Metalloproteinases and their inhibitors in tumor angiogenesis

Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression.