The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model

The vascular endothelial growth factor-A (VEGF-A), also known as the vascul ar permeability factor (VPF), has been shown to play an important role in m alignant ascites formation. The effects of VEGF-A are mediated through flt- 1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk- 1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this rec eptor in hepatic ascites formation has not yet been elucidated. In this stu dy, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary pe rmeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb tr eatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than th ose of VEGF-A nAb, The autophosphorylation of KDR/Flk-1 in the peritoneal w all was almost completely abolished by KDR/Flk-1 nAb, whereas a certain lev el of activation was still shown by VEGF-A nAb treatment. Another VEGF-fami ly, VEGF-C, which also binds KDR/Flk-1,was detected in the ascites. Further more, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results sugges t that KDR/Flk-1 is a major regulator of malignant hepatic ascites formatio n, and that in addition to VEGF-A, VEGF-C may also be involved in the malig nant ascites formation via KDR/Flk-1 activation.