Role of plasminogen activator-plasmin system in tumor angiogenesis

Abstract

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

Hyperforin, a bio‐active compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process

“…25 Urokinase is another proteinase that plays a central role in extracellular matrix remodeling associated with angiogenesis. 26 The results indicate that 10 lM hyperforin produces a complete inhibition of urokinase and 1 lM hyperforin inhibits urokinase by >60%. Other antiangiogenic agents inhibiting urokinase are genistein, aeroplysinin-1, 8-puupehedione and irsogladine, among others.…”

Bone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization

“…For immunohistochemical analysis, eyes were embedded in Tissue Tek for cryostat sectioning. Neovascularization was estimated by computer-assisted measurement on at least five sections per lesion of the b/c ratio (b, thickness from the bottom of the pigmented choroidal layer to the top of the neovascular membrane; c, thickness of the intact pigmented choroid adjacent to the lesion) as previously described [28][29][30].…”

Anti-angiogenic therapy of exudative age-related macular degeneration: current progress and emerging concepts

“…Wild-type control mice and uPARdeficient mice exhibited a robust choroidal angiogenic response. However, CNV did not develop in uPA-, tPA-, Plg-or PAI-1-deficient mice, thus demonstrating the contribution of the plasmin system in CNV [27,58]. Paradoxically, PAI-1, through its anti-proteolytic activity, appears to be a key regulator of CNV; it exhibits proangiogenic effects at physiological concentrations and anti-angiogenic actions at pharmacological concentrations [60].…”

“…Cell migration and tissue remodeling associated with pathological angiogenesis are regulated by different proteolytic systems, including MMPs and serine proteases of the plasmin system [27]. Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators are serine proteases that are both able to convert plasminogen into active plasmin and whose activities are inhibited by plasmino-gen-activator inhibitor type-1 (PAI-1).…”

“…Therefore, initial studies on angiogenesis in CNV were mainly focused on growth factors such as angiogenic factors and endogenous inhibitors. In addition, genes involved in matrix remodeling and endothelial cell migration, including matrix metalloproteinases (MMPs) and the plasmin system, have been reported as crucial in angiogenesis [27].…”