The Urokinase Plasminogen Activator System in Cancer: A Putative
                        Therapeutic Target

Killeen, Shane; Hennessey, Arthur; Hassan, Yasmeena; Waldron, Brian

doi:10.1358/dnp.2008.21.2.1188197

Cited by 13 publications

(8 citation statements)

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“…The molecular role of uPAR in cancer progression is well characterized. In addition to its participation in extracellular matrix degradation, uPAR elicits a number of -non-proteolytic- cellular responses involved in tumor progression and angiogenesis, such as cell migration, adhesion, differentiation and proliferation (19–22). uPAR is overexpressed in breast tumor cells as well as in tumor stroma, and its presence has been associated with an aggressive tumor phenotype and adverse prognosis (21, 23–26).…”

Section: Introductionmentioning

confidence: 99%

Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor

et al. 2009

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Oncolytic measles virus (MV) induces cell fusion and cytotoxicity in a CD46-dependent manner. Development of fully retargeted oncolytic MVs would improve tumor selectivity. The urokinase-type plasminogen activator receptor (uPAR) is a tumor and stromal target overexpressed in multiple malignancies. MV-H glycoproteins fully retargeted to either human or murine uPAR were engineered and their fusogenic activity was determined. Recombinant human (MV-h-uPA) and murine (MV-m-uPA) uPAR-retargeted MVs expressing enhanced green fluorescent protein (eGFP) were rescued and characterized. Viral expression of chimeric MV-H was shown by reverse transcription-PCR and Western blot. In vitro viral replication was comparable to MV-GFP control. The receptor and species specificity of MV-uPAs was shown in human and murine cells with different levels of uPAR expression. Removal of the NH 2 -terminal fragment ligand from MV-uPA by factor X(a) treatment ablated the MV-uPA functional activity. Cytotoxicity was shown in uPAR-expressing human and murine cells. MV-h-uPA efficiently infected human endothelial cells and capillary tubes in vitro. I.v. administration of MV-huPA delayed tumor growth and prolonged survival in the MDA-MB-231 breast cancer xenograft model. Viral tumor targeting was confirmed by immunohistochemistry. MV-muPA transduced murine mammary tumors (4T1) in vivo after intratumor administration. MV-m-uPA targeted murine tumor vasculature after systemic administration, as shown by dual (CD31 and MV-N) staining of tumor capillaries in the MDA-MB-231 model. In conclusion, MV-uPA is a novel oncolytic MV associated with potent and specific antitumor effects and tumor vascular targeting. This is the first retargeted oncolytic MV able to replicate in murine cells and target tumor vasculature in a uPAR-dependent manner.

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Section: Introductionmentioning

confidence: 99%

Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor

et al. 2009

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“…Suggested roles have been an inhibitor of kidney stone formation and urinary tract infections due to its proteolytic activity and endogenous antibiotic function, respectively (3,4). Increased uPA activity has been reported in several pathological conditions, such as chronic kidney disease (2), atherosclerosis, and malignant tumors (5,6). Endogenous plasma uPA levels may be elevated 2-4-fold in patients with chronic kidney disease due to increased uPA released from damaged kidneys (7,8).…”

