Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urinary trypsin inhibitor (UTI) is a Kunitz-type protease inhibitor. We have reported that UTI inhibited TNF-induced urokinase (uPA) production via a protein kinase C (PKC)-dependent mechanism. It is likely that UTI suppresses tumor cell invasion and metastasis by a mechanism, possibly by inhibiting uPA production. In the present study, we attempted to determine how UTI is associated with PKC, and how UTI is involved in uPA-dependent tumor cell invasion and metastasis. The increments of membrane-associated PKC activity by TNF were subsequently accompanied by a rapid loss of cytosol-associated PKC activity in U937 leukemia cells. Semi-quantitative immunoblotting of membrane and cytosol fractions showed that the translocation of PKC-alpha, -beta, and -epsilon were blocked by the addition of UTI in cells stimulated with TNF but not in cells stimulated with PMA, demonstrating that PKC itself is not sensitive to UTI. This effect was dependent on the carboxyl-terminus of UTI. In addition, UTI neither inhibited TNF binding to cellular receptors nor inactivate PKC and uPA activities directly. Taken together, the experiments suggest that the carboxyl-terminus of UTI may inhibit the PKC-signalling pathways upstream of diacylglycerol by a mechanism, possibly by interrupting the coupling of receptor and effector systems. UTI was shown to have an interesting new function besides being a protease inhibitor. This is the first report that UTI has a selective inhibition of TNF-activated PKC. We conclude that UTI suppresses tumor cell invasion and metastasis by a mechanism that UTI inhibits TNF-stimulated uPA production via a PKC-dependent mechanism.
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PMID:Urinary trypsin inhibitor, a Kunitz-type protease inhibitor, modulates tumor necrosis factor-stimulated activation and translocation of protein kinase C in U937 cells. 945 92

Recent studies have shown that urokinase (uPA) is an independent prognostic marker in breast cancer. uPA plays a key role in the degradation of tumor matrix and promotes tumor progression. Macrophage expression of uPA appears to be important in this context. Our objective in the present study was to provide evidence that tumor growth factor-beta (TGF-beta) released from breast cancer cells markedly up-regulates uPA expression in tumor-associated macrophages (TAMs). TAMs from 32 breast carcinomas were cultured. Blood monocytes from healthy donors and breast cancer patients as well as tissue macrophages from patients with fibrocystic changes of the breast were also examined. After TGF-beta incubation, uPA levels were tested by ELISA, and uPA mRNA levels were determined by Northern blot analysis. TGF-beta receptor and uPA cell surface fluorescence intensities were determined by flow cytometry; TGF-beta receptors were determined by Western blot analysis. Protein kinase-C dependence was also examined, and immunohistochemical stainings for uPA and TGF-beta were performed. We have demonstrated that TGF-beta markedly up-regulates basal uPA expression (mRNA and protein) in TAMs but only modestly increases uPA production in blood monocytes and tissue macrophages. Exposure of macrophages to TGF-beta1 led to a rapid and sustained increase in uPA mRNA levels, which was independent of de novo protein synthesis and completely inhibited by actinomycin D. H7 markedly reduced the ability of TGF-beta to stimulate uPA expression. Likewise, okadaic acid potentiated the ability of TGF-beta to up-regulate macrophage uPA expression. We suggest that TAMs are more responsive to TGF-beta stimulation than are blood monocytes and tissue macrophages because of different TGF-beta receptor densities. TGF-beta stimulates transcription of the uPA gene, increases uPA-mRNA stability, and activates uPA expression via protein kinase-C-dependent mechanisms. The ability of TGF-beta to induce macrophage uPA expression may provide an indirect mechanism by which this growth factor stimulates angiogenesis. It may be, therefore, that TAMs promote tumor progression and tumor angiogenesis.
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PMID:Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast. 946 Nov 22

