The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.
Compared with heparin management with the activated clotting time, heparin concentration-based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.
Recombinant adenoviral vectors expressing u-PA, t-PA, virus expressing either PAI-1 or PAI-2 before implantation PAI-1 and PAI-2 were employed to correlate the significantly reduced the incidence of lung metastasis by expression of components of the fibrinolytic system with 60% compared with control virus. However, only PAI-2 the invasiveness of HT 1080 tumor cells. Migration through reduced the incidence of lung and brain metastasis followTranswell inserts in vitro in the presence of plasminogen ing liver gene transfer. Although PAI gene transfer by either was increased up to 22% by overexpression of u-PA, route reduced primary tumor size, it had little effect on whereas t-PA had no effect. Gene transfer of PAI-1 or PAItumor vascularization or host survival. The migratory and 2 both reduced migration in a dose-dependent manner by metastatic phenotype of HT 1080 tumor cells is thus up to 43% with PAI-1 and 29% with PAI-2. Two routes of directly dependent on u-PA expression levels and can be gene transfer were used to alter metastasis of subcutanealtered by gene transfer of u-PA or plasminogen activator ously implanted HT 1080 cells expressing firefly luciferase inhibitors. in nude mice. Infection of cultured tumor cells with adeno-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.