title: Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth.
abstract: OBJECTIVE
  Patients with hepatocellular carcinoma (HCC) receiving living donor liver transplantation appear to possess significantly higher tumor recurrence than the recipients receiving deceased donor liver transplantation. The underlying mechanism for HCC recurrence after transplantation remains unclear. Here, we aim to investigate the impact of small-for-size liver graft injury on HCC recurrence after transplantation.
  
  
  METHODS
  The correlation between tumor recurrence, liver graft injury, CXCL10 expression and endothelial progenitor cell (EPC) mobilization was studied in 115 liver transplant recipients and rat orthotopic liver transplantation (OLT) models. The direct role of CXCL10/CXCR3 signaling on EPC mobilization was investigated in CXCL10(-/-) mice and CXCR3(-/-) mice. The role of EPCs on tumor growth and angiogenesis was further investigated in an orthotopic liver tumor model.
  
  
  RESULTS
  Clinically, patients with small-for-size liver grafts (<60% of standard liver weight, SLW) had significantly higher HCC recurrence (p=0.04), accompanied by more circulating EPCs and higher early-phase intragraft and plasma CXCL10 levels, than the recipients with large grafts (≥60% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10(-/-) mice and CXCR3(-/-) mice in comparison to wild-type controls. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners in vitro. Early-phase EPC/CXCL10 injection enhanced orthotopic liver tumor growth, angiogenesis and metastasis in nude mice.
  
  
  CONCLUSIONS
  Post-transplant enhanced CXCL10/CXCR3 signaling in small-for-size liver grafts directly induced EPC mobilization, differentiation and neovessel formation, which further promotes tumor growth. Targeting CXCL10/CXCR3 signaling may attenuate early-phase liver graft injury and prevent late-phase tumor recurrence/metastasis after transplantation.
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Chang-Chun
authors.initials: CC
authors.lastname: Ling
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Kevin T P
authors.initials: KT
authors.lastname: Ng
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Geng
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Jiang-Wei
authors.initials: JW
authors.lastname: Xiao
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Chang-Xian
authors.initials: CX
authors.lastname: Li
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Yuen-Yuen
authors.initials: YY
authors.lastname: Ma
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Wai-Ho
authors.initials: WH
authors.lastname: Yeung
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, China.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: See-Ching
authors.initials: SC
authors.lastname: Chan
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China; Center for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China.
authors.forename: Chung-Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China; Center for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, China. Electronic address: kwanman@hkucc.hku.hk.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation; D051379:Mice; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000209:etiology*; D051381:Rats; D054367:Receptors, CXCR3 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3
keywords: 1,1′dioctadecyl-3,3,32,32-tetramethylindocarbocyanine perchlorate-labeled acetylated LDL; AFP; DDLT; Dil-acLDLT; EC; EPC; GFP; GW; Graft injury; IFNγ; IR; Inflammation; LDLT; Liver transplantation; MVD; OLT; PBMC; SLW; Tumor recurrence; WT; deceased donor liver transplantation; endothelial cell; endothelial progenitor cell; graft weight; green fluorescent protein; interferon-gamma; ischemia-reperfusion; living donor liver transplantation; microvessel density; orthotopic liver transplantation; peripheral blood mononuclear cell; standard liver weight; wild type; α-fetoprotein