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Laboratories of ¹ Cellular and Molecular Biology and ² Medicinal Chemistry, National Cancer Institute, NIH, Bethesda, Maryland; ³ Department of Otolaryngology, Social Insurance Central General Hospital, Tokyo, Japan; and ⁴ Department of Cell Biology, Georgetown University, Washington, District of Columbia

Requests for reprints: Donald P. Bottaro, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 2B47, 9000 Rockville Pike, Bethesda, MD 20892-1501. Phone: 301-402-6499; Fax: 301-402-0922. E-mail: dbottaro{at}helix.nih.gov

Growth factor receptor bound protein 2 (Grb2) is an intracellular adaptor protein that participates in the signal transduction cascades of several angiogenic factors, including hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. We described previously the potent blockade of hepatocyte growth factor–stimulated cell motility, matrix invasion, and epithelial tubulogenesis by synthetic Grb2-Src homology 2 (SH2) domain binding antagonists. Here, we show that these binding antagonists block basic morphogenetic events required for angiogenesis, including hepatocyte growth factor–, vascular endothelial growth factor–, and basic fibroblast growth factor–stimulated endothelial cell proliferation and migration, as well as phorbol 12-myristate 13-acetate–stimulated endothelial cell migration and matrix invasion. The Grb2-SH2 domain binding antagonists also impair angiogenesis in vitro, as shown by the inhibition of cord formation by macrovascular endothelial cells on Matrigel. We further show that a representative compound inhibits angiogenesis in vivo as measured using a chick chorioallantoic membrane assay. These results suggest that Grb2 is an important mediator of key proangiogenic events, with potential application to pathologic conditions where neovascularization contributes to disease progression. In particular, the well-characterized role of Grb2 in signaling cell cycle progression together with our present findings suggests that Grb2-SH2 domain binding antagonists have the potential to act as anticancer drugs that target both tumor and vascular cell compartments.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J.V. Soriano is presently at American Type Culture Collection, P.O. Box 1549, Manassas, VA 20108.

⁵ J. Soriano and D. Bottaro, unpublished observations.

⁶ D. Bottaro, unpublished observations.

Received 5/19/04; revised 7/14/04; accepted 8/11/04.

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