This research proposal will examine the relative roles of the vascular cell integrins alphavbeta3 and alphavbeta5 during cytokine- and tumor- induced angiogenesis and provide a framework for comparison of angiogenic cytokine expression and integrin-mediated neovascularization of various tumor types. Previous studies as well as preliminary data indicate that the vascular integrin alphavbeta3 is preferentially expressed in tissues undergoing active angiogenesis, and that specific antagonists of this receptor target newly forming blood vessels and block angiogenesis and tumor growth while leaving preexisting adjacent blood vessels unaffected. Furthermore, distinct angiogenic factors induce neovascularization by separate pathways susceptible to alphavbeta3- or alphavbeta5-specific antagonists. Therefore, I will analyze the relationship between these two pathways in angiogenesis induced by cytokines which specifically activate one pathway. In addition, tumor-induced neovascularization will be analyzed for the relative roles of these pathways and compared to the spectrum of angiogenic factor expression. I will further analyze the effects of alphavbeta3 and alphavbeta5 antagonists on the metastasis of tumor cells implanted on the chick CAM and within human skin transplants on the SCID mouse.
| Silletti, S; Kessler, T; Goldberg, J et al. (2001) Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc Natl Acad Sci U S A 98:119-24 |
| Boger, D L; Goldberg, J; Silletti, S et al. (2001) Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin alpha(V)beta(3). J Am Chem Soc 123:1280-8 |
| Felding-Habermann, B; Silletti, S; Mei, F et al. (1997) A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins. J Cell Biol 139:1567-81 |
