It has been well established that tumor growth and metastasis critically depends on the process of angiogenesis. This is supported by our previous observations that antagonists of integrins alphavbeta3 and alphavbeta5 block angiogenesis and thereby suppress the growth and invasive properties of tumors in various animal models. Therefore the overall objective of this proposal is to elucidate the molecular mechanism(s) by which integrins alphavbeta3 and alphavbeta5 contribute to tumor-induced angiogenesis. Experiments will be designed to investigate how integrin-mediated signaling events influence endothelial cell migration and survival within the context of the extracellular matrix in vitro and in vivo. Angiogenesis depends on growth factors and vascular cell adhesion events. Recent findings reveal that two growth factor-dependent pathways of angiogenesis were shown to exist and were defined by their dependency on integrins alphavbeta3 and alphavbeta5, respectively. Angiogenesis on the chick chorioallantoic membrane induced by basic fibroblast growth factor (bFGF) depended on integrin alphavbeta3, whereas angiogenic initiated by vascular endothelial cell growth factor (VEGF) depended on alphavbeta5. It is our hypothesis that these angiogenesis pathways involve specific as well as common signaling molecules that depend on the coordinate signaling between both growth factor receptors and integrins. Studies are outlined in this proposal to test this hypothesis both in vitro and in vivo and to further elucidate the signaling pathway(s) leading to angiogenesis. To assist these efforts, we have established retroviral and adenoviral gene delivery strategies designed to influence blood vessel formation in vivo. It is our hypothesis that by delivering specific mutationally active or inactive signaling molecules we can not only regulate new blood vessel growth but we can begin to define the role of integrins alphavbeta3 and alphavbeta5 in this process. This information will be used to target the vascular supply of tumors in various animal models. We anticipate that by interfering with specific signaling molecules within the tumor vasculature it should be feasible to influence the growth and metastasis of tumors and thereby begin to develop new anti-cancer strategies.
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