Urokinase Plasminogen Activator Receptor Choreographs Multiple Ligand Interactions: Implications for Tumor Progression and Therapy

Mazar, Andrew P.

doi:10.1158/1078-0432.ccr-07-4863

Cited by 113 publications

(103 citation statements)

References 66 publications

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“…Several studies indicated that the urokinase system plays a central role in the control of extracellular matrix turnover, cell migration, invasion, cell signaling, angiogenesis, and metastasis. 23 A moderate to strong expression of uPA and uPAR in pancreatic cancer has been previously described 24 Our studies using immunohistochemistry and in situ hybridization confirm a strong expression of uPAR in virtually all pancreatic carcinomas and their precursors. Previous work from our and other groups demonstrated a high frequency of high-level amplifications of the chromosomal region 19q12-13.2 in pancreatic cancer by using comparative genomic hybridization.…”

Section: Discussionsupporting

confidence: 74%

Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

Hildenbrand

Niedergethmann

Marx

et al. 2009

The American Journal of Pathology

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The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are known to be involved in the invasion and metastasis of many solid tumors. In this study, we analyzed the role of the uPAR/uPA system in both the development and progression of pancreatic cancer in invasive ductal adenocarcinomas of the pancreas (PDA) and their premalignant precursors (PanIN lesions) in 50 patients with long-term clinical follow-up. We found overexpression of the uPAR in 48 of 50 invasive carcinomas as well as in a large proportion of high-grade PanIN lesions by immunohistochemistry and in situ hybridization. Fluorescence in situ hybridization analysis showed both high-and low-level amplification of the uPAR gene in ϳ50% of cases with strictly identical patterns between invasive cancers and their accompanying precursor lesions. These results suggest that PDA may develop from PanIN lesions along an alternative rather than a sequential molecular pathway. The detection of the gene amplification of uPAR was a highly significant, adverse prognostic parameter (P < 0.001) because it likely renders the tumors more sensitive to uPA and its proproliferative and anti-apoptotic signals. We conclude that the activation of the uPAR/uPA system is an early event in the development of PDA and that uPAR gene amplifications identify a subgroup of particularly aggressive tumors, making the uPAR/uPA system a critical and highly promising target for therapeutic in- Invasive ductal adenocarcinoma of the pancreas (PDA) represents the fourth most common cause of cancerrelated death and its incidence is still increasing.1 With an estimated number of 232,000 new cases per year, pancreatic cancer is among the most common malignancies worldwide.2 Moreover, it is one of the most lethal cancers, as indicated by a mortality incidence ratio of 98%.2 Once pancreatic cancer is clinically evident, it progresses at a rapid rate, and metastasis is often present already at the time of diagnosis.3 The mechanisms that regulate this aggressive growth behavior in pancreatic cancer are still poorly understood.Several studies indicate that during cancer cell invasion and metastasis proteolytic enzymes participate in the degradation of extracellular matrix components. The serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR, CD87) are involved in the control of extracellular matrix turnover, cell migration, invasion, and cell signaling leading to a variety of different responses under both physiological and pathological conditions. 4 -6 uPAR is a highly glycosylated 45-to 60-kDa protein that is attached to the cell membrane via glycosylphosphatidylinositol anchor. It consists of three

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Section: Discussionsupporting

confidence: 74%

Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

Hildenbrand

Niedergethmann

Marx

et al. 2009

The American Journal of Pathology

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“…The uPA system includes uPA, glycolipid-anchored uPA receptor (uPAR), and plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2) [85,87]. Binding of uPA zymogen (pro-uPA) to uPAR leads to uPA activation [85][86][87].…”

Section: Introduction Of Upa Systemmentioning

confidence: 99%

Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

Yue

Zhang

Chen

2012

Cancer Microenvironment

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The extracellular matrix (ECM) is an extracellular scaffold composed of complex mixtures of proteins that plays a pivotal role in tumor progression. ECM remodeling is crucial for tumor migration and invasion during the process of metastasis. ECM can be remodeled by several processes including synthesis, contraction and proteolytic degradation. In order to cross through the ECM barriers, malignant cells produce a spectrum of extracellular proteinases including matrix metalloproteinases (MMPs), serine proteases (mainly the urokinase plasminogen activator (uPA) system) and cysteine proteases to degrade ECM components. As major adhesion molecules to support cell attachment to ECM, integrins play critical roles in tumor progression by enhancing tumor cell survival, migration and invasion. Previous studies have shown that integrins can regulate the expression and activity of these proteases through different pathways. This review summarizes the roles of MMPs and uPA system in ECM remodeling and discusses the regulatory functions of integrins on these proteases in invasive tumors.

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“…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.…”

mentioning

confidence: 99%

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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Urokinase Plasminogen Activator Receptor Choreographs Multiple Ligand Interactions: Implications for Tumor Progression and Therapy

Cited by 113 publications

References 66 publications

Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix Remodeling

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

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