细胞外小囊泡（sEVs）在肿瘤微环境中细胞间载体交换中发挥关键作用。本研究旨在阐明肝细胞癌（HCC）源sEV-clathrin light chain A（CLTA）在重塑微血管环境中的功能和机制。使用酶联免疫吸附试验（ELISA）分析HCC患者循环sEV中的CLTA水平。通过多种功能性分析检查sEV-CLTA对HCC癌性特性的影响。使用质谱法确定sEV-CLTA在人脐静脉内皮细胞（HUVECs）中的下游效应蛋白。进行管形成、萌发、透过内皮侵袭和血管渗漏实验，以确定sEV-CLTA及其下游效应蛋白basigin（BSG）在HUVECs中的功能。在患者源移植瘤（PDXs）小鼠模型中测试BSG抑制剂SP-8356。与对照个体相比，HCC患者的循环sEV中CLTA水平显著增加，并且在手术后患者中减少。HCC源sEV-CLTA增强HCC的癌性特性，破坏内皮完整性并诱导血管新生。机制上，CLTA通过稳定和上调BSG来重塑微血管环境。最后，SP-8356单独或与索拉非尼联合可减弱PDXs的生长。该研究揭示了HCC源sEV-CLTA在微血管环境形成中的作用。抑制CLTA及其介导的途径可能为HCC患者阐明新的治疗策略。© 2023年作者。由代表国际细胞外囊泡学会的Wiley Periodicals, LLC发表《细胞外小囊泡杂志》。

Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV-clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme-linked immunosorbent assay (ELISA). The functions of sEV-CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV-CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans-endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV-CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP-8356, was tested in a mouse model of patient-derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV-CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP-8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV-CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.