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)

Cell contact with the extracellular matrix component, hyaluronan, plays a pivotal role in glioma cell invasion and proliferation. Although it is well established that glioma cells can bind hyaluronan to their surface via the expression of CD44, the cellular responses following ligand-receptor interaction remain poorly understood. Given that a large proportion of human high grade gliomas over express the epidermal growth factor receptor (EGFR) and ErbB2, this study aimed to investigate whether an interaction exists between CD44 and these receptor tyrosine kinases. Here we present evidence that CD44 co-immunoprecipitates with EGFR and ErbB2 in the glioma cell lines U87MG and SMA560. Hyaluronan treatment mediated the rapid and transient phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1 and ERK2) in glioma cell lines. This response to hyaluronan was augmented by the co-expression of EGFR. EGFR also differentially modified the hyaluronan induced expression of a number of genes associated with cellular invasion and proliferation. Northern blot analysis demonstrated that genes encoding urokinase type plasminogen activator (uPA), urokinase type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases (TIMP-1) and c- myc were up-regulated in response to hyaluronan. Furthermore, zymographic analysis revealed increased levels of uPA in the conditioned medium of hyaluronan stimulated cells. These results indicate a novel functional relationship between CD44 and EGFR in glioma cell lines. The capacity of CD44 to form stable complexes with receptor tyrosine kinases may provide a versatile system for the regulation of cellular invasion and proliferation that allows hyaluronan to activate signal transduction pathways and modulate gene expression via an EGFR-dependent manner. These findings provide new insights into the mode by which hyaluronan regulates the malignant phenotype and also suggest a role for EGFR-CD44 interactions in glial tumorigenesis.
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PMID:EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. 1209 35

Cutaneous melanoma is an invasive and early metastazising tumor. Melanoma cells detach from the primary tumor, penetrate the basement membrane, invade lymphatics and blood vessels, and form metastases. These processes all depend on coordinated expression and/or activation of proteolytic enzymes. In addition to aspartyl- and cysteineproteinases, serine proteinases including the plasminogen activator system (uPA, uPAR, tPA, PAI-1 and PAI-2) and matrix metalloproteinases (MMPs) with their tissue inhibitors (TIMPs) play an essential role in these processes. In addition, melanoma cells require specific adhesion molecules such as integrins and CD44 for interaction with other cells and components of the extracellular matrix (ECM); these are also involved in binding activated MMPs on the cell surface. In this review we discuss these functional aspects of melanoma progression.
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PMID:[Role of matrix-degrading enzymes in melanoma progression]. 1220 62

It has been established that fragmented hyaluronic acid (HA), but not native high molecular weight HA, can induce angiogenesis, cell proliferation and migration. We have studied the outside-in signal transduction pathways responsible for fragmented HA-mediated cancer cell invasion. In our study, we have studied the effects of CD44 stimulation by ligation with HA upon the expression of matrix metalloproteinases (MMPs)-2 and -9 as well as urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) and the subsequent induction of invasion of human chondrosarcoma cell line HCS-2/8. Our study indicates that (i) CD44 stimulation by fragmented HA upregulates expression of uPA and uPAR mRNA and protein but does not affect MMPs secretion or PAI-1 mRNA expression; (ii) the effects of HA fragments are critically HA size dependent: high molecular weight HA is inactive, but lower molecular weight fragmented HA (Mr 3.5 kDa) is active; (iii) cells can bind avidly Mr 3.5 kDa fragmented HA through a CD44 molecule, whereas cells do not effectively bind higher Mr HA; (iv) a fragmented HA induces phosphorylation of MAP kinase proteins (MEK1/2, ERK1/2 and c-Jun) within 30 min; (v) CD44 is critical for the response (activation of MAP kinase and upregulation of uPA and uPAR expression); and (vi) cell invasion induced by CD44 stimulation with a fragmented HA is inhibited by anti-CD44 mAb, MAP kinase inhibitors, neutralizing anti-uPAR pAb, anti-catalytic anti-uPA mAb or amiloride. Therefore, our study represents the first report that CD44 stimulation induced by a fragmented HA results in activation of MAP kinase and, subsequently, enhances uPA and uPAR expression and facilitates invasion of human chondrosarcoma cells.
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PMID:CD44 stimulation by fragmented hyaluronic acid induces upregulation of urokinase-type plasminogen activator and its receptor and subsequently facilitates invasion of human chondrosarcoma cells. 1240 8

Bikunin is a Kunitz-type protease inhibitor predominantly found in human amniotic fluid. In cancers, administration of bikunin may block tumor cell invasion by a direct inhibition of tumor cell-associated plasmin activity as well as by inhibiting urokinase-type plasminogen activator (uPA) expression at the gene and protein levels, possibly through suppression of CD44 dimerization and/or the MAP kinase signaling cascade. Treatment of cancer patients with bikunin may be beneficial in the adjuvant setting to delay the onset of metastasis development and/or in combination with cytotoxic agents to improve treatment efficacy in patients with advanced ovarian cancer.
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PMID:The protease inhibitor bikunin, a novel anti-metastatic agent. 1281 71

Activated dendritic epidermal Langerhans cells and metastatic tumour cells share many properties. Both cell types can invade the surrounding tissue, enter the lymphatic system and travel to regional lymph nodes. We have recently shown that fragments of the extracellular matrix component hyaluronan, which are typically produced at sites of inflammation, can activate dendritic cells. Upon activation, dendritic cells upregulate expression of matrix metalloproteases (MMPs). These observations prompted us to investigate whether exposure to hyaluronan fragments also induces MMP expression in tumour cells. Here, we report that MMP-9, MMP-13 and urokinase plasminogen activator are upregulated in murine 3LL tumour cells after exposure to mixed-size hyaluronan. Similarly upregulated MMP-9 and MMP-13 expression was observed in primary fibroblasts. By using size-fractionated hyaluronan preparations, we show that the enhanced expression of MMP-9 and MMP-13 is only induced by small hyaluronan (HA) fragments. Although our data suggest that HA-fragment-induced MMP-9 and MMP-13 expression is receptor mediated, they rule out an involvement of the hyaluronan receptors CD44, RHAMM/IHAP and TLR-4. Finally, we show that HA fragment-induced MMP-9 transcription is mediated via NF-kappa B. Our results suggest that the metastasis-associated HA degradation in tumours might promote invasion by inducing MMP expression.
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PMID:Hyaluronan-oligosaccharide-induced transcription of metalloproteases. 1465 75

In order to identify response predictors for a post-operative glioblastoma therapy consisting of tamoxifen, carboplatin and radiotherapy, expression of 12 antigens was evaluated in 36 newly diagnosed tumours and 13 recurrences. Results were correlated with the clinical course of the disease. Antigen expression was assessed immunohistochemically for CD44s, TGF-beta2, TGF-alpha, progesterone receptor, estrogen receptor, EGFR, urokinase, urokinase inhibitor 1, CD87, p53 protein and Ki-67. Vessel density was determined by labelling of endothelia with von Willebrand factor. Response to chemotherapy correlated positively with cell density (p < 0.05) and negatively with CD44 over-expression (p < 0.02). Further, a positive correlation between age and CD44 expression (p < 0.05) and a negative correlation between age and p53 accumulation (p < 0.01) was found. In tumour recurrences expression of CD44 was significantly higher in local recurrences than in distant multifocal recurrences (p < 0.02), suggesting that CD44 may predominantly be associated with cell adhesion in glioblastomas.
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PMID:CD44 expression and tumour cell density correlate with response to tamoxifen/carboplatin chemotherapy in glioblastomas. 1501 79

Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features. A large number of biomarkers have been shown to have potential predictive significance. One important aspect of this is to detect the transcripts of tumor-associated antigens (such as AFP, MAGEs, and CK19), which are proposed as predictive markers of HCC cells disseminated into the circulation and for metastatic recurrence. Another important aspect is to analyze the molecular markers for cellular malignancy phenotype, including DNA ploidy, cellular proliferation index, cell cycle regulators, oncogenes, and tumor suppressors (especially p53 gene), as well as telomerase activity. Molecular factors involved in the process of HCC invasion and metastasis, including adhesion molecules (E-cadherin, catenins, ICAM-1, laminin-5, CD44 variants, osteopontin), proteinases responsible for the degradation of extracellular matrix (MMPs, uPA system), as well as angiogenesis regulators (such as VEGF, intratumor MVD), have also been shown to be potential predictors for HCC metastatic recurrence and clinical outcomes. One important new trend is to widely delineate biomarkers with genomic and proteomic expression with reference to predicting metastatic recurrence, molecular diagnosis, and classification, which has been drawing more attention recently. Body fluid (particularly blood and urine) testing for biomarkers is easily accessible and more useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum and its genetic alterations is another important direction. More attention should be paid to these areas in the future. As understanding of tumor biology deepens, more and more new biomarkers with high sensitivity and specificity for HCC metastatic recurrence could be found and routinely used in clinical assays. However, the combination of the pathological features and some of the biomarkers mentioned above seems to be more practical up to now.
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PMID:Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature. 1520 47

Cancer invasion and metastasis develop through a sequence of processes involving loss of cell-cell and cell-matrix adhesions, proteolysis and induction of angiogenesis. We reviewed the current literature on the molecules that have been shown to play a significant role in these three steps of metastatisation in bladder cancer (BC) cells and their host microenvironment. Particular emphasis was given to markers that are assessable through immunohistochemistry and for which an additional prognostic value over the TNM variables has been recognized, in order to identify a subset of tumour markers readily available for application in daily clinical practice. We conclude that markers such as E-cadherin, Sialosyl-LeX, laminin, collagen IV, TSP-1 and MVD are useful prognostic markers, alpha, beta, and gamma catenin, MMP-2 and -9, uPAR, PD-ECGF and Bfgf can be considered potentially useful, while research on CD44, MMP-1 and -3, uPA, cathepsin D and VEGF has proved inconclusive. Further research in this field should concentrate on the molecules listed in the first group.
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PMID:Metastasis markers in bladder cancer: a review of the literature and clinical considerations. 1530 99

The primary determinant of outcome in patients with cancer is the development of distant metastasis. Metastasis is a multistep process involving disruption of cell-matrix adhesion, dissolution of the extracellular matrix, angiogenesis, invasion in the blood vessel wall, extravasation and establishment of a secondary growth. Nowadays, a large number of biochemical and cell biological studies have indicated the important role of extacellular matrix adhesion molecules, proteinases and angiogenic factors in the dissemination of cancer. Cell adhesion molecules, such as integrins, E-cadherin, catenins and CD44 appear to have some prognostic significance, especially in gastric, colorectal and lung cancer patients. Since matrix degrading proteinases are involved in cancer spread, they should be good candidates as prognostic factors. The proteinase which has been investigated in greatest detail is uPA in breast cancer. As a marker of cancer, its main value is to aid in selecting the subgroups of node-negative breast cancer patients that are unlikely to benefit from adjuvant chemotherapy. Cathepsin D and metalloproteinases (MMPs) look promising prognostic markers but further work is needed to establish their utility. Intratumoral angiogenesis is a putative prognostic indicator for some types of cancer. High expression of the angiogenic factor VEGF is associated with angiogenesis and an unfavourable survival.
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PMID:Tumor markers in cancer patients. an update of their prognostic significance. Part II. 1536 89

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90


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