Alteration of Circulating Extracellular Vesicle Protein Contents Is a Fingerprint of Chemotherapy-Induced Tissue Damage

Extracellular vesicles (EVs) including exosomes, microvesicles and apoptotic bodies are released from most cell types; especially under cellular stress conditions, including oxidative stress. The high abundance of EVs in biological fluids and their unique stability make them a potential biomarker for many diseases. It is well recognized that in addition to ionizing radiation, nearly 50% of current FDA approved chemotherapeutic drugs cause reactive oxygen species (ROS) in target tissues. However, the molecular cargo contained within EVs that are released from chemotherapy-treated cells, as well as their contribution to tissue injury are unknown. Here we report that EV contents mirror pathological conditions of the tissues affected by chemotherapy. In mice, systemic injection of doxorubicin (DOX), a potent and known ROS generator chemotherapeutic agent used for aggressive cancer, caused approximately two-fold increase in circulating EVs (DOX_EVs) compared to the saline treated controls (SAL_EVs). In mouse (n=4) and human serum (n=24), EVs exhibits a significantly higher level of 4-hydroxynonenal adducted proteins post chemotherapy (P