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

Zong-Tao Chai,Meng-Chao Wu,Hui-Chuan Sun,Xiu-Ping Zhang,Xiao-Dong Zhu,Shu-Qun Cheng,Jian-Yang Ao,Wan Yee Lau

doi:10.3389/fonc.2021.650963

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC), the most frequent type of pathological liver cancer, often extends into the portal vein branches
In clear cell renal cell carcinoma, AXL expression is proved to be positively related with anti-angiogenic drug resistance and poor survival
Further study demonstrated that GAS6/AXL signaling activated S100A10 expression through

Summary

Introduction

Hepatocellular carcinoma (HCC), the most frequent type of pathological liver cancer, often extends into the portal vein branches. The incidence of portal vein tumor thrombus (PVTT) has been reported to be 44% to 62.2% in patients with HCC [1,2,3]. The current treatment for HCC patients with PVTT remains controversial. HCC patients with PVTT limited to a first-order branch of the MVP or above [1, 4,5,6,7]. The Barcelona Clinic for Liver Cancer Staging System and Treatment Guidelines consider that HCC patients with PVTT have a low chance of a cure [8], and sorafenib is the only recommended therapeutic option [9, 10]. The median survival time of HCC patients with PVTT ranges from 2.7 to 4.0 months, if left untreated [2, 13]. The underlying molecular mechanisms of PVTT of HCC remain largely unknown

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Conclusion