Abstract
Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF or FGF-2) are potent pro-angiogenic factors and play a critical role in cancer development and progression. Clinical anti-VEGF therapy trials had a major challenge due to upregulated expression of other pro-angiogenic factor, like FGF-2. This study developed a novel chimeric decoy receptor VF-Trap fusion protein to simultaneously block activity of both VEGF and FGF pathways in order to achieve an additive or synergistic anti-tumor effect. Our in vitro data showed that VF-Trap potently blocked proliferation and migration of both VEGF- and FGF-2-induced vascular endothelial cells. In animal models, treatment of xenograft tumors with VF-Trap resulted in significant inhibition of tumor growth compared to blockage of the single molecule, like VEGF or FGF blocker. In addition, VF-Trap was also more potent in inhibition of ocular angiogenesis in a mouse oxygen-induced retinopathy (OIR) model. These data demonstrated the potent anti-angiogenic effects of this novel VF-Trap fusion protein on blockage of VEGF and FGF-2 activity in vitro and in animal models. Further study will assess its effects in clinic as a therapeutic agent for angiogenesis-related disorders, such as cancer and ocular vascular diseases.
Keywords:
Angiogenesis; Anti-angiogenic therapy; Cancer therapy; Dual decoy receptor; FGF-2; VEGF.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Angiogenesis Inhibitors / pharmacology*
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Animals
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CHO Cells
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cricetulus
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Female
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Fibroblast Growth Factor 2 / antagonists & inhibitors*
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Hyperoxia / complications
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Lung Neoplasms / blood supply
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Neovascularization, Pathologic*
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Neovascularization, Physiologic / drug effects*
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Recombinant Fusion Proteins / pharmacology*
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Retinal Neovascularization / drug therapy*
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Retinal Neovascularization / etiology
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Retinal Neovascularization / metabolism
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Retinal Neovascularization / physiopathology
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Retinal Vessels / drug effects*
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Retinal Vessels / metabolism
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Retinal Vessels / physiopathology
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Signal Transduction / drug effects
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Time Factors
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Recombinant Fusion Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Fibroblast Growth Factor 2