Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis.
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.
Shaked
Yuval
Y
Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M3N 4M5, Canada.
Bertolini
Francesco
F
Man
Shan
S
Rogers
Michael S
MS
Cervi
Dave
D
Foutz
Thomas
T
Rawn
Kimberley
K
Voskas
Daniel
D
Dumont
Daniel J
DJ
Ben-David
Yaacov
Y
Lawler
Jack
J
Henkin
Jack
J
Huber
Jim
J
Hicklin
Daniel J
DJ
D'Amato
Robert J
RJ
Kerbel
Robert S
RS
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
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