Abstract
Abstract The purpose of this study is to elucidate the mechanism of exosome secretion in Ovarian Cancer (OC). OC is the leading cause of death from gynecological cancers in western countries. Exosomes, 30-100 nm vesicles, contain various lipids, proteins, and nucleic acids, exhibit paracrine bioactivities as well as distant transfer of regulatory messages to other cells. In our lab, the presence of OC derived exosomes accelerated cancerous pathologies in mice, thus determining OC derived exosomes as having a pro cancerous effect and therefore a worthy target for OC therapy. The precise mechanism of the biogenesis and release of exosomes has yet to be elucidated; however, several studies have revealed the involvement of nSmase2, Tsap6 and Rab27a/b genes in these processes. OC is characterized by primary solid tumors, solid metastases, and effusions to the peritoneal and pleural cavities as the tumor progresses. In order to develop a relevant model for solid tumors and effusions in vitro we utilized 3D Macro-porous alginate scaffolds and 3D OVCAR 8 cell line spheroids respectively. In the present study, we examined the expression of the above mentioned genes at the mRNA and protein levels in human ovarian cancer samples derived from primary, metastatic lesions and from effusion derived OC cells and compared the expression profile to that of cell lines utilizing in our 3D in vitro model. Our results show that in OC samples, nSMmase2, Tsap6 and Rab27a mRNA expression are significantly higher in effusions vs solid tumors (p<0.026, p<0.0001 and p<0.02, respectively). Surprisingly, the protein content of these genes are significantly lower in effusions vs. the solid samples in these very same samples (p<0.001-0.0001). This discrepancy is explained by the presence of nSMmase2, Tsap6 and Rab27a proteins in effusion fluid-derived exosomes. Clinical analysis shows that elevated nSmase2 and Tsap6 mRNA expression correlates with poor survival (p<0.036) and less favorable response to chemotherapy, respectively (p<0.027). Furthermore, Rab27a protein is lower in pleural effusions compared to peritoneal effusions (p<0.013). In our in vitro model, mRNA analysis of OVCAR8 cells grown on alginate scaffold and spheroids show a higher expression of Tsap6 and Rab27a in spheroid cultures vs. scaffold cultures, corresponding with higher expression of these same genes in effusions vs. solid tumors in OC. To the best of our knowledge, this is the first study to attempt to develop a 3D in vitro model for the various forms of OC that will enable research on the exosome secretion mechanism in this disease, hopefully leading to a fuller understanding of the exosomes secretion process and to the development novel therapies to address this disease. Citation Format: Esther C. Broner, Tali Tavor Re'em, Claes Tropé, Ben Davidson, Reuven Reich. Exosome secretion in ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3197. doi:10.1158/1538-7445.AM2015-3197
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