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)

Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth.
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PMID:Oncostatin M induces angiogenesis in vitro and in vivo. 1044 61

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.
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PMID:Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. 1050 7

The expression patterns of vascular endothelial growth factor (VEGF) and its two receptors, flt-1 and KDR, were assessed in normal human melanocytes, transformed melanocytes expressing the simian virus 40 Tgene (SV40T), and melanoma cells derived from primary and metastatic lesions. Constitutive expression of VEGF, flt-1, and KDR mRNA and proteins was observed in the majority of primary and metastatic melanoma cell lines, and in SV40T-transformed melanocytes. VEGF expression in melanoma cell lines was further enhanced by exogenous growth factors including insulin and fetal calf serum. By contrast, neonatal melanocytes did not express VEGF or VEGF receptors and VEGF expression could not be induced by exogenous growth factors. Exogenous VEGF had no significant effects on melanoma cell proliferation or on production of a transcriptional target for VEGF, urokinase-type plasminogen activator. Down-regulation of VEGF expression in the metastatic melanoma cell line WM164 through transfection of a VEGF antisense construct similarly did not affect proliferation of the transfected cells in the presence or absence of exogenous VEGF. In summary, coexpression of VEGF and its receptors is a tumor-associated phenomenon in melanoma development. However VEGF production does not support autocrine proliferation of the melanoma cell lines tested.
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PMID:Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. 1054 69

A new human hepatocellular carcinoma (HCC) cell line with a highly metastatic potential was established from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) by means of alternating cell culture in vitro and growth in nude mice. The line, designated MHCC97, has been cultivated for 18 months and subcultured for more than 90 passages. The line was showed to be of human origin by karyotype analysis. The cells were either grown as compact colonies (in clusters) or as a monolayered sheet with about 31 h of population-doubling time, exhibited typical malignant epithelial in morphology and were positive for alpha-fetoprotein (AFP). Flow cytometric analysis of the cell DNA content showed an aneuploid pattern, and its index was 1.5 as compared to that of normal human peripheral blood lymphocytes. Karyotypic analyses of G- and C-banding techniques revealed that all cells presented chromosome abnormalities in number and structure. The number of cell line MHCC97 chromosome ranged from 59 to 65 with a modal number of 60 and 61. At least two common chromosome markers, i(1q) and der(4)t(4;?)(4pter-->q35::?), were present in all cells, and deletion of Y chromosome also occurred in all cells. The subcutaneous and intrahepatic xenografts were formed and metastatic lesions in lungs were found after the cells were inoculated into nude mice. The rate of metastasis to lungs was 100% using orthotopic inoculation. Reverse transcription polymerase chain reaction products revealed positive expressions of integrin alpha5 and beta1, urokinase type plasminogen activator receptor (uPAR), vascular endothelial growth factor and nm23-H1 mRNAs of cell line MHCC97. Immunostaining of c-Met, uPAR showed strongly positive in both subcutaneous xenografts and lung metastatic lesions; while positive in xenografts and negative in metastatic lesions for integrin alpha5, beta1. E-cadherin and P53 was not expressed either in xenograft or in the metastatic lesions. PCR products of HBsAg and HBxAg were both positive. The cell line MHCC97 still retained some characteristic features of original tumour. Establishment of cell line MHCC97 should be beneficial to the studies of HCC metastatic mechanisms.
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PMID:New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. 1055 51

Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, the ventricular ependyma, meninges, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal brain tissue. Our finding may suggest a functional co-operation of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.
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PMID:Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression. 1057 9

1. Fenestrated vessels can be reversibly induced in brain by agents that stimulate urokinase production. This plasminogen activator, like vascular endothelial growth factor and metalloproteinases, is secreted by tumor cells and may account for induction of fenestrated vessels. Why only some of the brain's barrier vessels are converted to fenestrated vessels is unknown. 2. The structures responsible for the filtering of solutes by fenestrated vessels may be the same as those of continuous, less permeable vessels: the glycocalyx on the surfaces of the endothelial cells and the subendothelial basal lamina. 3. Solutes leaving the cerebral ventricles immediately enter the interstitial clefts between the cells lining the ventricles. A fraction of a variety of solutes, injected into CSF compartments, is retained by subendothelial basal lamina, from which the solutes may be released in a regulated way. 4. The brain's CSF and interstitial clefts are the conduits for nonsynaptic volume transmission of diffusible signals, e.g., ions, neurotransmitters, and hormones. This type of transmission could be abetted by a parallel, cell-to-cell volume transmission mediated by gap junctions between astrocytes bordering CSF compartments and parenchymal astrocytes. 5. The width and contents of the interstitial clefts in fetal brain permit cell migration and outgrowth of neurites. The contents of the narrower and different interstitial clefts of mature brain permit solute convection but must be enzymatically degraded in order for cells to migrate through it.
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PMID:Permeable endothelium and the interstitial space of brain. 1069 5

