Targeting and inhibiting tumor angiogenesis.

摘要

Angiogenesis, the recruitment of new blood vessels from existing ones, is initiated early in tumor formation. Angiogenic and normal vessels are distinct with regard to their sets of cell surface molecules. These differences provide possibilities for applied in vivo targeting of angiogenic vasculature. RGD-directed integrins are examples of endothelial proteins expressed at high levels during angiogenesis. These integrins may be used as targets for physiological angiogenesis inhibitors that depend on adhesion molecules containing an RGD sequence for in vivo activity.; The first approach to target vasculature in vivo involves peptides that home to tumor blood and lymphatic vessels, and to normal blood vessels of the lung. Semiconductor nanoparticles coated with these peptides are shown to home specifically to tumor and normal lung vasculature. Nonspecific trapping of particles in the reticuloendothelial system could be minimized by co-coating with polyethylene glycol.; Second, a peptide that home to tumor blood vessels is shown to recognize cell surface nucleolin as a specific marker of angiogenic endothelium, and antibody treatments against nucleolin inhibit angiogenesis in vivo.; A third aspect of targeting angiogenic vasculature involves physiological angiogenesis inhibitors. These compounds share several features: they are comprised of beta-sheet structure; they bind to cell surface proteoglycans; and they depend on an adhesion molecule to be active. Anastellin, an angiostatic fibronectin fragment, is shown to be composed mainly of beta-sheet structure. Commonalities between anastellin and anginex, a beta-sheet structured synthetic peptide, were explored. Both anginex and anastellin are shown to aggregate with fibronectin in vitro, and to depend on plasma fibronectin for activity in vivo.; Work on physiological angiogenesis inhibitors was expanded to include the amyloid-beta peptide, a peptide associated with neuronal degeneration in Alzheimer's disease. A large body of evidence indicates that Alzheimer's disease may in part be an angiogenesis-dependent disorder. In this work, the beta-amyloid peptide appears to also be angiostatic.; In its entirety, this work demonstrates that the properties of angiogenic endothelium are important to explore, not only to find possible targets for diagnostic and therapeutic tools, but also to understand the mechanisms of angiogenesis in vivo.