 62 differentially expressed miRNAs in specimens obtained before vs. after chemotherapy treatment. We tested the effects of effusion derived exosomes on cell behavior in-vitro and on tumor spread in-vivo. Our results show that exosomes affect the interaction between cancer cells and their microenvironment. Pre-injection of exosomes to female SCID mice, followed by injection of cancer cells, caused shorter life span and larger tumor burden, compared to mice not pre-treated with exosomes. OC effusion derived exosomes might have autocrine and/or paracrine effects on cells, thus enhancing the oncogenic potential of cancer cells, or sensitizing the body to malignant dissemination. This is the first study to evaluate the differential expression of miRNAs in exosomes derived from OC ascites fluid. We believe that the differential expression and the distinct signatures of miRNAs possess diagnostic, prognostic and therapeutic potential. Citation Format: Olga Vaksman (Goreshnik), Ben Davidson, Claes G. Trope’, Reuven Reich. Ovarian carcinoma derived exosomes: miRNA signatures and role in cancer progression . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3052. doi:10.1158/1538-7445.AM2013-3052