Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accruing evidence suggests an association between increased activity of plasminogen activators and transformed cells, and urokinase activity with tumour aggressiveness. The PIP2 pathway seems to provide a link between oncogene-associated transformation, cellular proliferation, plasminogen-activator expression and tumour invasion and metastasis.
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PMID:The relationship of plasminogen activators and oncogenes to tumour invasion. 215 39

The distributions of urokinase and tissue plasminogen activators (uPA, tPA), uPA receptor (uPAR), and plasminogen activator inhibitors (PAI-1, PAI-2) were studied immunohistochemically in two subsets of colorectal adenocarcinomas with low and high aggressiveness, respectively: nine Dukes' stage A tumors with additional other good prognostic markers and 13 Duke's stage C tumors with also other poor prognostic markers (referred to as Dukes' stage A and Dukes' stage C tumors). The results showed that these components of the tissue destructive plasminogen activation system were accumulated at the invading front of the tumors. Both tumor groups showed accumulations of uPA, uPAR, and PAI-1 at the tumor-host interface compared with the location within the tumor epithelium and the adjacent normal mucosa and muscularis propria (all P < .05). However, the uPA level at the tumor-host interface in the Dukes' stage C tumors was twice the level in the Dukes' stage A tumors (P < .05). The uPAR level was also significantly higher in the Dukes' stage C tumors (P < .05), whereas the PAI-1 level was not significantly higher. This may indicate that uPA in more aggressive tumors exceeds the inhibitory capacity represented by PAIs, resulting in enhanced tissue destructive potential that promotes tumor invasion. uPA and uPAR antigen levels and the uPA/PAI-1 ratio at the tumor-host interface appeared to be related to tumor aggressiveness in colorectal cancer.
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PMID:Antigen levels of urokinase plasminogen activator and its receptor at the tumor-host interface of colorectal adenocarcinomas are related to tumor aggressiveness. 755 47

In an attempt to define the role of plasminogen activator in invasiveness and differentiation of human melanoma cells, the modulation of these parameters was studied in two melanoma clones characterized by marked differences in their basal features, using 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and retinoic acid, two differentiation inducers, and doxorubicin, a cytotoxic agent. TPA induced only slight reductions, whereas retinoic acid and doxorubicin caused an increase in invasiveness, enzymatic activity and differentiation in the clone showing low invasivity, low urokinase-type plasminogen activator levels and high differentiation. In contrast, in the clone showing high invasivity, high urokinase-type plasminogen activator levels and low differentiation it was found that: TPA was ineffective; retinoic acid induced a reduction of plasminogen activator but no modifications of invasiveness and differentiation; doxorubicin caused a decrease in invasiveness and plasminogen activator activity but no modification of morphological features. The different behaviour of the two clones thus could be related to the basal features of the clones. The results reported here indicate that in the presence of these drugs the associations between invasiveness and urokinase-type plasminogen activator activity and between invasiveness and differentiation are lost. Drug treatment therefore significantly affected the features of the clone characterized by low biological aggressiveness (high differentiation, low invasiveness), whereas the highly aggressive clone did not show a consistent response to drug treatment.
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PMID:Modification of invasion and differentiation in human melanoma cell clones. 795 Mar 60

Immunostaining of two invasion-associated proteolytic enzymes, cathepsin D (CD) and urokinase-type plasminogen activator (uPA), was assessed in cryostat sections of 86 stage-heterogeneous breast carcinomas using monoclonal antibodies. Most tumors displayed a focal and/or heterogeneous staining pattern. Overall, staining was more frequent in host-derived stromal and inflammatory cells (uPA 54%, CD 89%) than neoplastic epithelium per se (uPA 24%, CD 70%). Intense (i.e., 2+) stromal, but not neoplastic, CD was significantly correlated with nodal or systematic metastases (node negative--10% versus node positive/systemic--33%, p = 0.04). Further, cumulative staining of more than one enzyme (CD + uPA) or more than one tumor component (stroma + epithelium) correlated with metastatic disease (no metastases--35% versus metastatic--72%, p = 0.005). Neither stromal nor epithelial CD alone was significantly correlated with short-term recurrence free survival, however additive CD staining (i.e., stromal + epithelial) was strongly predictive, overall (both + -75% recurred versus both weak/negative--16% recurred, p = 0.0004) and in node positive patients (p = 0.02). We conclude that (a) enzymes putatively mediating extracellular matrix dissolution may be derived from multiple sources and (b) the metastatic capacity and/or clinical aggressiveness of breast carcinomas may reflect overall proteolytic enzyme expression, suggesting that cooperative enzyme interaction may be required for invasive growth and/or metastasis.
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PMID:Immunohistologic evaluation of invasion-associated proteases in breast carcinoma. 834 78

