Correlation between hypoxia-inducible factor and vascular endothelial growth factor expression under tumor neovascularization in hepatocellular carcinoma cell-implanted nude mice

Abstract

Background: In a tumor, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) are induced to promote angiogenesis for the growth and metastasis of cells. There have been very few studies to examine in vivo relation between HIF-1α and VEGF during tumor progression. Objective: To study the relationship between HIF-1αand VEGF expressions under neovascularization induced by hepatocellular carcinoma cells (HepG2) implanted in nude mice. Methods: Male BALB/c-nude mice 8-10 weeks of age were used. A chamber was prepared on the dorsal skin in which HepG2 was transplanted to induce a tumor. On the day of the experiment, and on days 2, 7, and 14, microcirculation within the chamber was observed using fluorescence videomicroscopy. Based on the recorded video images, capillary vascularity (CV) was measured to examine tumor neovascularization. VEGF expression was measured in blood (serum) withdrawn, using enzyme immunoassay, while HIF-1α expression was measured on samples isolated from tumor tissue, using immunohistochemistry. Results: The measured CV significantly increased on day 7 and 14 compared to the aged-matched controls (p<0.05). HIF-1α markedly expressed on day 2, and the expression declined on day 7 and 14 post-inoculation. VEGF expression in serum increased more on day 7 and 14 than on day 2. HIF-1α expression decreased with the increase in VEGF expression from 2 to 14 days after HepG2 implantation, showing a reverse correlation. Conclusion: HIF-1α expression existed prior to both VEGF expression and neovascularization in the tumor. An inhibitor of HIF-1α might be a therapeutic agent for reducing neovascularization via adaptation to hypoxia in tumors.