Antiangiogenic Approaches to Renal Cell Carcinoma: Assays for Inhibitors and Clinical Trials

Angiogenesis—the formation of new blood vessels from preexisting ones—is a complex process regulated by a number of soluble factors as well as important interactions between endothelial cells, extracellular matrix components, and adjacent cells (1 –5 ). Activation of the endothelial cell, which occurs when the balance between proangiogenic and antiangiogenic signals within a given microenvironment tilts in a positive direction, leads initially to increased expression of proteases, allowing the endothelial cell to mobilize itself and release inducers sequestered within the matrix (1 ,6 ,7 ). This is followed by endothelial-cell proliferation and migration and culminates in reorganization of the endothelial cell plexus to form tubules and eventually capillary structures that can conduct blood. Most proangiogenic factors—such as VEGF and basic fibroblast growth factor (bFGF)—are peptide growth factors that bind to transmembrane-receptor tyrosine kinases on the surface of the endothelial cell, initiating intracellular transduction pathways resulting in cellular activation (8 ,9 ). Other important angiogenic factors—the angiopoietins—further modulate this process by stabilizing or destabilizing interactions between small blood vessels and adjacent pericytes (10 ). Expression of angiopoietin 2 results in dissociation of pericytes, which can lead to endothelial-cell activation or vascular regression, depending on whether angioinductive or angioinhibitory signals predominate (10 ,11 ). In contrast, angiopoietin 1 stabilizes interactions with pericytes and promotes vascular quiescence (10 ,12 ).