Antiangiogenic Mechanism Of A Novel Vegf Targeted Agent

Angiogenesis is a prerequisite for tumor growth, invasion, metastasis and recurrence. It is a complex process that includes the proliferation, sprouting, elongation, and migration of endothelial cells. Among the various endogenous stimulators and inhibitors that control the angiogenic processes, the most intensively characterized proangiogenic factor is vascular endothelial growth factor (VEGF). VEGF is a critical promoter of blood vessel growth during embryonic development and neovascularization in tumors. VEGF stimulates proliferation and migration of endothelial cells and plays a pivotal role in vasculogenesis, angiogenesis, and endothelial integrity and survival. VEGF serves as a logical target for antiangiogenic cancer therapy because of its fundamental role in tumor angiogenesis.FP3, a fully human soluble decoy receptor protein targeting VEGF signaling pathways, is an engineered protein which contains the extracellular domain2of vascular endothelial growth factor receptor1(VEGFR1, Flt-1) and extracellular domain3and4of vascular endothelial growth factor receptor2(VEGFR2, Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1(IgG1). This study is to investigate the inhibitory effects of FP3, a novel VEGF blocker, on angiogenesis in vitro and tumor growth in vivo. In the present study, we investigated the inhibitory effects of FP3on angiogenesis, using cultured human umbilical vein endothelial cells (HUVECs) and rat aortic ring in vitro, and Chick Chorioallantoic Membrane (CAM) in vivo. We also assessed the effect of FP3on antiangiogenesis of tumor in vivo, by evaluating its ability to block the growth of LoVo colorectal tumor cell subcutaneous xenograft model in nude mice with the methods of tumor growth regression assay and immunohistochemical staining.Results:In experiments with HUVECs, FP3inhibited cell survival and proliferation, as well as tube formation and migration ability. In rat aortic ring assay, FP3suppressed VEGF-induced vessel sprouting. In CAM assay, FP3suppressed MCF-7human breast cancer cell-induced angiogenesis. In tumor growth regression assay, FP3significantly blocked the growth of LoVo tumor cell in subcutaneous tumor xenograft model in nude mice, and dramatically decreased the vessel density of tumor.Conclusions:FP3has excellent inhibitory effects on tumor angiogenesis both in vitro and in vivo, therefore, it could be used as an effective antiangiogenic agent.