Role of Plasminogen Activator Inhibitor-1 in Urokinase's Paradoxical In Vivo Tumor Suppressing or Promoting Effects

University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue, Suite 3400, Miami, FL 33136. .
Molecular Cancer Research (Impact Factor: 4.5). 08/2012; 10(10):1271-81. DOI: 10.1158/1541-7786.MCR-12-0145
Source: PubMed

ABSTRACT Tumor proteases and inhibitors have been associated with paradoxical effects on tumor progression in preclinical and clinical settings. We previously reported that urokinase (uPA) overexpression delays tumor progression in mammary cancer. This study aimed to determine the role of plasminogen activator inhibitor-1 (PAI-1) on uPA's paradoxical in vivo effects. Using syngeneic murine models, we found that stable uPA overexpression promoted in vivo growth of colon tumors (MC-38) naturally expressing high PAI-1, whereas growth inhibition was observed in renal tumors (RENCA) expressing lower PAI-1 levels. In murine mammary carcinoma (4T1), uPA overexpression shifted the uPA/PAI-1 balance in favor of the protease, resulting in significantly reduced tumor growth and metastases in vivo. Conversely, increased tumor progression was observed in stable PAI-1 overexpressing 4T1 tumors as compared with uPA-overexpressing and control tumors. These effects were associated with downregulation of metastases promoting genes in uPA-overexpressing tumors, such as metalloproteinases, CXCL-1, c-Fos, integrin α-5, VEGF-A, PDGF-α, and IL-1β. In PAI-1-overexpressing tumors, many of the above genes were upregulated. PAI-1 overexpressing tumors had increased total and new tumor microvessels, and increased tumor cell proliferation, whereas the opposite effects were found in uPA-overexpressing tumors. Finally, PAI-1 downregulation led to significant inhibition of 4T1 tumor growth and metastases in vivo. In conclusion, uPA's dual effects on tumor progression occur in the context of its interactions with endogenous PAI-1 expression. Our studies uncover novel mechanisms of in vivo tumor control by modulation of the balance between tumor proteases and inhibitors, which may be exploited therapeutically. Mol Cancer Res; 10(10); 1271-81. ©2012 AACR.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms of small molecules forming nanospecies and the effect of the nanospecies of small molecules on their pharmacological actions remain to be elucidated. As one of our efforts here, a uPA inhibitor, (5aS,12S,14aS)-5,14-dioxo-12-(2-tryptophanylthreo-nylbenzylester-N-yl-ethyl-1-yl)-1,2,3,5,5a,6,11,12,14,14a-decahydro-5H,14H-pyrolo[1,2:4,5]-pyrazino[1,2:1,6]pyrido[3,4-b]indole (CIPPCT) was presented. Energy-minimization, FT-MS and 2-D ROESY spectra defined CIPPCT taking -like conformation, and the intermolecular association drove CIPPCT to form a finger ring-like trimer. Images from transmission electron, scanning electron and atomic force microscopies consistently visualized that in aqueous solution at pH 6.7 and 10−10 M concentration, CIPPCT generally assembled nanoparticles of 9–67 nm in diameter. Mesoscale simulation demonstrated that a nanoparticle 9.4 nm in diameter contained 350 trimers. In vivo CIPPCT dose-dependently inhibited tumor growth in S180 mice. An ELISA assay confirmed that CIPPCT concentration-dependently downregulated serum uPA. The nanoparticles of CIPPCT are capable of occurring in mouse plasma and adhering on HeLa cells, and nanosized CIPPCT directly correlates the downregulation of uPA with inhibition of tumor growth.
    Medicinal Chemistry Communication 07/2014; 5(11). DOI:10.1039/C4MD00158C · 2.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Tumor cells are characterized by uncontrolled cell growth at a primary site which is caused by genetic alterations. Tumor cells that metastasize from their primary site to distant locations are commonly referred to as malignant. Cell migration is a critical step in this process. The ability of tumor cells to migrate and invade is partly controlled by proteolytic enzymes. These enzymes are secreted by either the tumor cells themselves or adjacent cells. They represent all classes of proteases including serine and cysteine proteases. Serine proteases, in particular urokinase plasminogen activator (uPA), initiate a proteolytic cascade that culminates in degrading components of the extracellular matrix (ECM). Some serine proteases are controlled by a superfamily of proteins known as Serpins. This minireview provides an overview of serpins that are vital in regulating tumor cell migration and progressing cancer.
    Biological Chemistry 11/2014; 396(3). DOI:10.1515/hsz-2014-0254 · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. We have previously rescued oncolytic measles viruses fully retargeted against human (MV-h-uPA) or murine (MV-m-uPA) uPAR. Here, we investigated the in vivo effects of systemic administration of MV-m-uPA in immunocompetent cancer models. MV-m-uPA induced in vitro cytotoxicity and replicated in a receptor-dependent manner in murine mammary (4T1) and colon (MC-38 and CT-26) cancer cells. Intravenous administration of MV-m-uPA to 4T1 tumor-bearing mice was not associated with significant clinical or laboratory toxicity. Higher MV-N RNA copy numbers were detected in primary tumors, and viable viral particles were recovered from tumor-bearing tissues only. Non-tumor-bearing organs did not show histological signs of viral-induced toxicity. Serum anti-MV antibodies were detected at day 14 of treatment. Immunohistochemistry and immunofluorescence studies confirmed successful tumor targeting and demonstrated enhanced MV-m-uPA-induced tumor cell apoptosis in treated compared with control mice. Significant antitumor effects and prolonged survival were observed after systemic administration of MV-m-uPA in colon (CT-26) and mammary (4T1) cancer models. The above results show safety and feasibility of uPAR targeting by an oncolytic virus, and confirm significant antitumor effects in highly aggressive syngeneic immunocompetent cancer models.Gene Therapy advance online publication, 16 January 2014; doi:10.1038/gt.2013.84.
    Gene therapy 01/2014; DOI:10.1038/gt.2013.84 · 4.20 Impact Factor


Available from
May 22, 2014