The urokinase plasminogen activator receptor as a gene therapy target for cancer

Pillay, Vinochani; Dass, Crispin R.; Choong, Peter F. M.

doi:10.1016/j.tibtech.2006.10.011

Cited by 101 publications

(75 citation statements)

References 34 publications

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“…uPAR has become a therapeutic target of interest for cancer and other pathologic conditions, including bone homeostasis (osteoporosis), neuron development, and atherosclerosis (32,(135)(136)(137). Pharmaceutical strategies of uPAR inactivation or blockade for in vivo evaluation have included RNA interference (85), adenovirus-mediated transfer of anti-sense uPAR (138), uPAR signaling blocked with anti-sense oligonucleotides or other small molecule inhibitors (139), adenovirus-mediated delivery of an uPA/uPAR antagonist (107), inhibitory monoclonal antibodies (140), and thalidomide (141).…”

Section: Upar As a Therapeutic Targetmentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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Since the recognition that plasminogen activator inhibitor-1 (PAI-1) is a powerful profibrotic molecule, there has been considerable interest in deciphering the extent to which this effect is mediated by its ability to inhibit serine proteases with downstream effects on fibrogenesis. This review will summarize current knowledge about the serine protease urokinase-type plasminogen activator and its high affinity receptor uPAR/CD87 as it pertains to chronic kidney disease (CKD) progression. An emerging theme is that the effects of PAI-1 and uPAR appear to be organ-and site-specific. Normal kidney tubules produce a large quantity of uPA that is secreted into the urinary space. Activity levels increase during CKD presumably due to new sources of production by macrophages and fibroblasts. By activating hepatocyte growth factor and degrading fibrinogen uPA may have anti-fibrotic effects. However CKD severity after experimental ureteral obstruction is not altered by endogenous uPA deficiency. Beneficial effects of exogenous uPA have been reported in experimental models of fibrosis in the lung and liver but CKD awaits exploration.Absent in normal kidneys uPAR is expressed by both renal parenchymal cells and inflammatory cells in a variety of pathological states. Such expression appears beneficial based on studies performed in uPAR-deficient mice. The uPAR promotes bacterial clearance in infectious diseases. In CKD uPAR expression is associated with high uPA activity but its most important effect appears to be due to scavenging activities and effects on cell recruitment and migration. Although uPAR itself is a non-signaling receptor, it interacts with a variety of co-receptors to modify cellular behavior. Best known are interactions with the low-density lipoprotein receptor-related protein (LRP-1) that lead to PAI-1 endocytosis and degradation, and interactions with several integrins to regulate matrix-dependent cell migration. Contacts with the receptor for the complement C5a component and the interleukin −6 receptor gp130 are examples of other recently recognized interactions.In addition to uPA, vitronectin and high molecular weight kininogen are alternate uPAR ligands that could be implicated in CKD progression. uPAR may also be shed from cell membranes. This soluble form (suPAR) has been detected in plasma and urine and is known to be a chemoattractant for leukocytes that express the formyl-peptide-receptor-like receptor

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Section: Upar As a Therapeutic Targetmentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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“…Components of the uPA system have an important role in tumourigenesis, extracellular matrix (ECM) degradation, angiogenesis, as well as in proliferation, migration and adhesion of tumour cells (Duffy and Duggan, 2004;Mondino and Blasi, 2004;Pillay et al, 2007). They are prognostic factors in different types of cancer.…”

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Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

et al. 2010

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BACKGROUND: The urokinase plasminogen activator (uPA) system is one of the best-investigated protease systems, both under physiological and pathological conditions, including various types of cancer. However, effects of co-expression of members of the uPA system in soft-tissue sarcoma (STS) patients at the protein level in both tumour tissue and serum have not been investigated yet. METHODS: We examined 82 STS patients for protein levels of uPA, PAI-1and uPAR in tumour tissue and serum by ELISA. RESULTS: A significant correlation between high antigen levels of uPA, PAI-1 or uPAR in tumour tissue, and of uPAR in serum, with poor outcome of STS patients was found for the first time. Most strikingly, we observed an additive effect of combined uPA, PAI-1 or uPAR levels in tumour tissue extracts with uPAR levels in serum on patients' prognosis. High uPA/uPAR, PAI-1/uPAR and uPAR/ uPAR antigen levels in tumour tissue/serum were associated with a 5.9-fold, 5.8-fold and 6.2-fold increased risk of tumour-related death (P ¼ 0.003, 0.001 and 0.002, respectively) compared with those patients who displayed low levels of the respective marker combination. CONCLUSION: As expression of members of the uPA system in tumour tissue and serum is additively correlated with prognosis of STS patients, our results suggest that combinations of these biomarkers can identify STS patients with a higher risk of tumour-related death.

