AXL Overexpression in Tumor-Derived Endothelial Cells Promotes Vessel Metastasis in Patients With Hepatocellular Carcinoma

Frontiers in Oncology

Jian-Yang Ao¹  Xiu-Ping Zhang²  Zong-Tao Chai²  Meng-Chao Wu²  Shu-Qun Cheng²  Hui-Chuan Sun³  Xiao-Dong Zhu³  Wan Yee Lau⁴ 

[1] Department of Biliary Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China;Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, China;Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China;

关键词: AXL;    endothelial cells;    vessel metastasis;    portal vein tumor thrombus;    hepatocellular carcinoma;   

DOI  :  10.3389/fonc.2021.650963

来源: DOAJ

【 摘 要 】

Portal vein tumor thrombus (PVTT) is one of the most serious forms of hepatocellular carcinoma (HCC) vessel metastasis and has a poor survival rate. However, the molecular mechanism of PVTT has not yet been elucidated. In this study, the molecular mechanism of AXL expressed in tumor-derived endothelial cells (TECs) in vessel metastasis was investigated. High AXL expression was observed in TECs, but not in the tumor cells of HCC patients with PVTT and this was associated with poor overall survival (OS) and disease-free survival (DFS). AXL overexpression was positively associated with CD 31 expression both in vitro and in vivo. AXL promoted the cell proliferation, tube formation, and migration of both TECs and normal endothelial cells (NECs). High expression of AXL in TECs promoted the cell migration, but not the proliferation of HCC cells. Further studies demonstrated that AXL promoted cell migration and tube formation through activation of the PI3K/AKT/SOX2/DKK-1 axis. AXL overexpression in HUVECs promoted tumor growth and liver or vessel metastasis of HCC in xenograft nude mice, which could be counteracted by treatment with R428, an AXL inhibitor. R428 reduced tumor growth and CD 31 expression in HCC in PDX xenograft nude mice. Therefore, AXL over-expression in TECs promotes vessel metastasis of HCC, which indicates that AXL in TECs could be a potential therapeutic target in HCC patients with PVTT.

【 授权许可】

Unknown