P52 Macrophage inflammatory protein-1 /CC chemokine ligand 3 and tumour-associated macrophages in hepatitis C virus-related hepatocellular carcinoma: relation to tumour progression and angiogenesis
Authors: H. El Aggan, M. Helmy, N. El Deeb, A. Zeid, M. Fawzy
Journal: Gut (2011)

<h3>Introduction</h3> Hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC), however, the mechanism of hepatocarcinogenesis in HCV infection is still undefined. Chemokines, which can induce the migration of leucocytes and activate inflammatory/immune responses, have recently been implicated in the regulation of tumour growth. <h3>Aim</h3> Therefore, the aim of the present work was to study the role of macrophage inflammatory protein-1 α/CC chemokine ligand 3 (MIP-1α/CCL3), a potent macrophage chemoattractant, in the pathogenesis of HCV-related HCC in relation to tumour progression and angiogenesis. <h3>Method</h3> 30 patients with HCV-related cirrhosis (15 patients with histologically-proven HCC and 15 patients without HCC) and 15 healthy subjects were enrolled in the study. The severity of liver disease was assessed according to Child-Pugh classification and the Model for End Stage Liver Disease (MELD) score. The tumour stage was classified using the Cancer of the Liver Italian Program (CLIP) scoring system. Histological tumour grading was performed according to the Edmondson and Steiner9s criteria and the surrounding liver tissue was examined for assessing the modified histological activity index (HAI), presence of cirrhosis and the grade of steatosis. Expressions of MIP-1α/CCL3, CD68 [a marker for tumour-associated macrophages (TAM)] and CD105 (Endoglin) [for tumour angiogenesis and determination of microvessel density (MVD)] were studied in HCC and adjacent non-neoplastic liver tissues by immunohistochemistry. Serum MIP-1α/CCL3 levels were measured using solid phase sandwich enzyme linked immunosorbant assay kit. The sensitivity and specificity of serum levels of MIP-1α/CCL3 as markers for diagnosis of HCC have been assessed by plotting a receiver-operating characteristic (ROC) curve. <h3>Results</h3> Patients with HCV-related HCCs showed significant increases in MIP-1α/CCL3 expression, CD68<sup>+</sup> TAM count and CD105<sup>+</sup> MVD in tumour tissues compared with adjacent non-neoplastic liver tissues (p=0.0004, p&lt;0.001 and p&lt;0.001 respectively). Serum MIP-1α/CCL3 levels were significantly higher in patients with and without HCC than in healthy subjects and in HCC patients than in patients without HCC (p&lt;0.001). By plotting a ROC curve, the sensitivity and specificity of serum MIP-1α/CCL3 in discriminating cirrhotic patients with and without HCC were found to be 100% and 93.3% respectively at a cut-off value of 17.5 pg/ml. The MIP-1α/CCL3 expression in HCC tissues showed positive correlations with serum MIP-1α/CCL3 levels; tumour size, stage, histopathological grade; serum α-fetoprotein levels and CD68<sup>+</sup> TAM count and CD105<sup>+</sup> MVD in HCCs (p&lt;0.05). Also, CD68<sup>+</sup> TAM count and CD105<sup>+</sup> MVD in HCC tissues were positively correlated (p&lt;0.001). On the other hand, no correlations were found between MIP-1α/CCL3 expression, CD68<sup>+</sup> TAM count and CD105<sup>+</sup> MVD in HCCs on one hand and serum levels of aminotransferases, Child-Pugh score, MELD score and HAI and steatosis grade in the surrounding liver tissue (p&gt;0.05). <h3>Conclusion</h3> The CC chemokine, MIP-1α/CCL3, may play an important role in the pathogenesis and progression of HCC in HCV-related liver disease, possibly, through migration of macrophages to tumour microenvironment and enhancement of angiogenesis. MIP-1α/CCL3 may also serve as a potential serum biological marker and a useful therapeutic target for HCC.