Exosomes impact survival to radiation exposure in cell line models of nervous system cancer

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// Oliver D. Mrowczynski 1 , Achuthamangalam B. Madhankumar 1 , Jeffrey M. Sundstrom 2 , Yuanjun Zhao 2 , Yuka Imamura Kawasawa 3 , Becky Slagle-Webb 1 , Christine Mau 1 , Russell A. Payne 1 , Elias B. Rizk 1 , Brad E. Zacharia 1 and James R. Connor 1 1 Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA 2 Department of Ophthalmology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA 3 Department of Pharmacology, Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA Correspondence to: Oliver D. Mrowczynski, email: omrowczynski@pennstatehealth.psu.edu Keywords: exosomes; radiation; resistance; glioma; glioblastoma Received: October 05, 2017 Accepted: October 21, 2018 Published: November 16, 2018 ABSTRACT Radiation is utilized in the therapy of more than 50% of cancer patients. Unfortunately, many malignancies become resistant to radiation over time. We investigated the hypothesis that one method of a cancer cell’s ability to survive radiation occurs through cellular communication via exosomes. Exosomes are cell-derived vesicles containing DNA, RNA, and protein. Three properties were analyzed: 1) exosome function, 2) exosome profile and 3) exosome uptake/blockade. To analyze exosome function, we show radiation-derived exosomes increased proliferation and enabled recipient cancer cells to survive radiation in vitro . Furthermore, radiation-derived exosomes increased tumor burden and decreased survival in an in vivo model. To address the mechanism underlying the alterations by exosomes in recipient cells, we obtained a profile of radiation-derived exosomes that showed expression changes favoring a resistant/proliferative profile. Radiation-derived exosomes contain elevated oncogenic miR-889, oncogenic mRNAs, and proteins of the proteasome pathway, Notch, Jak-STAT, and cell cycle pathways. Radiation-derived exosomes contain decreased levels of tumor-suppressive miR-516, miR-365, and multiple tumor-suppressive mRNAs. Ingenuity pathway analysis revealed the most represented networks included cell cycle, growth/survival. Upregulation of DNM2 correlated with increased exosome uptake. To analyze the property of exosome blockade, heparin and simvastatin were used to inhibit uptake of exosomes in recipient cells resulting in inhibited induction of proliferation and cellular survival. Because these agents have shown some success as cancer therapies, our data suggest their mechanism of action could be limiting exosome communication between cells. The results of our study identify a novel exosome-based mechanism that may underlie a cancer cell’s ability to survive radiation.

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