In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/ Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P ¼ 0.006), lymphatic metastasis (N-status; P ¼ 0.005) and distant dissemination (M-status; P ¼ 0.009), as well as with a decreased 3-year-survival rate (P ¼ 0.01). In summary, strong expression of CXCR4 is significantly associated with progressed hepatocellular cancer.

Abstract. Despite many pathophysiological analyses, the process of tumor dissemination of hepatocellular carcinoma (HCC) remains vague. In diverse tumor entities, expression of the chemokine receptor, CCR7, has been linked to tumor dissemination and poor prognosis. Therefore, we evaluated, whether CCR7 exerts similar effects in human HCC. CCR7 expression analysis was performed in vitro on human hepatoma cell lines (Huh7, Hep3B, wt HepG2, p53 dominant negative transfected HepG2). In addition, CCR7 expression was evaluated in 39 patients with hepatocellular cancer and correlated with both, tumor and patients characteristics. Human hepatocellular carcinoma samples and hepatoma cell lines displayed variable intensities of CCR7 expression. In patients, CCR7 expression was significantly associated with progressed local tumors (P=0.02) and lymphatic metastasis (P=0.02). Strong expression of CCR7 promotes intrahepatic and lymphatic HCC dissemination. IntroductionHepatocellular carcinoma (HCC) is one of the most common cancer entities with an annual incidence of more than 500,000 cases and raising incidence rates in Western countries during the 1990s (1,2). HCC is often related to liver cirrhosis commonly resulting from chronic inflammatory liver disease, such as chronic viral hepatitis or autoimmune hepatitis/ cholangitis, but also from other diseases, such as chronic alcohol abuse or consumption of mycotoxin and aflatoxin B1 (3). Hepatocarcinogenesis is regarded as a slow process in which diverse genomic alterations accumulate, modifying the phenotype of hepatocytes and leading to monoclonal and dysplastic hepatocyte populations (4). As progress of dysplastic hepatocytes to hepatocellular carcinoma might occur simultaneously in different foci or nodules, variable genomic alterations can be found within the same liver indicating a genetic heterogeneity of lesions (5). Diverse molecular determinants including mutations and loss of heterozygosity (LOH) in certain tumor-suppressor genes and oncogenes have been summarized in the pathway of molecular pathogenesis of human hepatocellular carcinoma (4,5). Nonetheless, additional pathogenic alterations are considered to instrumentally mediate the progression and dissemination of human HCC.Diverse results suggest that chemokine receptors may direct lymphatic and hematogenous spreading and may furthermore influence the sites of metastatic growth of different tumors (6). Chemokines and their G-protein-coupled receptors mediate pro-and anti-inflammatory responses (7). CCR7, the receptor for the chemokine, CCL21, is expressed on naïve T-cells, on memory T cells, B cells and mature dendritic cells and is considered to play an important role in lymphocyte cell trafficking and homing to lymph nodes (8,9). Most recently, CCR7 has shifted into focus as it might play an important role in tumor spreading. CCR7 expression positively correlated with lymphatic metastasis and poor prognosis in rectal, gastric and esophageal squamous cell carcinoma (10-12). Supporting data from in vivo models u...

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