Phenotype Changes in Tumor Vessels Associated with the Progression of Hepatocellular Carcinoma

Abstract

Human hepatocellular carcinoma (HCC) is characterized by hypervascularity and tumor staining in angiograms, and tumor angiogenesis is considered indispensable for tumor growth. HCC is also characterized by an obvious multistage process of tumor progression. To find out in which stage of human hepatocarcinogenesis angiogenesis occurs, we have carried out a pathological study, of the phenotypic changes in tumor vessels taken from surgically resected liver tumors showing each step of the progression. Eleven early advanced HCCs (advanced HCC component in early HCC nodule, eAd HCC), seven early HCCs (eHCC) and six adenomatous hyperplasias (AH), the non-tumorous liver surrounding each and five normal livers were studied by lectin histochemistry and immunohistochemistry. The sinusoidal endothelial cells from the non-tumorous liver were shown to be negative for UEA-I (Ulex europaeus I), but the endothelial cells from the sinusoidal tumor vessels in advanced HCC components were strongly positive. In AH and eHCC, half the tumors were negative and the other half focally positive. In the early HCC lesion of eAdHCC, the rate of positivity for UEA-I was a little higher than in AH and eHCC but lower than in advanced HCC lesions in eAdHCC. Immunohistochemically, laminin was not detected in the sinusoids in the non-tumorous liver or in the sinusoidal tumor vessels in AH and eHCC. In eAdHCC, however, two early HCC lesions and four advanced HCC lesions were positive. An immunohistochemical examination for muscle actin revealed an increase in arterial tumor vessels in six advanced HCC lesions and one early HCC lesion of eAdHCC. The results indicate the emergence of UEA-I-positive sinusoidal tumor vessels to be most pronounced during the progression from eHCC to advanced HCC, and laminin-positive sinusoidal tumor vessels or actin-positive arterial tumor vessels to emerge mainly in advanced HCC.