Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis

Yuval Shaked, Francesco Bertolini, Shan Man, Michael S. Rogers, Dave Cervi, Thomas Foutz, Kimberley Rawn, Daniel Voskas, Daniel J. Dumont, Yaacov Ben-David, Jack Lawler, Jack Henkin, Jim Huber, Daniel J. Hicklin, Robert J. D'Amato, Robert S. Kerbel*

*Corresponding author for this work

Research output: Contribution to journalArticle

328 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)101-111
Number of pages11
JournalCancer Cell
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Shaked, Y., Bertolini, F., Man, S., Rogers, M. S., Cervi, D., Foutz, T., Rawn, K., Voskas, D., Dumont, D. J., Ben-David, Y., Lawler, J., Henkin, J., Huber, J., Hicklin, D. J., D'Amato, R. J., & Kerbel, R. S. (2005). Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell, 7(1), 101-111. https://doi.org/10.1016/j.ccr.2004.11.023