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

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.

Proangiogenic effects of tumor cells on endothelial progenitor cells vary with tumor type in an in vitro and in vivo rat model

“…EPCs can contribute to tumor progression by providing structural support for vascularization and secretion of angiogenic factors to induce an angiogenic switch (17)(18)(19). Because the cross-talk between tumor cells and EPCs might be bidirectional and varies according to the differentiated degree and grade of tumors among different tumors, the question arises whether the tumor microenvironment can participate in and facilitate EPC motility depending on the tumor type.…”

Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma

“…Ephrin A1 may activate CXCL12/CXCR4 in HCC (20). The high expression of EphA1 in HCC cells may lead to a high CXCL12 concentration within the tumor microenvironment, which can then activate CXCL12/CXCR4 signaling and enhance the recruitment of endothelial progenitor cells (EPCs) to HCC.…”

“…The high expression of EphA1 in HCC cells may lead to a high CXCL12 concentration within the tumor microenvironment, which can then activate CXCL12/CXCR4 signaling and enhance the recruitment of endothelial progenitor cells (EPCs) to HCC. Wang et al (20) demonstrated that the upregulation of EphA1 expression in HCC cells promoted the chemotaxis of EPCs towards tumor cells and the tube formation of EPCs.…”

“…In vivo experiments that blocked ephA1/CXCL12/CXCR4 signaling significantly reduced the growth of HCC xenografts (20). EphA1 increased CXCL12 expression in HCC cells via the phosphoinositide-3 kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR) pathways (21).…”

Roles of EphA1/A2 and ephrin‐A1 in cancer

“…Furthermore, ephrin‐A1‐induced EphA1 activation promoted SDF‐1 secretion and chemotaxis of endothelial progenitor cells to HCC through the SDF‐1/CXCR4 signaling pathway . Small interfering RNA (siRNA)‐mediated inhibition of the EphA1/SDF‐1/CXCR4 pathway abolished tube formation in vitro and decreased tumor size and angiogenesis due to an inhibition of endothelial progenitor cell homing to the tumor tissue …”