Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion.
OBJECTIVE
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 PKC alpha-isoform to the plasma-membrane, but had no effect on the activity of Erks and p38(MAPK). 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-alpha 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.
Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Düsseldorf, Germany.
Marcus
M
Schmitt
Axel
A
Horbach
Ralf
R
Kubitz
Andrea
A
Frilling
Dieter
D
Häussinger
D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein
D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D013755:Tetradecanoylphorbol Acetate