Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma
Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma
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血管 CXCR4 表达促进肝细胞癌中的血管萌芽和对索拉非尼治疗的敏感性
DOI：
10.1158/1078-0432.ccr-16-2131
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发表时间：
2017-02
影响因子：
11.5
通讯作者：
Zheng Limin
中科院分区：
文献类型：
--
作者：
Xu Jing;Liang Jing;Meng Ya-Ming;Yan Jing;Yu Xing-Juan;Liu Chao-Qun;Xu Li;Zhuang Shi-Mei;Zheng Limin
目的：C-X-C趋化因子受体4型（CXCR 4）已知参与发育和成人血管生成;然而，其在肿瘤血管生成中的作用仍然很大程度上未知。本文旨在探讨血管CXCR 4在肝细胞癌（HCC）血管结构调节中的作用及其临床应用价值。实验设计：采用免疫组化和免疫荧光法检测CXCR 4在HCC中的表达。通过体外和小鼠实验确定CXCR 4+细胞的特性。Kaplan-Meier生存分析CXCR 4表达与预后的关系。结果如下：我们发现CXCR 4选择性地表达于HCC组织中的一部分肿瘤内皮细胞（TEC）上，而不表达于癌周区域的肝内皮细胞上。TEC上高水平的CXCR 4倾向于在肿瘤中形成窦状血管，并预测HCC患者的预后不良。CXCR 4+内皮细胞（EC）显示了尖端细胞的功能特征，尖端细胞相关标志物的表达增加。功能研究表明，CXCR 4可直接促进体外和体内血管出芽。有趣的是，索拉非尼治疗降低了培养物中CXCR 4 + EC的频率，并抑制了窦状血管的形成和CXCR 4 High异种移植肿瘤的生长。此外，索拉非尼治疗前切除的肿瘤组织中CXCR 4血管密度高与索拉非尼治疗的晚期HCC患者生存期延长相关。结论：这些数据表明，CXCR 4是一种新的HCC血管标记物，用于血管发芽，并可作为索拉非尼治疗HCC患者的潜在治疗靶点和预测因子。Clin Cancer Res; 23（15）; 4482-92.©2017 AACR.
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 by in vitro and 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 sprouting in vitro and in vivo. Interestingly, sorafenib treatment reduced the frequency of CXCR4+ ECs in culture and inhibited the formation of sinusoidal vasculature and growth of CXCR4High xenograft 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.
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影响因子：
3.7
作者：
Fischer, Thomas;Nagel, Falko;Jacobs, Stefan;Stumm, Ralf;Schulz, Stefan
通讯作者：
Schulz, Stefan
影响因子：
45.3
作者：
Poon, RTP;Ng, IOL;Wong, J
通讯作者：
Wong, J
影响因子：
51.1
作者：
Faivre, Sandrine;Raymond, Eric;Cheng, Ann Lii
通讯作者：
Cheng, Ann Lii
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
DOI：
10.1038/nrm3176
发表时间：
2011-08-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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