Model of tumor-induced changes in extracellular matrix during angiogenesis. Tumor-associated angiogenic factors induced enhanced vascular permeability, resulting in disruption of the subendothelial basement membrane and formation of a fibrin-rich provisional matrix. The endothelial cell responding to this stimulus must traverse not only the subendothelial basement membrane but also this provisional matrix. Moreover, the type I collagen and fibronectin containing interstitial matrix forms a third distinct type of extracellular matrix that endothelial cells recruited to support tumor growth must cross. During the angiogenic response endothelial cells must penetrate several types of extracellular matrix. MMP activity is required for this response. As discussed in the text, the role of specific MMPs, such as MT-1-MMP, may change as endothelial cells come in contact with different extracellular matrix environments. Moreover, the type of extracellular matrix may alter the profile of MMP expression. Studies on these effects may identify extracellular matrix–specific roles for different members of the MMP family. Such information would be useful for selecting the appropriate MMP for targeting with selective synthetic MMP inhibitors.