The application and mechanism of plasminogen activator inhibitor-1 as a cancer therapeutic agent

Tumor progression involves the disruption of anatomical barriers and penetration of tumor cells into normal adjacent host tissues, as well as the recruitment of pre-existing blood vessels, a process called angiogenesis. Such migratory and tissue remodeling events are regulated by different proteolytic systems, one of which is plasminogen activation system. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and as such is thought to be a important regulator of plasminogen activation system. Recently, a considerable amount of data regarding the role of PAI-1 in angiogenesis and tumor growth has been obtained with diverse results. These results arise because of different tumor models, the PAI-1 sources (tumor cells versus host cells), and the spatial location of PAI-1. Therefore, it is necessary to examine the therapeutic potential of PAI-1 under the conditions that closely mimic clinical settings.;In order to fully exploit PAI-1's therapeutic potential as an anti-tumor agent, we established the AY-27/F344 orthotopic rat bladder cancer model. PAI-1 was intravesically delivered into the bladder lumen, which enables prolonged contact of intralumenal tumors with PAI-1 and better control of PAI-1 concentration. Rats bearing bladder tumor were treated with either PAI-1 or BSA control twice/week for two weeks. Gross differences between PAI-1 and control were evident at necropsy. PAI-1-treated tumors showed significantly smaller tumor size and total bladder weight when compared to BSA-treated tumors. Gross and histological organ survey (including: heart, lung, liver, kidney, spleen) did not reveal any PAI-1 related toxicity or thrombosis. Tissue analysis showed marked inhibition of tumor invasion and angiogenesis. This suggests the potential of PAI-1 as a therapeutic agent in the treatment of bladder cancer, and a clinical trial is being developed.;The effects of PAI-1 on early angiogenesis have been widely studied. However, very little is known about its effects on the vasculature of established tumors. We have created stable PC3 tetracycline-responsive cell lines, where expression of PAI-1 (TO-PAI-1 cell line) or GFP (TO-GFP cell line) was induced by administrating doxycycline in order to regulate its expression. Mice xenografted with either TO-GFP or TO-PAI-1 cells showed similar tumor growth rate in the absence of doxycycline. After addition of doxycycline in drinking water, xenografted TO-PAI-1 tumors showed a significant decrease of tumor growth in comparison with xenografted TO-GFP tumors. This is due to a wave of endothelial apoptosis occurring within 2 days of PAI-1 induction, ultimately resulting in decreased angiogenesis.;Because vitronectin has been shown to be specifically present around microvessels and may serve as the adhesion molecular for endothelial cells during angiogenic response, we examined the vitronectin-dependent effect of PAI-1 in angiogenesis by characterizing the biological responses of two endothelial cell lines, HUVEC and HMEC-1. Our results demonstrated the inhibitory effects of PAI-1 on endothelial cell growth, cell attachment, cell migration, and cell invasion. Interestingly, PAI-1 only manifests its inhibitory effects in the presence of vitronectin.;Taken together, our results suggested that PAI-1 can interfere with tumor progression through its ability to affect both tumor invasion and angiogenesis, and these observations implicated PAI-1 as a promising agent for further investigation of its use in cancer therapy.