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)

Tumor angiogenesis progresses by a dynamic balance between tumor vascular regression and growth. Angiopoietin (Ang)-2 (the natural antagonist for the angiogenic Tie-2 receptor) and vascular endothelial growth factor (VEGF) are thought to be critical regulators in this process; therefore, these may play a critical role in cancer aggressiveness. The aim of this study was to clarify the clinical and biological significance of the expression of Ang-2 in human gastric cancers and to investigate the relationship between Ang-2 together with VEGF and the induction of proteases such as matrix metalloproteinases (MMPs) in the process of tumor development. Eighty-five individuals with gastric cancer, who had undergone surgery without preoperative treatment, were studied. A stable transfectant of the human MKN-7 gastric cancer cell lines with an Ang-2 expression vector was used for the experimental study. First, we examined the relationship between the mRNA expression of Angs by Northern blot analysis and clinicopathological features. High Ang-2-expression cases showed more frequent vascular involvement and more advanced stages of disease compared with low Ang-2-expression cases (P < 0.05). With regard to prognosis, the survival time for patients in the high-Ang-2 mRNA group was significantly shorter (P < 0.05). When we examined the localization of Ang-2 in human gastric cancers, immunohistochemical analysis revealed that this protein was expressed predominantly in cancer tissues when compared with normal tissues. Interestingly it was expressed not only in endothelia cells (ECs) but also in cancer cells. Second, Ang-2-transfected cells were implanted in vivo into the gastric walls of nude mice. Ang-2-transfectant mice developed highly metastatic tumors with hypervascularity as compared with MKN-7 or control vector-transfectant tumors. There was a significant correlation between Ang-2 mRNA expression and lower grade of vessel maturation. Third, on the basis of the in vivo data, we focused on production of proteases such as MMPs to investigate possible mechanisms in these processes. MMP-1, MMP-9, and urokinase-type plasminogen activator in ECs were strongly up-regulated by Ang-2 in the presence of VEGF in vitro. These data suggest that production of Ang-2 is implicated in tumor development in human gastric cancers. Its production may contribute to tumor angiogenesis by induction of proteases in ECs, which may be enhanced in the presence of VEGF.
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PMID:Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. 1128 Jul 79

Endometrial angiogenesis is not well studied, but has potential as a model for studies of physiological angiogenesis. Migration as well as proliferation of vascular endothelial cells are modulated by other endometrial cells. This study analyzes the chemotactic signal released from endometrial tissue in a wound assay using human microvascular endothelial cells. Endometrial tissue explants stimulate migration, and this effect is significantly weaker with explants taken at midcycle than those obtained earlier or later in the cycle. Migration is inhibited more than 50% by either blocking antibodies to the urokinase plasminogen activator receptor (uPAR) or enzymatic removal of uPAR from the cell surface. Also, migration is inhibited more than 50% by antibodies to epidermal growth factor (EGF), but not by antibodies to vascular endothelial growth factor or basic fibroblast growth factor. The combination of anti-EGF and anti-uPAR antibodies does not further reduce the response, suggesting that these antibodies target a common pathway. Conditioned medium from endometrial explants contains EGF, and EGF stimulates the migration of endothelial cells in a dose-dependent way. This effect is completely blocked by antibodies to uPAR. These data suggest up-regulation of the uPA system by EGF. Conditioned medium from EGF-treated cells contains less uPA than medium from control cells. In contrast, binding of radiolabeled uPA reveals an increased number of uPA-binding sites in EGF-treated cells. Increased expression of uPAR potentially increases the activation and assembly of focal adhesion sites, a prerequisite for cell migration. We conclude that the endometrial migratory signal has two components. The major part of the signal is blocked by antibodies to EGF, and the response is mediated via up-regulation of uPAR in the endothelial cells. The other part of the signal is unknown, and the response does not involve uPAR. Decreased endometrial chemotactic signal at midcycle is probably related to decreased release of EGF, which is secondary to increased binding to endometrial cell membranes.
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PMID:Paracrine stimulation of capillary endothelial cell migration by endometrial tissue involves epidermal growth factor and is mediated via up-regulation of the urokinase plasminogen activator receptor. 1129 9

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.
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PMID:Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer. 1137 60

