Immunohistochemical localization of a urokinase-type plasminogen activator system in squamous cell carcinoma of the oral cavity: association with mode of invasion and lymph node metastasis

Nozaki, Shinichi; Endo, Yuichi; Kawashiri, Shin‐ya; Nakagawa, Kiyomasa; Yamamoto, Etsuhide; Yonemura, Y; Sasaki, Takuma

doi:10.1016/s1368-8375(97)00028-6

Cited by 73 publications

(80 citation statements)

References 19 publications

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“…Cells with high expression levels of uPAR were strongly invasive in Matrigel and fibroblast spheroids. These findings are in line with data from Nozaki et al, 21 demonstrating a correlation between uPA/uPAR and invasion capacity of tumors of the oral cavity by immunohistochemical techniques. The significance of the expression of uPA components in tumors remains a matter of debate as some publications report no correlation between uPA, uPAR and PAI-1 expression or activity and tumor cell invasion.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system

Ertongur

Lang

Mack

et al. 2004

Intl Journal of Cancer

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The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades. This is mainly due to the so-called minimal residual disease, i.e., remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases. To metastasize, tumor cells take advantage of proteases to invade and remodel surrounding tissues. Here, we analyzed the efficiency of WX-UK1, a novel 3-amidinophenylalanine-based inhibitor of the uPA system, at inhibiting the invasive capacity of carcinoma cells. First, uPAR expression was characterized in different carcinoma cell lines, including SCCHN, breast and cervical carcinoma. Thereafter, the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts. uPAR expression levels correlated positively with invasion capacity, which could be significantly inhibited by WX-UK1. Despite improvements in surgical and radiotherapeutic techniques, the 5-year survival rate of patients suffering from SCCHN has remained poor and nearly unchanged over the last decades, primarily due to their tendency to develop locoregional and distant metastases. 1 This underlines the necessity of new modalities to treat MRD, 2 i.e., the spread of occult malignant cells to locoregional and/or distant sites and inhibition of metastasis formation. Both MRD and metastasis formation are major causes of recurrence and therefore death in cancer patients.Tumor invasion and metastasis formation are complex biologic processes depending on matrix-degrading proteolytic systems that allow tumor cells to detach from their primary site; migrate through the surrounding tissue, blood or lymph vessels; and distribute to distant sites. 3 One of the major proteolytic systems involved in these processes is the urokinase-type plasminogen activation system with its key components: uPA, the cell-surface receptor uPAR (CD87) and the inhibitor PAI-1. 4,5 Plasmin, generated from its precursor plasminogen by activators such as uPA, catalyzes the degradation of extracellular matrix components and is important for fibrinolysis. Proteases such as plasmin and others increase the invasion capacity and tissue-remodeling ability of carcinoma cells. 6 Upon binding to its receptor on the surface of various cell types, the activator can induce direct plasmin-mediated proteolysis or indirect activation of other proteinases, like metalloproteases, by triggering signal-transduction pathways and thereby facilitate matrix degradation and tumor invasion. 6 uPA can also be activated by cysteine proteases like cathepsin B or L, which are located intracellularly and at tumor cell surfaces. 7 Additionally, components of the uPA system are overexpressed in malignant tumors such as breast, gastric, esophageal, lung, prostate, colorectal and others, 8 correlating with a poor prognosis. High levels of uPA components were also measured in head-and-neck carcinomas and can be used as a prognostic...

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Section: Discussionsupporting

confidence: 93%

“…10,21 Our results are in line with these findings and, interestingly, show higher uPAR expression in single tumor cells than in tight cell aggregates, according to the hypothesis that the presence of uPA-system components is essential for the invasive capacity of single cells.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system

Ertongur

Lang

Mack

et al. 2004

Intl Journal of Cancer

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show abstract

“…Staining methods. Immunohistochemical staining was performed by using by the labeled streptavidin-biotin (LSAB) method following deparaffinization and rehydration as described by Nozaki et al (10). The sections were reacted with the following primary antibodies: anti-maspin antibody (Lab Vision, Fremont, CA, USA) 300-fold diluted with PBS at 4˚C overnight (11) and anti-uPA and uPAR (10) (no.…”

Section: Introductionmentioning

confidence: 99%

Expression of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor and maspin in oral squamous cell carcinoma: Association with mode of invasion and clinicopathological factors

Yoshizawa

Nozaki²,

Kitahara³

et al. 2011

Oncol Rep

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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.

show abstract

Immunohistochemical localization of a urokinase-type plasminogen activator system in squamous cell carcinoma of the oral cavity: association with mode of invasion and lymph node metastasis

Cited by 73 publications

References 19 publications

Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system

Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system

Expression of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor and maspin in oral squamous cell carcinoma: Association with mode of invasion and clinicopathological factors

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

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