title: Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma.
abstract: Purpose:C-X-C chemokine receptor type 4 (CXCR4) is known to be involved in both developmental and adult angiogenesis; however, its role in tumor angiogenesis remains largely unknown. Here, the role of vascular CXCR4 in regulating vascular structure in hepatocellular carcinoma (HCC) was assessd, and the clinical value of CXCR4 was explored.Experimental Design:The expression of CXCR4 in HCC was determined by IHC and immunofluorescence. Characteristics of CXCR4+cells were determined byin vitroand mice experiments. Kaplan-Meier survival analysis was used to determine the correlation of CXCR4 expression with prognosis.Results:We found that CXCR4 is selectively expressed on a fraction of tumor endothelial cells (TECs) in HCC tissues, but not on the hepatic endothelium in peritumoral area. High levels of CXCR4 on TECs tended to develop a sinusoidal vasculature in tumors and predicted poor prognosis for patients with HCC. CXCR4+endothelial cells (EC) displayed the functional features of tip cells, with increased expression of tip cell-related markers. Functional studies revealed that CXCR4 could directly promote vessel sproutingin vitroandin vivoInterestingly, sorafenib treatment reduced the frequency of CXCR4+ECs in culture and inhibited the formation of sinusoidal vasculature and growth of CXCR4Highxenograft tumors. Moreover, high CXCR4 vascular density in resected tumor tissues before sorafenib treatment was associated with prolonged survival in patients with advanced HCC treated with sorafenib.Conclusions:These data revealed that CXCR4 is a novel HCC vascular marker for vessel sprouting and could serve as a potential therapeutic target and a predictive factor for sorafenib treatment in patients with HCC.Clin Cancer Res; 23(15); 4482-92. ©2017 AACR.
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Life Sciences, Sun Yat-sen University, Guangzhou, P.R. China.|Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.|Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.affiliation: School of Life Sciences, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Meng
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
authors.forename: Xing-Juan
authors.initials: XJ
authors.lastname: Yu
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
authors.forename: Chao-Qun
authors.initials: CQ
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of Life Sciences, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Shi-Mei
authors.initials: SM
authors.lastname: Zhuang
authors.affiliation: Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China. zhenglm@mail.sysu.edu.cn.|School of Life Sciences, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000235:genetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D010671:Phenylurea Compounds; D019718:Receptors, CXCR4; D009536:Niacinamide; D000077157:Sorafenib