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Venous thromboembolism (VTE) is the second-leading cause of cancer-associated mortality. Neutrophil extracellular trap formation (i.e., NETosis) is a crucial process in forming VTE in cancer patients. Nevertheless, how cancer cells contribute to NETosis remains unclear. This study investigated the potential activation effects of cancer cell-derived extracellular vesicles (CC-EVs) on neutrophils. Both small and large EVs (sEVs and lEVs) released from cancer cells are found to significantly induce NETosis in neutrophil-like HL-60 (dHL-60) cells. Following an in-depth exploration of EV-induced NETosis, the specific molecular pathways involved in this biological process are elucidated. CYBA enriched in CC-lEVs is delivered to dHL-60, leading to a rapid increase in intracellular ROS levels and upregulation of citH3 expression. This cascade resulted in decondensed chromatin release and subsequent NETosis along with elevated MPO-DNA levels. Injection of CC-lEVs into mice caused more pronounced VTE, which is accompanied by increased peripheral blood levels of the MPO-DNA and thrombin-antithrombin complex. Inhibiting CYBA expression or ROS generation prevented NETosis in vitro and significantly reduced VTE in vivo. In conclusion, CC-lEVs induce NETosis through the CYBA-ROS-citH3 pathway and increase VTE risk. Targeting CYBA expression or ROS production can provide novel strategies for preventing and treating VTE in high-risk cancer patients.
Li et al. (Mon,) studied this question.