Chang-Chun Ling1, Kevin T P Ng1, Yan Shao1, Wei Geng1, Jiang-Wei Xiao1, Hui Liu1, Chang-Xian Li1, Xiao-Bing Liu1, Yuen-Yuen Ma1, Wai-Ho Yeung1, Xiang Qi1, Jun Yu2, Nathalie Wong3, Yuan Zhai4, See-Ching Chan1, Ronnie T P Poon5, Chung-Mau Lo1, Kwan Man6. 1. Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, China. 2. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China. 3. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, China. 4. Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, USA. 5. 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. 6. 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.
Abstract
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(-/-) 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.
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(-/-) 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: Zhiwei Hu; Samira A Brooks; Valérian Dormoy; Chia-Wen Hsu; Hsue-Yin Hsu; Liang-Tzung Lin; Thierry Massfelder; W Kimryn Rathmell; Menghang Xia; Fahd Al-Mulla; Rabeah Al-Temaimi; Amedeo Amedei; Dustin G Brown; Kalan R Prudhomme; Annamaria Colacci; Roslida A Hamid; Chiara Mondello; Jayadev Raju; Elizabeth P Ryan; Jordan Woodrick; A Ivana Scovassi; Neetu Singh; Monica Vaccari; Rabindra Roy; Stefano Forte; Lorenzo Memeo; Hosni K Salem; Leroy Lowe; Lasse Jensen; William H Bisson; Nicole Kleinstreuer Journal: Carcinogenesis Date: 2015-06 Impact factor: 4.944
Authors: Hui Liu; Chang Chun Ling; Wai Ho Oscar Yeung; Li Pang; Jiang Liu; Jie Zhou; Wei Yi Zhang; Xiao Bing Liu; Tak Pan Kevin Ng; Xin Xiang Yang; Chung Mau Lo; Kwan Man Journal: Cell Death Dis Date: 2021-05-14 Impact factor: 8.469
Authors: Chang Xian Li; Bing L Wong; Chang Chun Ling; Yuen Yuen Ma; Yan Shao; Wei Geng; Xiang Qi; Sze Hang Lau; Sui Yi Kwok; Na Wei; Fei Chuen Tzang; Kevin T P Ng; Xiao Bing Liu; Chung Mau Lo; Kwan Man Journal: BMC Cancer Date: 2014-04-27 Impact factor: 4.430
Authors: Kevin Tak-Pan Ng; Oscar Wai-Ho Yeung; Yin Fan Lam; Jiang Liu; Hui Liu; Li Pang; Xin Xiang Yang; Jiye Zhu; Weiyi Zhang; Matthew Y H Lau; Wen Qi Qiu; Hoi Chung Shiu; Man Kit Lai; Chung Mau Lo; Kwan Man Journal: Cell Death Discov Date: 2021-07-21