The Clinicopathological Significance of Heparanase and Basic Fibroblast Growth Factor Expressions in Hepatocellular Carcinoma

Heparan sulfate plays an essential role for insolubility of the components of extracellular matrix and represents a storage depot for various growth factors. Therefore, heparanase produced by a given tumor may facilitate tumor invasiveness and angiogenesis through the release of heparan sulfate-bound growth factors. Although the growth factors responsible for angiogenesis in hepatocellular carcinoma (HCC) have recently been investigated, the clinicopathological significance of heparanase in connection with basic fibroblast growth factor (bFGF) expression in HCC has not been evaluated so far. Fifty-five patients who had undergone hepatic resection for HCC without preoperative treatment were included in the present study. Expression of heparanase mRNA was evaluated by reverse transcription-PCR, and bFGF was examined by Western blotting using a monoclonal antibody. Tumor angiogenesis was evaluated by immunostaining with a factor VIII-related monoclonal antibody. Expression of heparanase mRNA was detected in 47% of HCCs and was significantly correlated with larger tumor size (P = 0.01), presence of portal vein invasion (P = 0.01), and higher overall tumor invasiveness (P = 0.02). Moreover, its expression was correlated with tumor microvessel density (MVD; P = 0.02). There was a direct correlation between the levels of bFGF proteins and MVD in HCCs (P = 0.0001), and, furthermore, concomitant expression of bFGF and heparanase was associated with higher tumor MVD as compared with expression of either factor alone (P = 0.01). In conclusion, the expression of heparanase in HCC enhances growth, invasion, and angiogenesis of the tumor, and bFGF seems to be a potent angiogenic factor for HCC.