563 Recent work from several laboratories indicates that the coordination of endothelial cell adhesion events with growth factor receptor inputs regulates endothelial cell responses during angiogenesis. Analyses of the signaling pathways downstream of integrins, cadherins and growth-factor receptors are providing an insight into the molecular basis of known anti-angiogenic strategies, as well as into the design of novel therapies. Addresses The Scripps Research Institute, IMM-24, 10550 North Torrey Pines Road, La Jolla, California 92037, USA Correspondence: David A Cheresh; e-mail: cheresh@scripps.edu Current Opinion in Cell Biology 2001, 13:563–568 0955-0674/01/$ —see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations bFGF basic fibroblast growth factor ECM extracellular matrix EGF epidermal growth factor FAK focal adhesion kinase PDGF platelet-derived growth factor PKC protein kinase C VEGF vascular endothelial growth factor Introduction Angiogenesis depends on endothelial cell interactions with the extracellular matrix. The coordination of integrins and growth factor inputs provides specificity during neovascu- larization associated with development and pathological processes. Evidence from various experimental systems demonstrates the physiological importance of the coordina- tion of signals from growth factors and the extracellular matrix (ECM) to support cell proliferation and migration. Several examples of cross-talk between these two important classes of receptors indicate that integrin ligation is required for growth-factor-induced biological processes. Integrins can directly associate with growth factor receptors, thereby reg- ulating the capacity of integrin–growth-factor-receptor complexes to propagate downstream signaling. In addition to cell–ECM interactions, regulation of cell–cell adhesion by VE (vascular endothelial)-cadherins is critical during angiogenesis. For example, VE-cadherins mediate endothe- lial barrier function, angiogenesis and can also support cross-talk with VEGF (vascular endothelial growth factor) receptors [1,2]. As the role of VE-cadherins in angiogenesis has been recently reviewed [3–5], our review will focus on the recent progress in the study of integrins and growth-fac- tor receptors during endothelial cell signaling leading to adhesion-dependent migration, survival and angiogenesis. The anti-angiogenic effect of αv integrin antagonists indi- cates a central role for integrins and cell adhesion during angiogenesis. Although other integrins clearly contribute to blood vessel formation during development (vasculoge- nesis) and neovascularization in tumor/growth factor models (angiogenesis), specific integrins may regulate dis- tinct endothelial responses. The evidence for a general role for integrin-mediated endothelial cell adhesion during angiogenesis comes from recent findings suggesting that the anti-angiogenic effects of Endostatin and other ECM fragments (Table 1) appear to involve specific integrin interaction(s). In combination, these studies suggest that an understanding of the molecular interactions between endothelial cells and the ECM will be important in the design of anti-angiogenic strategies with therapeutic appli- cations in humans. Integrins and the extracellular matrix Cell adhesion to the extracellular matrix is mediated by integrins, a family of heterodimeric transmembrane pro- teins comprising at least 16 α and 8 β subunits in mammals [6]. Different combinations of single α and β subunits dimerize to form approximately 24 different receptors with distinct and often overlapping specificity for ECM pro- teins. The biological significance of the range of ECM–integrin specificities during cell adhesion is not known. Although integrins support specific cell–ECM interactions for endothelial cell adhesion and migration, the identification of the underlying mechanisms by which specific subsets of integrins mediate development, wound healing and angiogenesis remains a challenge [6–9]. Integrins are widely recognized as important molecules for the transduction of positional cues from the ECM to the intracellular signaling machinery. For example, integrin lig- ation induces a wide range of intracellular signaling events, including the activation of Ras, MAP kinase, focal adhesion kinase (FAK), Src, Rac/Rho/cdc42 GTPases, PKC and PI3K (phosphatidylinositol 3-kinase) [7,10–12]. In addition, inte- grin ligation increases intracellular pH and calcium levels, inositol lipid synthesis, cyclin synthesis and the expression of immediate early genes [13] and promotes cell survival [14–17]. Interestingly, many of the signaling pathways and effectors activated by integrin ligation are also activated fol- lowing growth-factor stimulation. This suggests that integrin and growth-factor-mediated cellular responses may synergize and coordinate biochemical responses. The physiological importance of integrins during angiogen- esis has been most extensively studied in the case of the αv integrins. Antagonists of integrins αvβ3 and αvβ5 block growth-factor- and tumor-induced angiogenesis in multiple animal models [15,18]. Furthermore, recent data from clin- ical trials suggest that antagonists of αvβ3 and/or αvβ5 may have a clinical benefit in humans with solid tumors [19 • ]. Direct genetic approaches using knockout mouse models indicates that targeted deletion of the αv gene is lethal, Adhesion events in angiogenesis Brian P Eliceiri and David A Cheresh