Abstract
Development of antiangiogenic therapies would be significantly facilitated by quantitative surrogate pharmacodynamic markers. Circulating peripheral blood endothelial cells (CECs) and/or their putative progenitor subset (CEPs) have been proposed but not yet fully validated for this purpose. Herein, we provide such validation by showing a striking correlation between highly genetically heterogeneous bFGF- or VEGF-induced angiogenesis and intrinsic CEC or CEP levels measured by flow cytometry, among eight different inbred mouse strains. Moreover, studies using genetically altered mice showed that levels of these cells are affected by regulators of angiogenesis, including VEGF, Tie-2, and thrombospondin-1. Finally, treatment with a targeted VEGFR-2 antibody caused a dose-dependent reduction in viable CEPs that precisely paralleled its previously and empirically determined antitumor activity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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Validation Study
MeSH terms
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Angiogenesis Inhibitors / metabolism
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Biological Assay / methods
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Biomarkers*
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Cell Survival
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelial Cells / physiology*
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Fibroblast Growth Factors / metabolism
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Flow Cytometry
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Humans
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Male
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Neovascularization, Pathologic*
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Phenotype
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Receptor, TIE-2 / genetics
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Receptor, TIE-2 / metabolism
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Stem Cells / drug effects
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Stem Cells / physiology*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Angiogenesis Inhibitors
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Biomarkers
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Vascular Endothelial Growth Factor A
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Fibroblast Growth Factors
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Receptor, TIE-2
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Vascular Endothelial Growth Factor Receptor-2