Exosomes confer pro-survival signals to alter the phenotype of prostate cells in their surrounding environment

// Elham Hosseini-Beheshti 1, 3 , Wendy Choi 3 , Louis-Bastien Weiswald 4 , Geetanjali Kharmate 3 , Mazyar Ghaffari 1, 3 , Mani Roshan-Moniri 1, 3 , Mohamed D. Hassona 3 , Leslie Chan 3 , Mei Yieng Chin 3 , Isabella T. Tai 4 , Paul S. Rennie 2, 3 , Ladan Fazli 2, 3 , Emma S. Tomlinson Guns 2, 3 1 Department of Experimental Medicine University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada 2 Department of Urologic Sciences University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada 3 The Vancouver Prostate Centre University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada 4 Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada Correspondence to: Emma S. Tomlinson Guns, e-mail: eguns@prostatecentre.com Keywords: exosomes, cancer development, cancer progression Received: June 17, 2015      Accepted: December 22, 2015      Published: January 28, 2016 ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Current research on tumour-related extracellular vesicles (EVs) suggests that exosomes play a significant role in paracrine signaling pathways, thus potentially influencing cancer progression via multiple mechanisms. In fact, during the last decade numerous studies have revealed the role of EVs in the progression of various pathological conditions including cancer. Moreover, differences in the proteomic, lipidomic, and cholesterol content of exosomes derived from PCa cell lines versus benign prostate cell lines confirm that exosomes could be excellent biomarker candidates. As such, as part of an extensive proteomic analysis using LCMS we previously described a potential role of exosomes as biomarkers for PCa. Current evidence suggests that uptake of EV’s into the local tumour microenvironment encouraging us to further examine the role of these vesicles in distinct mechanisms involved in the progression of PCa and castration resistant PCa. For the purpose of this study, we hypothesized that exosomes play a pivotal role in cell-cell communication in the local tumour microenvironment, conferring activation of numerous survival mechanisms during PCa progression and development of therapeutic resistance. Our in vitro results demonstrate that PCa derived exosomes significantly reduce apoptosis, increase cancer cell proliferation and induce cell migration in LNCaP and RWPE-1 cells. In conjunction with our in vitro findings, we have also demonstrated that exosomes increased tumor volume and serum PSA levels in vivo when xenograft bearing mice were administered DU145 cell derived exosomes intravenously. This research suggests that, regardless of androgen receptor phenotype, exosomes derived from PCa cells significantly enhance multiple mechanisms that contribute to PCa progression.

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