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