title: EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway.
abstract: BACKGROUND
  Endothelial 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.
  
  
  METHODS
  Co-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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Our findings indicate that targeting the EphA1/SDF-1 signaling pathway might be a therapeutic anti-angiogenesis approach for treating HCC.
authors.affiliation: Environmental and Public Health School of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Chonglin
authors.initials: C
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Pengyi
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Junjian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Qiandong
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Qitong
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China. zmt0417@hotmail.com.
authors.forename: Mengtao
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China. cg_2188@hotmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology* / Q000637:transplantation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D036082:Receptor, EphA1 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D036082:Receptor, EphA1
keywords: Endothelial progenitor cells; EphA1; Hepatocellular carcinoma; Neovascularization; SDF-1/CXCR4