Pharmacokinetic Approach for the Elucidation of Elevated Plasma Small Extracellular Vesicle (sEV) Concentration in Cancer.

The abundance of circulating plasma small extracellular vesicles (sEVs) has been reported to be elevated in cancer; however, the underlying mechanism remains unclear. In this study, a pharmacokinetic approach was used to determine the factors contributing to elevated plasma sEV levels during cancer in a tumor-bearing mouse model. Mouse plasma-derived sEVs (MP-sEVs) isolated from tumor-bearing mice showed increased protein concentrations and physicochemical characteristics comparable to MP-sEVs isolated from healthy mice. The steady-state concentration of sEVs is determined by the balance between the MP-sEV production and clearance. Thus, to determine whether tumorigenesis influences sEV clearance, isolated MP-sEVs were intravenously administered to either tumor-bearing or healthy mice. The results showed minimal differences in sEV clearance rates, suggesting that sEV production is the driving force of elevated MP-sEV concentrations. Lastly, CD63-gLuc stably expressing B16BL6-bearing mice were used to estimate the contribution of tumor cell-derived sEVs in the plasma. The gLuc activity of the MP-sEVs isolated was below the limit of detection, and it was estimated that the tumor cell-derived sEVs comprised at most 0.5% of the total MP-sEVs. Taken together, these results suggest that cells other than tumor cells contribute to elevated plasma sEV levels in cancer.