Carcinogenesis in the human colon is associated with a marked increase of urokinase type plasminogen activator and a decrease of tissue type plasminogen activator. This study was performed to determine the concentrations of urokinase type plasminogen activator and tissue type plasminogen activator in normal tissue and carcinomas along the upper part of the gastrointestinal tract. Activity and antigen levels of both activators were determined in homogenates of endoscopically obtained biopsies from normal and carcinomatous tissues. Although the concentrations of tissue type plasminogen activator and urokinase type plasminogen activator in normal squamous epithelium of the oesophagus were low compared with those in columnar epithelium from the stomach, the urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio of the different locations showed hardly any difference. Significant but heterogeneous increases were found in urokinase type plasminogen activator concentrations of biopsy specimens originating from carcinomas of both epithelial cell types. A decrease in tissue type plasminogen activator concentrations, as found in human colon carcinomas, could only be shown in carcinomas of columnar epithelium origin but not in squamous cell carcinomas of the oesophagus. The increase of urokinase type plasminogen activator and urokinase type plasminogen activator/tissue type plasminogen activator antigen ratio and the decrease of tissue type plasminogen activator in the carcinomas did not show a significant correlation with known prognostic determinants as differentiation grade, TNM classification, intestinal metaplasia, inflammation, and ulceration. The heterogeneous increase of urokinase type plasminogen activator in oesophageal and stomach carcinomas, together with the recently described association of urokinase type plasminogen activator in tissue extracts of breast carcinomas with aggressiveness and prognosis, may be relevance to prognostic studies, may be of relevance to prognostic studies in oesophageal and gastric cancer.
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PMID:Plasminogen activators in normal tissue and carcinomas of the human oesophagus and stomach. 843 57

The prostate gland is the most common site of cancer in men in the United States. The biologic behavior of an individual tumor, however, varies widely, with some cancers taking a relatively indolent course and other progressing rapidly to disseminated disease. Prognostic factors that might help predict a tumor's aggressiveness and invasiveness are limited. The expression of urokinase plasminogen activator was evaluated in 36 human prostate cancer specimens. Using an immunohistochemical method with monoclonal antibody #394, 70.6% (12 of 17) of cancer specimens with extracapsular extension showed increased expression of urokinase plasminogen activator, compared with 26.6% (4 of 15) of specimens without capsular invasion. Increased expression was localized to the glandular cytoplasm, with tumor stroma yielding predominantly negative results. These findings provide additional evidence of the role of urokinase in determining the biologic behavior and metastatic potential of prostate cancer.
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PMID:Urokinase-type plasminogen activator expression in human prostate carcinomas. 868 32

We compared macrophage density, assessed by enumeration of peritumoral mononuclear cell immunoreactivity for HAM 56, to clinicopathologic features and to immunostaining for two "invasion-associated" proteases (Cathepsin D and Urokinase plasminogen activator) in 80 breast carcinomas. Diffuse (2+) infiltrates of HAM 56- positive mononuclear cells were present in 27 cases (34%) and 43 (54%) exhibited focal (1+) infiltrates. Presence of 2+ macrophage infiltrates correlated significantly with poor differentiation. None of the seven well-differentiated cases exhibited 2+ infiltrates, whereas 9/43 (21%) moderately differentiated and 18/30 (60%) poorly differentiated tumors were diffusely infiltrated (p = .001). Wide-spread macrophage infiltrates were also more frequent in cases with advanced stage (23% of node negative vs 40% of node positive cases, p = NS). Forty-four percent of the cases with diffuse macrophage infiltrates were cathepsin D positive (i.e. in host derived cells) vs only 18% with focal macrophage infiltrates (p = .002). A similar relationship was observed between staining for HAM 56 and urokinase-type plasminogen activator (p = .02). Disease recurrences (50 months median follow-up) were more frequent in patients with 2+ (17/27, 63%) as opposed to 0+ (1/10, 10%) macrophage infiltrates (p = .01). We conclude that the density of stromal macrophage infiltrates is associated with clinical aggressiveness in breast carcinomas. Further, this relationship may reflect contribution of host derived macrophages to invasion and metastasis through elaboration of proteases which putatively mediate degradation and remodeling of extracellular matrix.
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PMID:Clinicopathologic analysis of macrophage infiltrates in breast carcinoma. 882 15

