CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma.
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.
Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, PR China.
Qiang
Q
Gao
Ying-Jun
YJ
Zhao
Xiao-Ying
XY
Wang
Shuang-Jian
SJ
Qiu
Ying-Hong
YH
Shi
Jian
J
Sun
Yong
Y
Yi
Jie-Yi
JY
Shi
Guo-Ming
GM
Shi
Zhen-Bin
ZB
Ding
Yong-Sheng
YS
Xiao
Zhong-Hua
ZH
Zhao
Jian
J
Zhou
Xiang-Huo
XH
He
Jia
J
Fan
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D045744:Cell Line, Tumor; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009389:Neovascularization, Pathologic; D011379:Prognosis; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology*
C423727:CXCL16 protein, human; C106330:CXCR6 protein, human; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus