EGCG suppresses tumor growth by inhibiting activation of the VEGF/VEGFR axis in the xenograft model of human colon cancer and hepatoma

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Epidemiologic and experimental animal studies suggest that green tea catechins have anti-carcinogenic effects at various organ sites. We previously reported that (-)-epigallocatechin gallate (EGCG), the major biologically active component of green tea, causes inhibition of growth and induction of apoptosis in human colon cancer and hepatoma cells and this is associated with inhibition of the activation of several member of receptor tyrosine kinases (RTKs), including EGFR, HER2, and IGF-1R (Shimizu M, et al., Clin Cancer Res, 2005 and Cancer Lett, 2008). In this study we investigated tumor-suppressing effects of EGCG in nude mice xenograft model of human colon cancer and hepatoma, focusing on the expression levels of the vascular endothelial growth factor receptor-2 (VERFR2), which also belong to the RTKs. SW837 human colon cancer or HuH7 human hepatoma cells (5×10⁶) were inoculated subcutaneously into male BALB/c nude mice aged 5 weeks. They were then given water containing EGCG (0.01% or 0.1%) up to day 35. The mice were killed at day 35 and the xenografts were analyzed histopathologically and biochemically. We found that both in SW837 and HuH7 xenografts tumor growth was significantly inhibited by drinking with EGCG. Treatment with EGCG inhibited activation of the VEGFR2 and its multiple downstream signaling molecules, including ERK, Akt, and Stat3 proteins, and subsequently induced apoptosis in the xenograft tumors. Treatment with EGCG also decreased the protein and mRNA expression levels of VEGF in the xenograft tumors. These results suggest that EGCG could inhibit growth of colon cancer and hepatoma by inducing antiangiogenic and apoptotic effects in vivo. Our findings thus provide evidence that the VEGF/VEGFR is one of the critical targets of EGCG and, therefore, tea catechins might be useful for controlling the progression of hypervascular tumor characterized by neovascularization, such as colon cancer and hepatoma.