Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth

详细信息    查看全文

• 作者：Chang-Chun Ling ; Kevin T.P. Ng ; Yan Shao ; Wei Geng ; Jiang-Wei Xiao ; Hui Liu ; Chang-Xian Li ; Xiao-Bing Liu ; Yuen-Yuen Ma ; Wai-Ho Yeung ; Xiang Qi ; Jun Yu ; Nathalie Wong ; Yuan Zhai ; See-Ching Chan ; Ronnie T.P. Poon ; Chung-Mau Lo ; Kwan Man
• 关键词：OLT ; orthotopic liver transplantation ; EPC ; endothelial progenitor cell ; SLW ; standard liver weight ; LDLT ; living donor liver transplantation ; GW ; graft weight ; IR ; ischemia-reperfusion ; IFN纬 ; interferon-gamma ; DDLT ; deceased donor liver transplantation ; AFP ; 伪-fetoprotein ; GFP ; green fluorescent protein ; Dil-acLDLT ; 1 ; 1&prime ; dioctadecyl-3 ; 3 ; 32 ; 32-tetramethylindocarbocyanine perchlorate-labeled acetylated LDL ; MVD ; microvessel density ; EC ; endothelial cell ; PBMC ; peripheral blood mononuclear
• 刊名：Journal of Hepatology
• 出版年：January, 2014
• 年：2014
• 卷：60
• 期：1
• 页码：103-109
• 全文大小：1969 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Background & Aims

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^{鈭?鈭?/sup> mice and CXCR3鈭?鈭?/sup> 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 (猢?0% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10^{鈭?鈭?/sup> mice and CXCR3鈭?鈭?/sup> 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.