We have established human oral-squamous-cancer cell lines, BHY and HN, derived from non-metastatic cancer and metastatic cancer respectively. We examined the expression of matrix-degrading enzymes and their inhibitors in these cell lines. Both cell lines expressed pro-matrix metalloproteinase (MMP)1, proMMP2, proMMP9, membrane-type MMP and urokinase-type plasminogen activator. In addition to these enzymes, BHY cells secreted proMMP7 and procathepsin L, while HN cells secreted a large amount of active MMP2. BHY cells secreted a tissue inhibitor of matrix metalloproteinase, TIMP2, but only a trace level of TIMP1. Contrary to BHY cells, HN cells secreted TIMP1, but only a trace level of TIMP2. When we inoculated these cells into the masseter muscle of nude mice, both types of cell formed solid tumors, whose microscopic appearance was identical to that of the original tumors. BHY tumors were highly differentiated squamous-cell carcinomas, and invasive to the masseter muscle and the mandibular bone. Despite their local aggressiveness, BHY tumors did not metastasize to any distant organs. HN tumors were poorly differentiated squamous-cell carcinomas, weakly invasive to the muscle, but not to the mandibular bone. However, HN tumors frequently metastasized to cervical lymph nodes. These results suggest that the net activity of MMP2 (active MMP2/TIMP2) and cathepsin L secreted from cancer cells may contribute respectively to lymph-node metastasis and to bone invasion by oral cancer cells.
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PMID:Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines. 898

The activation of zymogen and the amount of proteinase and its inhibition are important in determining the eventual activity of matrix-degrading enzymes involved in tumor aggressiveness. To evaluate a gene complement leading to matrix metalloproteinase 2 (MMP-2; Mr 72,000 gelatinase) activity, membrane type 1 MMP (MT1-MMP), urokinase-type plasminogen activator, MMP-2, and tissue inhibitor of metalloproteinase 2 transcriptional levels were measured in gastric carcinoma biopsies. Comparative tumor:normal tissue reverse transcription-PCR in a cohort of 25 patients revealed up to a 10-fold difference in the expression of MT1-MMP, a metalloproteinase that has been proposed as a membrane receptor activator of MMP-2; a 1-unit increment resulted in a 30% risk to survival. A 20% risk also resulted from a 1-unit increment in the MT1-MMP: MMP-2 ratio, which showed differences of up to 15-fold. Instead, the expression of urokinase-type plasminogen activator, which trips off a cascade ending in the activation of MMP-2, as well as the expression of MMP-2 itself and its inhibitor, tissue inhibitor of metalloproteinase 2, lacked correlation with patient follow-up. Zymography revealed MMP-2 activities that were often in conflict with the transcription results and also with follow-up. The results suggest the evaluation of MT1-MMP and/or MT1-MMP:MMP-2 transcription as a new preoperative molecular-level prognostic factor for gastric carcinoma.
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PMID:Augmented membrane type 1 matrix metalloproteinase (MT1-MMP):MMP-2 messenger RNA ratio in gastric carcinomas with poor prognosis. 974 37

The plasminogen activating system plays a key role in the cascade of tumour-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in the expression of this system, consisting of urokinase- and tissue-type plasminogen activators (uPA and tPA, respectively), plasminogen activator inhibitors (PAI-1, PAI-2) and uPA receptor, have been associated with tumour aggressiveness in a variety of solid malignant tumours. This paper describes a study of squamous intraepithelial lesions (SILs, n=36), squamous cell carcinomas (SCCs, n=42), and normal mucosa (n=5) of the uterine cervix by in situ hybridization with (35)S-labelled RNA probes. uPA transcripts were absent from normal mucosa and non-invasive lesions, but present in atypical epithelial cells of all microinvasive carcinomas ( n=19) and in some of the more advanced invasive carcinomas (n=11). PAI-1 transcripts were found in stromal cells of most tissue samples with, however, significantly increased levels in invasive SCC compared with SIL, microinvasive SCC, and normal mucosa. uPA-positive invasive carcinomas often displayed additional PAI-1 expression by tumour cells. At variance with uPA, tPA transcripts were found in atypical epithelial cells of low- and high-grade SILs. In the majority of SCCs tested (27/29 cases), the HPV 16 E6/E7 oncogene and uPA transcription were correlated. uPA and PAI-1 expression indicates invasive growth when expressed by atypical epithelial cells of squamous cervical lesions. Moreover, the presence of uPA transcripts is indicative of early invasive growth. uPA and tPA seem to have different functions in the development of invasive properties in uterine cervical squamous epithelium.
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PMID:Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix. 1054 82


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