Chemokine receptors CXCR4 and CCR7 influence proliferation and dissemination of human hepatocellular cancer

Background/aims: Despite many pathophysiological analyses, the process of tumor dissemination of hepatocellular carcinoma (HCC) remains vague. In diverse other tumor entities, expression of the chemokine receptors CXCR4 and CCR7 has been linked to tumor dissemination and poor prognosis. Therefore, we evaluated, if the expression of these chemokine receptors exerts similar effects in human HCC. Methods: Expression analysis and functional assays (translocation, proliferation and invasion) were in vitro performed to elucidate the impact of SDF-1a on human hepatoma cells lines (Huh7, Hep3B, wt HepG2, p53 dominant negative transfected HepG2). In addition, expression of CXCR4 and CCR7 was evaluated in 39 patients with histologically confirmed hepatocellular cancer. Expression intensities of tumor samples were correlated with both, tumor and patients characteristics. Results: Human hepatocellular carcinoma samples and hepatoma cell lines displayed variable intensities of CXCR4 and CCR7 expression. Loss of p53 function resulted in unchanged CXCR4 expression. Exposure to SDF-1a mediated a perinuclear translocation of CXCR4 from the membrane and cytoplasma in Huh7/Hep3B cells and increased proliferation and invasive potential of Huh7 cells. These SDF1-a mediated effects were completely absent in HepG2 cells. Both, CXCR4 and CCR7 expression was significantly associated with progressed local tumors (P=0.006; P=0.02, respectively) and lymphatic metastasis (P=0.005; P=0.02, respectively). Furthermore, strong CXCR4 expression was significantly associated with distant metastasis (P=0.009) and a decreased 3-year-survival rate (P=0.01). Conclusion: Strong expression of CXCR4 and CCR7 by hepatocellular carcinoma cells is significantly associated with locally progressed tumors, with lymphatic dissemination and in the case of CXCR4 also with distant dissemination in human HCC.