Angiogenesis, the formation of new capillary blood vessels, occurs almost exclusively in the microcirculation. This process is controlled by the interaction between factors with positive and negative regulatory activity. In this study, we have compared the effect of two well described positive regulators, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) on bovine adrenal cortex-derived microvascular endothelial (BME) and bovine aortic endothelial (BAE) cells. The parameters we assessed included (a) cellular reorganization and lumen formation following exposure of the apical cell surface to a three-dimensional collagen gel; (b) organization of the actin cytoskeleton; (c) expression of thrombospondin-1 (TSP-1), an endogenous negative regulator of angiogenesis; and (d) extracellular proteolytic activity mediated by the plasminogen activator (PA)/plasmin system. We found that (a) collagen gel overlay induces rapid reorganization and lumen formation in BME but not BAE cells; (b) FGF-2 but not VEGF induced dramatic reorganization of actin microfilaments in BME cells, with neither cytokine affecting BAE cells; (c) FGF-2 decreased TSP-1 protein and mRNA expression in BME cells, an effect which was specific for FGF-2 and BME cells, since TSP-1 protein levels were unaffected by VEGF in BME cells, or by FGF-2 or VEGF in BAE cells; (d) FGF-2 induced urokinase-type PA (uPA) in BME and BAE cells, while VEGF induced uPA and tissue-type PA in BME cells with no effect on BAE cells. Taken together, these findings reveal endothelial cell-type specific responses to FGF-2 and VEGF, and point to the greater specificity of these cytokines for endothelial cells of the microvasculature than for large vessel (aortic) endothelial cells. Furthermore, when viewed in the context of our previous observation on the synergistic interaction between VEGF and FGF-2, our present findings provide evidence for complementary mechanisms which, when acting in concert, might account for the synergistic effect.
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PMID:Response of bovine endothelial cells to FGF-2 and VEGF is dependent on their site of origin: Relevance to the regulation of angiogenesis. 1150 Sep 40

Endothelial cell migration is stimulated by members of the vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) families, and is dependent on extracellular proteolytic activity provided by enzymes of the plasminogen activator (PA) system. Here we report that in bovine microvascular endothelial cells (BME cells), bFGF principally increased urokinase-type PA (u-PA) while tissue-type PA (t-PA) was increased mainly by VEGF. In bovine aortic endothelial cells (BAE cells), bFGF increased u-PA, whereas VEGF had no effect. Co-added bFGF and VEGF increased t-PA mRNA levels and enzyme activity in both cell types in a synergistic manner. Tissue-type plasminogen activator (t-PA) immunoreactivity colocalized with von Willebrand factor, a marker for Weibel-Palade bodies. Co-added bFGF and VEGF increased the number of t-PA-positive cells as well as the number of t-PA-positive granules per cell. Localization of t-PA in regulated storage granules endows endothelial cells with the potential to rapidly increase proteolytic activity in the pericellular environment.
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PMID:Synergistic induction of t-PA by vascular endothelial growth factor and basic fibroblast growth factor and localization of t-PA to Weibel-Palade bodies in bovine microvascular endothelial cells. 1152 25

Cyr61 is a heparin-binding, extracellular matrix-associated protein of the CCN family, which also includes connective tissue growth factor, Nov, WISP-1, WISP-2, and WISP-3. Cyr61 is capable of multiple functions, including induction of angiogenesis in vivo. Purified Cyr61 mediates cell adhesion and induces adhesive signaling, stimulates cell migration, enhances cell proliferation, and promotes cell survival in both fibroblasts and endothelial cells. In this study, we have used cDNA array hybridization to identify genes regulated by Cyr61 in primary human skin fibroblasts. The Cyr61-regulated genes fall into several groups known to participate in processes important for cutaneous wound healing, including: 1) angiogenesis and lymphogenesis (VEGF-A and VEGF-C); 2) inflammation (interleukin-1beta); 3) extracellular matrix remodeling (MMP1, MMP3, TIMP1, uPA, and PAI-1); and 4) cell-matrix interactions (Col1alpha1, Col1alpha2, and integrins alpha(3) and alpha(5)). Cyr61-mediated gene expression requires heparin binding activity of Cyr61, cellular de novo transcription, and protein synthesis and is largely dependent on the activation of p42/p44 MAPKs. Cyr61 regulates gene expression not only in serum-free medium but also in fibroblasts cultured on various matrix proteins or in the presence of 10% serum. These effects of Cyr61 can be sustained for at least 5 days, consistent with the time course of wound healing in vivo. Interestingly, Cyr61 can interact with transforming growth factor-beta1 to regulate expression of specific genes in an antagonistic, additive, or synergistic manner. Furthermore, we show that the Cyr61 gene is highly induced in dermal fibroblasts of granulation tissue during cutaneous wound repair. Together, these results show that Cyr61 is inducibly expressed in granulation tissues after wounding and that Cyr61 activates a genetic program for wound repair in skin fibroblasts. We propose a model in which Cyr61 integrates its activities on endothelial cells, fibroblasts, and macrophages to regulate the processes of angiogenesis, inflammation, and matrix remodeling in the context of cutaneous wound healing.
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PMID:The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts. 1158 15

