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

Metastatic spread of tumor cells depends upon intravasation of malignant cells from the primary site and extravasation into the distant organs following remodeling of the basement membrane. We have investigated the metastatic potential of five tumorigenic human colon carcinoma cell lines, LS 174T, SW 620, WiDr, SW 480 and Caco-2 using intrasplenic injection in nude mice. LS 174T is most aggressive causing liver metastasis in all animals within 6 weeks. SW 620 and WiDr produced liver metastasis in 70% and 30% of the animals but after a period of 12 weeks whereas SW 480 and Caco-2 were not metastatic. LS 174T exhibited high cell-associated urokinase-type plasminogen activator (u-PA) and high secreted u-PA and tissue plasminogen activator (t-PA) levels. WiDr, SW 480 and Caco-2 had essentially similar low levels of cell associated u-PA but WiDr had higher secreted u-PA levels as comprated to the SW 480 and Caco-2 cells. The level of secreted MMP-2 (72 kDa gelatinase) was highest in the most metastatic cell line, LS 174T, and lower in other less metastatic ones. These data show that metastatic behavior of human colon tumor cells correlates with the enhanced secretion of plasminogen activators and MMP-2 by these cells.
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PMID:Metastasis of human colon tumor cells in vivo: correlation with the overexpression of plasminogen activators and 72 kDa gelatinase. 780 12

Plasminogen activators (PAs) and their inhibitors (PAIs) can be produced by tumor cells and surrounding inflammatory cells and fibroblasts. The present study evaluate both the expression and release of PAs (uPA and tPA) and PAIs (PAI-1 and PAI-2) from cultured cells, and also the expression of uPA receptor (uPAR). Immunocytochemistry showed that PAs, PAIs and uPAR were present to different extents on the surface of colon carcinoma cells (Caco-2, HT-29), malignant melanoma cells (LOX) and normal fibroblasts. uPA immunoreactivity was intermediate in Caco-2, HT-29 and LOX and weak in the fibroblasts. tPA immunoreactivity was intermediate in Caco-2 and LOX and weak in HT-29 and fibroblasts. PAI-1 and PAI-2 immunoreactivities were absent in HT-29, weak in Caco-2 and strong in fibroblasts. In LOX the immunoreactivity was intermediate for PAI-1 and strong for PAI-2. uPAR immunoreactivity was weak in Caco-2, HT-29 and LOX and negative in fibroblasts. ELISAs on conditioned medium detected that the colon carcinoma cells Caco-2 and HT-29 did not release any PAs or PAIs. LOX released tPA (median 9 ng/million cells at 72 hours), PAI-1 (1050 ng/million cells) and PAI-2 (245 ng/million cells), and fibroblasts released uPA (1 ng/million cells) and PAI-1 (910 ng/million cells). These results show that both tumor cells and fibroblasts express tissue destructive enzymes, PAs and PAIs, whereas only the tumor cells express the uPAR required for focalization and regulation of PA activity at the cell surface. The melanoma cells LOX and fibroblasts also released PAs and PAIs, in contrast to the colon carcinoma cells Caco-2 and HT-29.
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PMID:Expression and release of plasminogen activators, their inhibitors and receptor by human tumor cell lines. 787 65

We have studied the cellular content and the extracellular release of cathepsins B and D, and of plasminogen activator, in 2 different tumor cell populations before confluence and after late confluence: the HT-29 colon carcinoma cell line, which contains primarily undifferentiated cells, and a subpopulation derived from this cell line, which contains cells committed to differentiation into mucus-secreting goblet cells after confluence. In both populations, cellular cathepsin-B activity increased after confluence, and latent cathepsin B was found in all culture media. In the parental cell line, cellular cathepsin D activity decreased after confluence; however, cathepsin D was secreted at high levels into the extracellular medium. In contrast, in the subpopulation of cells committed to differentiation, cellular cathepsin D activity increased after confluence, and cathepsin D was not secreted into the extracellular medium, but was immunolocalized in the apical brush border of the differentiated cells. Plasminogen activator of urokinase type was identified by immunocytochemistry. Both subconfluent cell populations, and the post-confluent undifferentiated cell population, produced plasminogen activator activity at similar levels. In contrast, in the differentiated postconfluent cells, the production of plasminogen activator activity was markedly lower. Our data show that the differentiation of HT-29 colon carcinoma cells into mucus-secreting cells impairs the secretion of plasminogen activator and cathepsin D, but does not affect cathepsin B.
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PMID:The state of differentiation of HT-29 colon carcinoma cells alters the secretion of cathepsin D and of plasminogen activator. 791 58

