**2.3 Heparanase in malignant diseases of the liver**

The expression of heparanase in malignant diseases has been extensively studied, including the effects of several heparanase inhibitors that were evaluated in several malignant diseases. In one study, it was shown that heparanase-1 degrades the HS chains on cells of hepatocellular carcinoma (HCC), a process that resulted in the secretion of vascular endothelial growth factor C (VEGF-C) into the medium of HCC cells, while VEGF-C was shown to promote lymphatic endothelial cell growth leading to facilitating lymphatic metastasis [76]. Chen et al. showed elevated expression of heparanase mRNA and protein in HCC cells, where it accelerates cell adhesion in HCC metastasis, an effect that was significantly attenuated following silencing of the enzyme [77]. In the study of Liu et al., the authors showed that inhibiting heparanase activity by the inhibitor PI-88 exerted favorable effects in patients with HCC. Heparanase inhibition resulted in significant delay in the onset of recurrence of HCC, and provided significant survival benefit for up to three years of follow up [78].
