Abstract | BACKGROUND & AIMS: 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.
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Authors | 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 |
Journal | Journal of hepatology
(J Hepatol)
Vol. 60
Issue 1
Pg. 103-9
(Jan 2014)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 23994383
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- CXCL10 protein, human
- CXCR3 protein, human
- Chemokine CXCL10
- Receptors, CXCR3
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Topics |
- Animals
- Chemokine CXCL10
(physiology)
- Endothelial Cells
(cytology)
- Hematopoietic Stem Cell Mobilization
- Humans
- Liver Neoplasms
(blood supply, pathology, surgery)
- Liver Transplantation
- Mice
- Neoplasm Metastasis
- Neoplasm Recurrence, Local
(etiology)
- Rats
- Receptors, CXCR3
(physiology)
- Signal Transduction
(physiology)
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