title: Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma.
abstract: BACKGROUND
  This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).
  
  
  METHODS
  The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.
  
  
  RESULTS
  Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.
  
  
  CONCLUSIONS
  PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. pyzhuang@gmail.com.
authors.forename: Peng-Yuan
authors.initials: PY
authors.lastname: Zhuang
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. wangjiandong@163.com.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. tangzhaohui@aliyun.com.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. xp05zhou@163.com.
authors.forename: Xue-Ping
authors.initials: XP
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. quanzhiwei@gmail.com.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Quan
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. ilmare@gmail.com.
authors.forename: Ying-Bin
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. junshen_xh@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018920:Coculture Techniques; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D019869:Phosphatidylinositol 3-Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2