The angiopoietin/Tie receptor system may contribute to angiogenesis and vascular remodeling by mediating interactions of endothelial cells with smooth muscle cells and pericytes. The temporal expression of angiopoietin-1 (Angpo-1), angiopoietin-2 (Angpo-2), Tie-1, and Tie-2 mRNA was studied in a focal cerebral ischemia model in rats. The cDNA fragments obtained from reverse transcription polymerase chain reaction amplification were cloned and used as a probe to detect individual genes. Northern blot analysis showed a delayed increase of a 4.4-kb Angpo-1 transcript for up to 2 weeks after ischemia, eightfold higher than the values of the sham-operated controls. A biphasic expression of a 2.4-kb Angpo-2 transcript was noted, peaking at 24 hours (6.4-fold) and 2 weeks (4.6-fold) after ischemia. The expression of Tie-2 mRNA (4.3 kb), a receptor for Angpo-1, and Tie-1 mRNA (4.3 kb) also increased starting 24 hours after reperfusion and remained elevated for up to 2 weeks after ischemia. The temporal profiles of the expression of these genes were different from those of other angiogenic genes such as basic fibrobast growth factor/fibroblast growth factor receptor and vascular endothelial growth factor/vascular endothelial growth factor receptor and proteolytic enzymes (tissue-type plasminogen activator and urokinase plasminogen activator) and their inhibitors (plasminogen activator inhibitor-1). The expression patterns of these genes could be related to progressive tissue liquefaction and neovascularization after ischemia in this stroke model. Differential expression of these angiogenesis genes suggests the involvement of complex regulatory mechanisms that remain to be characterized.
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PMID:Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. 1069 77

The development of a blood supply is crucial to the growth and metastasis of cancer. The factors involved in this are complex, however tumour hypoxia and macrophage infiltration are responsible for the synthesis of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and the fibroblast growth factors. These factors stimulate proliferation of vascular endothelial cells, the synthesis of proteases such as urokinase type plasminogen activator (uPA) and the matrix metalloproteases, which result in digestion of the extracellular matrix and allow endothelial cell invasion. Endothelial cell motility is promoted by binding of extracellular matrix proteins such as vitronectin and fibronectin to integrins expressed on the plasma membrane of endothelial cells. Interfering with any of these steps may inhibit the process of angiogenesis and drugs aimed at modulation of angiogenesis are currently undergoing evaluation in early clinical studies. This paper reviews our current understanding of angiogenesis and how it may be used as a target for the treatment of cancer.
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PMID:Tumour vasculature as a target for anticancer therapy. 1081 61

Levels of lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) are elevated in the plasma and ascites of ovarian cancer patients, but not in most other tumor types. LPA increases cell proliferation, cell survival, resistance to cisplatin, cell shrinkage, and production of vascular endothelial growth factor, urokinase plasminogen activator, and LPA itself in ovarian cancer cells, but not in normal ovarian surface epithelial cells. PSP24 and members of the endothelial differentiation gene (EDG) family (EDG1, EDG2, EDG4, and EDG7) of G protein-coupled receptors mediate LPA signaling. Ovarian cancer cell lines do not express EDG1 mRNA, have variable EDG2 mRNA and protein levels, and frequently exhibit levels of EDG4 mRNA and protein, suggesting that EDG4 may contribute to the deleterious effects of LPA in ovarian cancer. In contrast, activation of the EDG2 LPA receptor on ovarian cancer cells may lead to apoptosis and counter the effects of other LPA receptors. Thus, the development of agonists and antagonists for the appropriate spectrum of LPA receptors may alter proliferation, apoptosis, or response to therapy of ovarian cancer cells. Indeed, over 60% of all current drugs target the G protein-coupled family of receptors, making the LPA receptor family a "drugable" target. LPC, although not as thoroughly studied, increases cellular proliferation and mediates multiple other functions through unique signaling pathways.
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PMID:Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. 1081 54

Angiogenesis is an important phenomenon for the growth and metastasis of solid tumors. The present study examined the characterization of angiogenic factors produced by human oral squamous cell carcinoma (oral SCC) cell lines established from lymph node metastatic tumors and primary tumor in different patients. The conditioned medium of HSC3 with the strongest metastatic ability among the examined lines enhanced a tube-forming activity of bovine carotid artery endothelial (BAE) cells in collagen gel cultures. The treatment of HSC3 with anti-vascular endothelial growth factor (VEGF) antibody or anti-basic fibroblast growth factor (bFGF) antibody, either alone or in combination, attenuated the activity of urokinase-type plasminogen activator (uPA) in the endothelial cells stimulated by the conditioned medium of HSC3. In contrast, neither anti-interleukin-8 (IL-8) antibody nor anti-hepatocyte growth factor (HGF beta) antibody affected uPA activity in the endothelial cells. Among these HSC cell lines, HSC3 secreted VEGF with the highest (1.92 +/- 0.24 ng/10(6) cells/24 h) level and bFGF. The level of bFGF secreted by HSC3 was lower than that secreted by BAE cells. Other oral SCC cell lines secreted lower levels of VEGF and undetectable levels of bFGF. By reverse transcriptase-polymerase chain reaction analysis of mRNA the production of VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206 in these cell lines was able to be detected. Moreover, the conditioned medium of HSC3 enhanced the tyrosine phosphorylation and expression of kinase insert domain-containing receptor (KDR/flk-1) in the endothelial cells. These results suggest that oral SCC promotes angiogenesis via expression of VEGF and upregulation of their receptor KDR/flk-1 expression in endothelial cells.
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PMID:Human oral squamous cell carcinoma cell lines promote angiogenesis via expression of vascular endothelial growth factor and upregulation of KDR/flk-1 expression in endothelial cells. 1088 25


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