Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion

Background/Aims Vascular endothelial growth factor (VEGF) is expressed by many tumors, including hepatocellular carcinoma (HCC) and is involved in tumor angiogenesis. Little is known about its role for HCC infiltration into normal liver parenchyma. Methods The effects of VEGF on the integrity of tight junctions were studied in HepG2 cells and human HCC by means of confocal laser scanning microscopy. Results VEGF induced within 45 min a marked loss of pseudocanaliculi and disruption of occludin-delineated tight junctions. This effect of VEGF was mimicked by phorbol-12-myristate-13-acetate (PMA) and was sensitive to protein kinase C (PKC) inhibition by Gö6850. VEGF induced within 15 min the translocation of the PKCα-isoform to the plasma-membrane, but had no effect on the activity of Erks and p38MAPK. Sections from surgically removed HCC showed expression of VEGF in the tumor and occludin disassembly in normal liver parenchyma next to the tumor. Conclusions VEGF induces disruption of tight junctions in a PKC-α dependent manner. In addition to its known angioneogenic properties, VEGF may promote HCC spreading into normal liver parenchyma. The data may provide another rationale for the use of VEGF antagonists for tumor therapy.