Changes of Plasma and Liver Tissue Levels of VEGF, bFGF and Endostatin in the N, N- Diethylnitrosamine-induced Hepatocarcinogenesis and Progression in Rat Liver

ABSTRACT

PURPOSE: Proangiogenic and antiangiogenic growth factors are related to control of cancer progression and metastasis. The expression of Factor VIII-Related antigen in liver, that is marker of the vascular endothelial cell antigen, may be an indicator of neovascularization. This study aimed to monitor the change of plasma and tissue levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and endostatin in rat liver carcinogenesis and to determine the possibility of the future predictive indicator and antiangiogenic therapy application. METHODS: Sprague-Dawley Rats received 120 ppm concentration diethylnitrosamine (DEN) in drinking water as a carcinogen and in control and experimental groups, sequentially sacrificed by three and seven rats at 3, 6, 9, 12, 15 and 18 weeks, respectively. The liver tissue was examined with light microscopy, immunohistochemistry and enzyme immunoassay method. RESULTS: In hepatocarcinogenesis, the preneoplastic nodules appeared at 6 weeks after oral 120 ppm concentration DEN administration. The hepatocellular carcinomas and their pulmonary metastatic foci developed at 15 weeks and 18 weeks, respectively. The immunohistochemical staining of Factor VIII-Related antigen was negative in all sinusoids in normal control livers, but focal or scattered expression in preneoplastic nodules and diffuse expression were found in hepatocellular carcinomas. The tissue levels of VEGF and bFGF were found to have a direct correlation with the plasma levels, but not endostatin. The levels of VEGF and bFGF increased slightly in preneoplastic nodules and markedly elevated in hepatocellular carcinoma. However, there was no significant difference between the levels of VEGF and bFGF and the state of metastasis. There was no significant relation between the levels of endostatin and carcinogenesis and progression of the rat liver. CONCLUSION: From the above results, it could be suggested that VEGF and bFGF may play an important role in initiation and progression of hepatocellular carcinomas in rat liver, but not endostatin. Also, there was no correlation between the levels of VEGF and bFGF and the state of metastasis. Therefore, further study to determine the relationship between the angiogenic regulators and its receptors will serve as a promising research in the predictive indicator and antiangiogenic therapy.