EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway.

Yi Wang,Qiandong Zhu,Hongqi Shi,Yunfeng Shan,Fang Wu,Zhengping Yu,Fuxiang Yu,Jianfei Huang,Gang Chen,Chonglin Tao,Qitong Song,Junjian Li,Pengyi Guo,Mengtao Zhou,Haitao Yu

doi:10.1186/s13046-016-0339-6

Abstract

BackgroundEndothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); thus, they are associated with a poor prognosis. However, the specific molecular mechanism underlying the homing of EPCs to the HCC neovasculature remains unrevealed.MethodsCo-culture experiments of endothelial progenitor cells with HCC cells with modulation of EphA1 were performed in vitro. Using EPCs as angiogenic promoters by injecting them into HCC xenograft-bearing nude mice via their tail veins to test homing ability of EPCs changed according to different EphA1 level in HCC xenograft.ResultsIn this study, we found that the up-regulation of EphA1 expression in HCC cells could affect not only the chemotaxis of EPCs to tumor cells and endothelial cells (ECs) but also the tube formation ability of EPCs in a paracrine fashion. Further, we revealed that the increased expression of EphA1 in HCC cells led to an increased SDF-1 concentration in the tumor microenvironment, which in turn activated the SDF-1/CXCR4 axis and enhanced the recruitment of EPCs to HCC. In addition, the EphA1-activated SDF-1 expression and secretion was partially mediated by the PI3K and mTOR pathways. In vivo experiments demonstrated that blocking EphA1/SDF-1/CXCR4 signaling significantly inhibited the growth of HCC xenografts. Using immunohistochemistry and immunofluorescence assays, we verified that the inhibition of tumor angiogenesis was at least partially caused by the decreased number of EPCs homing to tumor tissue.ConclusionsOur findings indicate that targeting the EphA1/SDF-1 signaling pathway might be a therapeutic anti-angiogenesis approach for treating HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0339-6) contains supplementary material, which is available to authorized users.

Highlights

Endothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); they are associated with a poor prognosis
Our findings indicate that targeting the EphA1/SDF-1 signaling pathway might provide a therapeutic anti-angiogenesis approach to HCC
The results demonstrated that the enhanced EphA1 expression in EphA1-negative HLE cells resulting from ephrinA1-Fc recombinant protein increased the chemotaxis of EPCs to HLE cells, while the decreased EphA1 expression resulting from EphA1 siRNA transfection in EphA1-positive Huh7 cells had the opposite effect (Fig. 1b)

Summary

Introduction

Endothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); they are associated with a poor prognosis. The specific molecular mechanism underlying the homing of EPCs to the HCC neovasculature remains unrevealed. Hepatocellular carcinoma (HCC) is the most common primary liver tumor; it is the second leading cause of cancer-related death worldwide, and its incidence is increasing yearly [1]. There is an urgent need to develop novel therapeutic approaches for advanced HCC. Drugs targeting angiogenic pathways, such as sorafenib, have been proven to have specific antitumor effects [2]. The development of anti-angiogenic strategies that are more effective for treating HCC remains a challenging task

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