Different extracellular matrix proteins have been described as binding proteins for growth factors, influencing their storage or presentation towards cellular receptors. The multifunctional adhesive glycoprotein vitronectin (VN), which is found in the circulation and widely distributed throughout different tissues, has been implicated in the regulation of vascular cell functions, and these activities could be related to interactions with various growth factors. In vitro, soluble VN interfered with transforming growth factor-beta (TGF-beta) binding to isolated extracellular matrix and was found to associate with TGF-beta1 and TGF-beta2 as well as with other growth factors such as vascular endothelial growth factor, epidermal growth factor, or basic fibroblast growth factor in a saturable manner. In particular, binding of TGF-beta was maximal for the heparin-binding multimeric isoform of VN, whereas VN in a ternary complex with thrombin and antithrombin or plasma VN exhibited weaker binding. Plasminogen activator inhibitor-1 (PAI-1) or heparin, but not desulfated glycosaminoglycans, interfered with binding of VN to TGF-beta, and soluble PAI-1 was able to dissociate VN-bound TGF-beta. Upon limited plasmin proteolysis of VN, only the fragments comprising the intact aminoterminal portion of VN bound to TGF-beta as did a synthetic peptide (amino acids 43 to 62), indicating that TGF-beta and PAI-1 share common binding site(s) on VN. Although VN did not influence TGF-beta bioactivity for mink lung epithelial cells, TGF-beta dose dependently inhibited both urokinase-receptor as well as alpha(v)-integrin-dependent adhesion to VN. This activity of TGF-beta was reminiscent of the antiadhesive function of PAI-1. In atherosclerotic tissue sections, staining patterns of VN and TGF-beta indicated their colocalization. These findings describe VN as a new binding protein for TGF-beta, whereby specific functions of both factors become modulated by this interaction.
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PMID:Molecular interactions and functional interference between vitronectin and transforming growth factor-beta. 1179 24

Activation of the insulin-like growth factor-1 receptor (IGF-1R) by IGF-1 is associated with the risk and progression of many types of cancer, although despite this it remains unclear how activated IGF-1R contributes to cancer progression. In this study, gene expression changes elicited by IGF-1 were profiled in breast epithelial cells. We noted that many genes are functionally linked to cancer progression and angiogenesis. To validate some of the changes observed, the RNA and/or protein was confirmed for c-fos, cytochrome P450 1A1, cytochrome P450 1B1, interleukin-1 beta, fas ligand, vascular endothelial growth factor, and urokinase plasminogen activator. Nuclear proteins were also temporally monitored to address how gene expression changes were regulated. We found that IGF-1 stimulated the nuclear translocation of phosphorylated AKT, hypoxic-inducible factor-1 alpha, and phosphorylated cAMP-responsive element-binding protein, which correlated with temporal changes in gene expression. Next, the promoter regions of IGF-1-regulated genes were searched in silico. The promoters of genes that clustered together had similar regulatory regions. In summary, IGF-1 inscribes a gene expression profile relevant to cancer progression, and this study provides insight into the mechanism(s) whereby some of these changes occur.
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PMID:Insulin-like growth factor-1 inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells. 1198 40

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV). Latent membrane protein-1 (LMP-1) is an EBV-encoded oncoprotein and is detected in approximately 50-70% of patients with NPC. LMP-1 is thought to play an essential role in tumorigenesis of NPC. In addition to its transforming properties, LMP-1 has been suggested to be associated with promotion of metastasis. Metastasis is a phenomenon composed of multiple sequential cascades. Reduction of tumor cell adhesion, degradation of extracellular matrix, basement membrane, enhancement of cell motility, and promotion of neovascularization are thought to be essential steps. LMP-1 down-regulates expression of E-cadherin, induces matrix metalloproteinase-9 and urokinase type-plasminogen activator through activation of NF-kappaB and AP-1, and enhances cell motility via ets-1 activation. LMP-1 also induces vascular endothelial growth factor through cyclooxygenase-2 activation and interleukin-8 through NF-kappaB activation. Clinical studies suggested the association of these factors with metastatic status of patients with NPC. In this review, the role of LMP-1 in the metastasis of NPC is discussed.
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PMID:Promotion of metastasis in nasopharyngeal carcinoma by Epstein-Barr virus latent membrane protein-1. 1216 95


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