CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma
CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma
复制标题
CXCR6上调有助于形成促炎性肿瘤微环境，从而促进肝细胞癌的转移和不良的患者预后
DOI：
10.1158/0008-5472.can-11-4032
复制
发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Gao, Qiang;Zhao, Ying-Jun;Fan, Jia
CXC趋化因子及其同源受体广泛参与癌症发病机制。在这项研究中，我们报告了CXCR 6表达和肿瘤发生之间的因果关系，在人类肝细胞癌（HCC）的设置。在CXC趋化因子受体中，只有CXCR 6在所有研究的肝癌细胞系中检测到。此外，在肝癌组织中，CXCR 6的表达显著高于非癌肝组织。癌细胞中CXCR 6或其配体CXCL 16的减少减少了体外细胞侵袭和体内肿瘤生长、血管生成和转移。重要的是，CXCR 6的缺失通过抑制促炎细胞因子的产生导致肝细胞瘤异种移植物中Gr-1+中性粒细胞浸润减少和新血管生成减少。临床上，CXCR 6的高表达是HCC复发率增加和生存率降低的独立预测因子。表达高水平CXCR 6的人HCC样本也含有增加数量的CD 66 b+中性粒细胞和微血管，并且CXCR 6和中性粒细胞的组合是比单独使用的任一标记物上级的复发和存活的预测因子。总之，我们的研究结果表明，CXCR 6的表达升高促进了HCC的侵袭性和促肿瘤炎症环境，并与患者预后不良相关。这些结果支持抑制CXCR 6-CXCL 16通路可以改善HCC治疗后的预后的概念。Cancer Res; 72（14）; 3546-56. (c)2012年AACR。
CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment. Cancer Res; 72(14); 3546-56. (c) 2012 AACR.