Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor‐derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV–vWF levels are found in a larger cohort of HCC–sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late‐stage HCC patients markedly augment angiogenesis, tumor–endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti‐vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF‐overexpressing cells. sEV–vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF‐A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co‐administration of anti‐vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient‐derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor‐derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor–endothelial intercellular communication.