Vascular Endothelial Growth Factor Tightly Regulates In Vivo Development of Murine Hepatocellular Carcinoma Cells

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Abstract
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