The plasminogen activation (PA) system of human Co115 colon carcinoma cells was investigated. Analysis at the levels of protein and mRNA of cultured cells and of histozymography of tumor xenografts in nude mice showed that Co115 cells produce only tissue type PA (t-PA) and no urokinase (u-PA). Also, mRNA for the u-PA receptor and for PA inhibitor type 2 (PAI-2), but not for PAI-1, were detected. We developed a quantitative degradation assay using glutaraldehyde-immobilized 125I-laminin to investigate the capacity of Co115 cells to degrade laminin. Laminin degradation by Co115 cells was completely inhibited by 100 micrograms/ml of polyclonal anti-t-PA IgG, by the plasmin inhibitors aprotinin (100 micrograms/ml) or epsilon-aminocaproic acid (EACA; at 0.3 M), but not by antibodies against u-PA or u-PAR nor by nonimmune IgG. Cycloheximide-treated Co115 cells were unable to degrade laminin but increased laminin degradation induced by conditioned medium of Co115 cells or recombinant t-PA. No potentiation was observed when Co115 cells and laminin were kept separated by Transwell inserts. Our results suggest that Co115 human colon carcinoma cells degrade laminin by potentiating t-PA-mediated plasminogen activation at the cell surface which requires close contact between tumor cells and laminin substrate.
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PMID:Human Co115 colon carcinoma cells potentiate the degradation of laminin mediated by tissue-type plasminogen activator. 796 13

1,2-Diglycerides with long-chain fatty acid residues related to nutritional fat (LCDGs) specifically affect growth and urokinase secretion in human colonic tumor cells, but not in normal mucosa. This allows them to advance and enhance carcinogenesis in the colon and rectum. SW480 colon carcinoma cells are LCDG sensitive in the same way as primary colonic tumor cells and have therefore been used as a model system to study the mechanism of LCDG action and to search for inhibitors of tumor development in the colon. Using this model system, we have shown that the effects of LCDGs are transmitted by protein kinase C and abolished by downregulation of the enzyme. Retinol, retinoic acid, and beta-carotene in nanomolar concentrations inhibit LCDG-induced growth and urokinase secretion and block stimulation of protein kinase C. Although retinol and retinoic acid at higher concentrations also display stimulatory activity, beta-carotene does not. At 100 nM, a concentration that can easily be reached in the plasma of humans, beta-carotene reduces LCDG-induced urokinase secretion about 50%. Inasmuch as beta-carotene does not have side effects due to intrinsic activities and storage effects, beta-carotene and foods rich in carotenes could be useful in the prevention of colorectal cancer.
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PMID:Retinoids inhibit protein kinase C-dependent transduction of 1,2-diglyceride signals in human colonic tumor cells. 805 26

Plasminogen activators (PA) have been implicated with the degradation of extracellular matrix during the invasive growth of metastasising tumour cells. The significance of PA expression in tumour cells for the in vivo growth of malignant tumours is still a matter of debate. We, therefore, performed immunohistological studies on human colon tumours using monoclonal antibodies against urokinase- (u-PA) and tissue-type plasminogen activator (t-PA) as well as against plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2). Normal colorectal mucosa of seven samples was negative for all four constituents of the PA system. Tumour epithelium of 64 colorectal carcinomas and 10 liver metastases was consistently negative for both, PA and their inhibitors. However, two of four human colon carcinoma cell lines weakly expressed u-PA, PAI-1 and PAI-2. Intestinal dendritic or fibroblast-like cells within the tumour tissue strongly expressed u-PA and, at a lower level, also t-PA, PAI-1 and PAI-2. Vascular endothelial cells were weakly positive for all components of the PA system in colon carcinoma. Our findings indicate that colon carcinoma cells in their natural environment do not express constituents of the PA system. PA activity, previously found in colon carcinoma tissue, is most likely derived from interstitial cells.
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PMID:Plasminogen activators and plasminogen activator inhibitors in human colorectal carcinoma tissues are not expressed by the tumour cells. 851 31

Surveillance colonoscopy and biopsy are inaccurate methods of predicting the likelihood of ulcerative colitis patients to develop colon carcinoma. We examined uPA and PAI-1 as potential markers for assessing these patients and those with familial polyposis who are at risk of developing colon cancer. For comparison, biopsies of normal colon and Crohn's disease were evaluated. We examined 77 colonic mucosa specimens taken from patients undergoing elective resection for benign and malignant colonic disease. uPA and PAI-1 were measured using a monoclonal antibody-based ELISA kit (American Diagnostica, Greenwich, CT) and expressed as ng/mg extract protein. Intra- and interassay controls of uPA gave CV = 3-4% and CV = 8-9%, respectively, while those for PAI-1 were 6-7% and 10-11%, respectively. The Mann-Whitney test showed that both uPA and PAI-1 expression were significantly higher in colon cancer, chronic ulcerative colitis, and Crohn's disease than in normal colon. uPA in familial polyposis samples was similar to that of normal colon, while PAI-1 was much lower than in normal colon. Neither patient age nor sex appeared to influence the expression of these potential markers in any tissue. The pattern of uPA and PAI-1 expression in normal, benign and malignant colon suggests these proteins deserve further consideration as markers for assessing colon carcinoma risk.
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PMID:Expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in colon disease. 858 11

