Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells

Hepatology. 1998 Dec;28(6):1489-96. doi: 10.1002/hep.510280607.


Angiogenesis is essential for the development of a solid tumor, including hepatocellular carcinoma (HCC). HCC is a well-known hypervascular tumor. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. Its role has not been clarified in vivo in HCC development. We used a self-contained, tetracycline-regulated retroviral vector system to elucidate the effect of VEGF on murine HCC development in a xenograft experimental model. By delivering the VEGF gene within the retroviral vector and under the control of a tetracycline-regulated promoter, we were able to manipulate VEGF expression in vivo tumor by providing tetracycline in the drinking water. Overexpression of VEGF showed a marked increase in tumor development accompanied by augmentation of neovascularization. The degree of tumor enlargement corresponded to the level of VEGF gene expression. Suppression of VEGF led to a decrease in tumor growth at the established tumor size, whether relatively small or large. The level of VEGF expression did not alter the proliferation of HCC cells in vitro. In a double-chamber chemoinvasion assay, the in vitro invasion activity of VEGF-transduced cells was not changed. In the presence of endothelial cells (EC), however, VEGF-transduced cells showed a marked increase in their in vitro invasion activity. These results suggested that VEGF plays a critical role in the development of HCC in cooperation with EC

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Movement / physiology
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / physiology*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology
  • Gene Expression Regulation / physiology
  • Genetic Vectors / drug effects
  • Humans
  • Liver Neoplasms / pathology*
  • Lymphokines / genetics
  • Lymphokines / physiology*
  • Mice
  • Neoplasm Invasiveness
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • Retroviridae / genetics
  • Tetracycline / pharmacology
  • Tumor Cells, Cultured / pathology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Lymphokines
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Protein Synthesis Inhibitors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Tetracycline