Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer

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// Nicolas Bovy 1 , Benoît Blomme 1 , Pierre Frères 2 , Stella Dederen 1 , Olivier Nivelles 1 , Michelle Lion 1 , Oriane Carnet 3 , Joseph A. Martial 1 , Agnès Noël 3 , Marc Thiry 4 , Guy Jérusalem 5 , Claire Josse 2 , Vincent Bours 2 , Sébastien P. Tabruyn 1 and Ingrid Struman 1 1 Laboratory of Molecular Angiogenesis, GIGA-R, University of Liège, Belgium 2 Laboratory of Human Genetics, GIGA-R, University of Liège, Belgium 3 Laboratory of Tumor & Development Biology, GIGA-R, University of Liège, Belgium 4 Laboratory of Cell and Tissues Biology, University of Liège, Belgium 5 Department of Medical Oncology, CHU, Liège, Belgium Correspondence to: Ingrid Struman, email: // Keywords : Exosomes, microRNAs, Cancer, miR-503, Angiogenesis Received : January 30, 2015 Accepted : February 17, 2015 Published : March 10, 2015 Abstract The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression. They are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo. Consequently, we hypothesized that circulating endothelial miRNAs could be transferred to tumor cells and modify their phenotype. Using exogenous miRNA, we demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes. Using miRNA profiling, we identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions. The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities. We then identified two targets of miR-503, CCND2 and CCND3. Moreover, we measured increased plasmatic miR-503 in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells. Taken together, our data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment.

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