The impact of prognostic markers on disease-free and overall survival reflects their relative role in tumour biology. Breast cancer and colon carcinoma can be taken as examples to demonstrate the clinical and biological relevance of 'new markers' of neoplastic disease. In breast cancer, receptor-bound urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 seem to play an important role in the dissolution of the surrounding tissue and the formation of tumour stroma. These processes are prerequisites for invasion and metastasis. The study of 'classical' and 'new' prognostic factors showed that uPA and PAI-1 content of breast cancer tissue are strong and independent prognostic factors. Also in colorectal cancer the prognostic relevance of plasminogen activators and inhibitors was analysed. In particular, low tissue plasminogen activator (tPA) levels, as antigen or as activity, high uPA: tPA antigen ratio in corresponding normal mucosa, high levels of uPA-related antigen and activity and of PAI-2 antigen in neoplastic tissue, and high uPA (neoplastic mucosa): tPA (normal mucosa) ratio, were all parameters associated with a poor overall survival. In conclusion, all these observations show the clinical importance of plasminogen activators and inhibitors at tissue levels with respect to cancer development and survival of patients affected by breast carcinoma or colorectal neoplasia. These new prognostic markers will also permit a better patient selection for a possible adjuvant treatment.
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PMID:Fibrinolysis components as prognostic markers in breast cancer and colorectal carcinoma. 869 36

Inflammation may promote malignant invasion by enhancing cancer cell-associated proteolysis. Here we present the effect of inflammatory cytokines on the plasminogen activation system of eight human colon carcinoma cell lines. Tumour necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) increased in several, but not all, cell lines the production of urokinase-type plasminogen activator (uPA), tissue-type PA (tPA) and plasminogen activator inhibitor type 1 (PAI-1) as analysed by zymography, enzyme immunoassays and Northern analysis. Interleukin 6 (IL-6) had no effect. uPA receptor (uPAR) mRNA levels were also upregulated. However, each individual cell line responded differently following exposure to TNF-alpha or IL-1 beta. For example, there was a dose-dependent up-regulation of uPA and PAI-1 in SW 620 cells, whereas increased uPA production in SW 1116 cells was not accompanied by an increase in PAI-1. The TNF-alpha stimulatory effect was blocked by anti-TNF-alpha Fab fragments. All cell lines expressed both types of TNF receptor mRNAs, whereas no transcript for TNF-alpha, IL-1 beta, IL-6, IL-6 receptor or the IL-1 receptors was found. Our results demonstrate that TNF-alpha and IL-1 beta stimulate the plasminogen activation system in tumour cell but the responses differed even in cells derived from the same tissue origin.
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PMID:Modulation of the plasminogen activation system by inflammatory cytokines in human colon carcinoma cells. 882 48

Neoplastic transformation in the normal human brain occurs as a result of the accumulation of a series of genetic alterations. These genetic alterations include the loss, gain or amplification of different chromosomes which lead to altered expression of proteins that play important roles in the regulation of cell proliferation. Several common genetic alterations at the chromosomal level (loss of 17p, 13q, 9p, 19, 10, 22q, 18q and amplification of 7 and 12q) have been observed. These alterations lead to changes in the expression of several genes; protein 53 (p53), retinoblastoma (RB), interferon (INF) alpha/beta, cyclic AMP dependent kinase number 2 (CDKN2), mutated in multiple advanced cancers 1 (MMAC1), deleted-in-colon carcinoma (DCC), epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), platelet derived growth factor receptor (PDGFR), MDM2, GL1, CDK4 and SAS during the genesis and progression of human gliomas. Recent studies suggest that altered expression of several other genes [MET; MYC; transforming growth factor beta (TGF beta); CD44; vascular endothelial growth factor (VEGF); human neurological-related cell adhesion molecule (hNr-CAM); neuroglial cell adhesion molecule (NCAM L1); p21waf1/Cip1; TRKA; mismatch repair genes (MMR); C4-2; D2-2] and proteins [e.g., cathepsins, tenascin, matrix metalloproteases, tissue inhibitors of metalloproteases, nitric oxide synthase, integrins, interleukin-13 receptor (IL-13R), Connexin43, urokinase-type plasminogen activator receptors (uPARs), extracellular matrix proteins and heat shock proteins] are associated with the genesis of human gliomas. Taken together, these findings point to the accumulation of multiple genetic mutations coupled with extensive changes in gene expression in the etiology of human gliomas.
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PMID:Molecular changes during the genesis of human gliomas. 940 26


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