title: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M3N 4M5, Canada.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rogers
authors.forename: Dave
authors.initials: D
authors.lastname: Cervi
authors.forename: Thomas
authors.initials: T
authors.lastname: Foutz
authors.forename: Kimberley
authors.initials: K
authors.lastname: Rawn
authors.forename: Daniel
authors.initials: D
authors.lastname: Voskas
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Jack
authors.initials: J
authors.lastname: Henkin
authors.forename: Jim
authors.initials: J
authors.lastname: Huber
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D015415:Biomarkers; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2