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“…[3][4][5] The spread of cancer cells from the primary site to a distant location is known to follow a sequence that requires their detachment from the primary site, migration through the local stroma and invasion into and then extravasation from the vascular tree, before finally migrating toward, adhering to and proliferating at a distant site to form a metastatic tumor. 6 Although the molecular mechanisms underlying metastasis are complex, the degradation of components of extracellular matrix (ECM) and basement membrane is a key step in the metastatic cascade of cancer cells. One protease system intimately connected to this key step is the urokinase-type plasminogen activator (u-PA) system.…”

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confidence: 99%

“…[8][9][10]12 Furthermore, besides its action as a serine proteinase receptor, u-PAR is also involved in many other aspects of malignant tumor, such as migration, adhesion, angiogenesis, proliferation, apoptosis, tumor cell dormancy and differentiation through intercellular signaling pathways. 6,10,11 Moreover, u-PAR is correlated with drug resistance-related gene multidrug resistance-1 (MDR-1). 13 It is widely accepted that u-PAR has a crucial role in invasion, metastasis and progression of various cancers including OSCC as a versatile signaling orchestrator.…”

mentioning

confidence: 99%

“…13 It is widely accepted that u-PAR has a crucial role in invasion, metastasis and progression of various cancers including OSCC as a versatile signaling orchestrator. 6,10,11,[14][15][16] Therefore, u-PAR may represent a highly attractive target of gene therapy for oral cancer. In addition to u-PAR, other important metastasisrelated genes, including MMP-2, MMP-9, vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor-D (VEGF-D) and vascular endothelial growth factor receptor-3 (VEGFR-3), are reported to be involved in oral cancer invasion and metastasis.…”

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confidence: 99%

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RNAi targeting urokinase‐type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo

Zhou

Tang

Liang

et al. 2009

Intl Journal of Cancer

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It has been admitted that urokinase-type plasminogen activator receptor (u-PAR) is overexpressed in many human malignant tumors including oral squamous cell carcinoma (OSCC) and plays an important role in a variety of cancer key cellular events as a versatile signaling orchestrator. In our study, a retroviral vector expressing u-PAR-specific siRNA was injected into OSCC xenografts of nude mice to observe its inhibitory effects on OSCC. Our data demonstrate that siRNA targeting u-PAR markedly suppressed tumor growth, reduced the expression of proliferation-related gene, Ki-67 and increased cell apoptosis, accompanying with the efficient and specific inhibition of endogenous u-PAR expression in OSCC. More importantly, the mRNA and protein expression of MMP-2, MMP-9, VEGF-C, VEGF-D and VEGFR-3 that are intimately involved in oral cancer invasion and metastasis, was simultaneously downregulated significantly as determined by quantitative real-time RT-PCR, Western blot and immunohistochemistry; and Gelatin and fibrin zymography showed that MMP-9, MMP-2 and u-PA enzymatic activities were significantly reduced in u-PAR-specific siRNA group, compared to those in control groups. In addition, the expression of MDR-1 gene related to drug resistance was obviously inhibited by silencing of u-PAR. These findings suggest that RNAi targeting u-PAR could effectively inhibit the metastasis and progression of OSCC in vivo. Thus, it may be used as a potent and specific therapy for oral cancer, especially in inhibiting and preventing cancer cell invasion and metastasis. ' UICCKey words: RNA interference; urokinase-type plasminogen activator receptor; oral squamous cell carcinoma; metastasis; cancer progression Oral squamous cell carcinoma (OSCC) accounts for about 80% of all oral malignant tumors. The 5-year survival rate for patients with OSCC was still poor, approximately 56%, despite advances in chemotherapy, radiotherapy and surgical therapy in the past 20 years.1,2 The relatively high mortality of OSCC is predominantly associated with widespread lymphatic and distant metastasis.

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The urokinase plasminogen activator receptor as a gene therapy target for cancer

Cited by 101 publications

References 34 publications

Urokinase and its receptors in chronic kidney disease

Urokinase and its receptors in chronic kidney disease

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

RNAi targeting urokinase‐type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo

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