Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival

Background: The chemokine and bone marrow-homing receptor CXCR4 is implicated in metastases of various cancers. This study was conducted to analyze the association of CXCR4 expression with hepatocellular carcinoma (HCC) bone metastasis and patient survival. Methods: Tumor tissue from HCC patients with (n = 43) and without (n = 138) bone metastasis was subjected to immunohistochemical staining for CXCR4 using tissue microarrays. Immunoreactivity was evaluated semi-quantitatively. A receiver-operating characteristic-based approach and logistical regression analysis were used to determine the predictive value of clinicopathologic factors, including CXCR4 expression, in bone metastasis. Patient survival was analyzed by Kaplan-Meier curves and log-rank tests. Results: CXCR4 overexpression was detected in 34 of 43 (79.1%) patients with bone metastases and in 57 of 138 (41.3%) without bone metastases. CXCR4 expression correlated with (correlation coefficient: 0.551, P < 0.001) and was predictive of HCC bone metastases (AUC: 0.689; 95% CI: 0.601 -0.776; P < 0.001). CXCR4 staining intensity correlated with the bone metastasis-free survival (correlation coefficient: -0.359; P = 0.018). CXCR4 overexpression in primary tumors (n = 91) decreased overall median survival (18.0 months vs. 36.0 months, P < 0.001). Multivariable analysis identified CXCR4 as a strong, independent risk factor for reduced disease-free survival (relative risk [ RR]: 5.440; P = 0.023) and overall survival (RR: 7.082; P = 0.001). Conclusion: CXCR4 expression in primary HCCs may be an independent risk factor for bone metastasis and may be associated with poor clinical outcome.