mentioning

confidence: 99%

A Novel Signaling Pathway

Zhang

Kernan

Thomas

et al. 2009

Journal of Biological Chemistry

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The nicotinic acetylcholine receptor ␣1 (nAChR␣1) was investigated as a potential fibrogenic molecule in the kidney, given reports that it may be an alternative urokinase (urokinase plasminogen activator; uPA) receptor in addition to the classical receptor uPAR. In a mouse obstructive uropathy model of chronic kidney disease, interstitial fibroblasts were identified as the primary cell type that bears nAChR␣1 during fibrogenesis. Silencing of the nAChR␣1 gene led to significantly fewer interstitial ␣SMA ؉ myofibroblasts (2.8 times decreased), reduced interstitial cell proliferation (2.6 times decreased), better tubular cell preservation (E-cadherin 14 times increased), and reduced fibrosis severity (24% decrease in total collagen). The myofibroblast-inhibiting effect of nAChR␣1 silencing in uPAsufficient mice disappeared in uPA-null mice, suggesting that a uPA-dependent fibroblastic nAChR␣1 pathway promotes renal fibrosis. To further establish this possible ligand-receptor relationship and to identify downstream signaling pathways, in vitro studies were performed using primary cultures of renal fibroblasts. 35 S-Labeled uPA bound to nAChR␣1 with a K d of 1.6 ؋ 10 ؊8 M, which was displaced by the specific nAChR␣1 inhibitor D-tubocurarine in a dose-dependent manner. Pre-exposure of uPA to the fibroblasts inhibited [ 3 H]nicotine binding. The uPA binding induced a cellular calcium influx and an inward membrane current that was entirely prevented by D-tubocurarine preincubation or nAChR␣1 silencing. By mass spectrometry phosphoproteome analyses, uPA stimulation phosphorylated nAChR␣1 and a complex of signaling proteins, including calcium-binding proteins, cytoskeletal proteins, and a nucleoprotein. This signaling pathway appears to regulate the expression of a group of genes that transform renal fibroblasts into more active myofibroblasts characterized by enhanced proliferation and contractility. This new fibrosis-promoting pathway may also be relevant to disorders that extend beyond chronic kidney disease.

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“…Although current knowledge is somewhat limited as to the degree and diversity of PAS involvement in normal physiology and various disease states,132, 133 the inhibition of plasmin activity might provide a novel avenue for the treatment of a variety of conditions 134. The role of PAS dysregulation in the progression, invasion and metastasis of various cancers has received particular interest in the last few decades 135–137. The utility of the different components of the PAS as prognostic cancer markers, their role(s) in cancer aetiology and their promise as therapeutic targets have recently been reviewed extensively42, 129, 138, 139 and will therefore only be discussed briefly.…”

Section: Rationale For Plasmin Inhibition To Regulate Cell Migratimentioning

confidence: 99%

Natural and Engineered Plasmin Inhibitors: Applications and Design Strategies

Swedberg¹,

Harris²

2012

ChemBioChem

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The serine protease plasmin is ubiquitously expressed throughout the human body in the form of the zymogen plasminogen. Conversion to active plasmin occurs through enzymatic cleavage by plasminogen activators. The plasminogen activator/plasmin system has a well-established function in the removal of intravascular fibrin deposition through fibrinolysis and the inhibition of plasmin activity; this has found widespread clinical use in reducing perioperative bleeding. Increasing evidence also suggests diverse, although currently less defined, roles for plasmin in a number of physiological and pathological processes relating to extracellular matrix degradation, cell migration and tissue remodelling. In particular, dysregulation of plasmin has been linked to cancer invasion/metastasis and various chronic inflammatory conditions; this has prompted efforts to develop inhibitors of this protease. Although a number of plasmin inhibitors exist, they commonly suffer from poor potency and/or specificity of inhibition that either results in reduced efficacy or prevents clinical use. Consequently, there is a need for further development of high-affinity plasmin inhibitors that maintain selectivity over other serine proteases. This review summarises clearly defined and potential applications for plasmin inhibition. The properties of naturally occurring and engineered plasmin inhibitors are discussed in the context of current knowledge regarding plasmin structure, specificity and function. This includes design strategies to obtain the potency and specificity of inhibition in addition to controlled temporal and spatial distribution tailored for the intended use.

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The Urokinase Plasminogen Activator System in Cancer: A Putative Therapeutic Target

Cited by 13 publications

References 0 publications

Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor

Tumor and Vascular Targeting of a Novel Oncolytic Measles Virus Retargeted against the Urokinase Receptor

A Novel Signaling Pathway

Natural and Engineered Plasmin Inhibitors: Applications and Design Strategies

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