TY - JOUR
T1 - Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis
T2 - Implications for cellular surrogate marker analysis of antiangiogenesis
AU - Shaked, Yuval
AU - Bertolini, Francesco
AU - Man, Shan
AU - Rogers, Michael S.
AU - Cervi, Dave
AU - Foutz, Thomas
AU - Rawn, Kimberley
AU - Voskas, Daniel
AU - Dumont, Daniel J.
AU - Ben-David, Yaacov
AU - Lawler, Jack
AU - Henkin, Jack
AU - Huber, Jim
AU - Hicklin, Daniel J.
AU - D'Amato, Robert J.
AU - Kerbel, Robert S.
N1 - Funding Information:
We thank Cassandra Cheng for her excellent secretarial work. We are grateful to numerous colleagues for their comments and suggestions regarding the studies summarized in this manuscript and Dr. Douglas Hanahan for critical reading of the manuscript. This work was supported primarily by grants to R.S.K. from the National Cancer Institute of Canada, and also from the National Institutes of Health (NIH) (CA-41233) and the Canadian Institutes of Health Research (CIHR). Support was also received from Associazione Italiana per la Ricerca sul Cancro (AIRC), Instituto Superiore di Sanita (ISS), and the 6th EU framework program “Angiotargeting” to F.B. and from HL68003 and CA92644 (NIH) to J.L. R.S.K. is a Canada Research Chair in Molecular Medicine. Y.S. is a recipient of a postdoctoral fellowship award from the CIHR. D.C. is supported by a studentship award from the CIHR. D.V. is supported by a studentship award from the Heart and Stroke Foundation of Canada (HSFC). D.J.D. is supported by a grant from NIH (NHLBI-R01 HL63224-01A1). Y.B.-D. is supported by grants from NCIC and CIHR. R.J.D. is supported by grants from the NIH (R01-EY12726).
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2004.11.023
DO - 10.1016/j.ccr.2004.11.023
M3 - Article
C2 - 15652753
AN - SCOPUS:19944432454
SN - 1535-6108
VL - 7
SP - 101
EP - 111
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