Tissue factor (TF) has been implicated in several important biologic processes, including fibrin formation, atherogenesis, angiogenesis, and tumor cell migration. In that plasminogen activators have been implicated in the same processes, the potential for interactions between TF and the plasminogen activator system was examined. Plasminogen was found to bind directly to the extracellular domain of TF apoprotein (amino acids 1-219) as determined by optical biosensor interaction analysis. A fragment of plasminogen containing kringles 1 through 3 also bound to TF apoprotein, whereas isolated kringle 4 and miniplasminogen did not. Expression of TF on the surface of a stably transfected Chinese hamster ovary (CHO) cell line stimulated plasminogen binding to the cells by 70% more than to control cells. Plasminogen bound to a site on the TF apoprotein that appears to be distinct from the binding site for factors VII and VIIa as judged by a combination of biosensor and cell assays. TF enhanced two-chain urokinase (tcuPA) activation of Glu-plasminogen, but not of miniplasminogen, in a dose-dependent, saturable manner (half maximal stimulation at 59 pmol/L). TF apoprotein induced an effect similar to that of relipidated TF, but a relatively higher concentration of the apoprotein was required (half maximal stimulation at 3.8 nmol/L). The stimulatory effect of TF on plasminogen activation was confirmed when plasmin formation was examined directly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In accord with this, TF inhibited fibrinolysis by approximately 74% at a concentration of 14 nmol/L and almost totally inhibited the binding of equimolar concentrations of plasminogen to human umbilical vein endothelial cells and human trophoblasts. Further, CHO cells expressing TF inhibited uPA-mediated fibrinolysis relative to a wild-type control. TF apoprotein and plasminogen were found to colocalize in atherosclerotic plaque. These data suggest that plasminogen localization and activation may be modulated at extravascular sites through a high-affinity interaction between kringles 1 through 3 of plasminogen and the extracellular domain of TF.
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PMID:Tissue factor regulates plasminogen binding and activation. 949 Jun 81

Prognostic factors are highly needed to divide node negative breast cancer patients into groups of low versus high risk of recurrence and death. In order to invade and spread, cancer cells must degrade extracellular matrix proteins. Accordingly, tumor levels of molecules involved in this degradation might be associated with patient outcome. Previous work has demonstrated that high levels of the aspartyl protease cathepsin D in breast cancer are associated with a poor prognosis and similar findings have been reported for molecules involved in the urokinase pathway of plasminogen activation. Interactions between different protease systems have been described and data suggest that several proteolytic enzymes may be operable at the same time in a tumor. In the present study we measured cathepsin D (n=162), uPA (n=116), uPAR (n=109) and PAI-1 (n=135) in tumor cytosols obtained from a population of node negative breast cancer patients. A significant correlation was found between levels of uPA, uPAR, and PAI-1. Levels of cathepsin D were directly related to levels of uPA and uPAR. With a median observation time of 4.81 years, univariate survival analyses showed that high levels of uPA and cathepsin D significantly predicted a shorter disease free survival, while only high levels of cathepsin D were able to significantly predict a shorter overall survival. Tumor levels of uPAR and PAI-1 gave mixed results depending on the cut-off point chosen. Interestingly, multivariate analysis demonstrated that PAI-1 and cathepsin D were independent significant prognostic indicators for disease-free survival while only cathepsin D was helpful in overall survival. The five year relapse rate of patients with low PAI-1 and low cathepsin D was 13% while patients who had greater than the median value for both of these molecules had a 5 year relapse rate of 40%. These data would indicate that at least two different protease systems are active in spread of node negative breast cancer and that measurement of these molecules may aid in the decisions to be made when offering adjuvant treatment to these patients.
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PMID:Low cathepsin D and low plasminogen activator type 1 inhibitor in tumor cytosols defines a group of node negative breast cancer patients with low risk of recurrence. 949 71

Despite our recent advances in characterizing the molecular basis of breast and prostate cancer and their early detection with the aid of new imaging and diagnostic techniques, these cancers continue to be the leading causes of cancer-related deaths. This limited success in achieving our ultimate goal of cancer control is due to our inability to block the production of various factors produced in the later stages of these cancers that cause this high rate of mortality. A key requirement in the complex process of tumor invasion is the ability of tumor cells to produce and recruit growth factors and proteolytic enzymes within the tumor cell environment to promote neovascularization, tumor growth and promote extracellular matrix (ECM) degradation to facilitate tumor metastasis. One such protease, urokinase (uPA), has been strongly implicated in the progression of several malignancies including breast and prostate cancer. Along with uPA, its cell surface receptor (uPAR) is also believed to be involved due to its ability to recruit uPA within the tumor cell environment. In recent years, novel in vivo models of breast and prostate cancer have been developed which have clearly demonstrated the significance of uPA and uPAR in the invasion and metastases of these hormone-dependent cancers. The availability of these in vivo models has now permitted us to evaluate the molecular, chemical and immunotherapeutic strategies targeted against the uPA/uPAR system. This review describes the mechanism of uPA actions in tumor progression and analyses the usefulness of these in vivo models to authenticate uPA/uPAR as a therapeutic target and evaluates the benefits of blocking uPA/uPAR interactions alone or in combination with currently available treatment modalities against this cancer. Based on these results, there is an urgent need to develop and optimize strategies which will ultimately allow us to control the progression of these malignancies and enhance our ability to effectively manage these patients.
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PMID:Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. 949 55

We present a systematic analysis of the sensitivity and specificity of immunohistochemical stainings for components of the plasminogen activation system, i.e., uPA, tPA, PAI-1, PAI-2, and uPAR, on routinely processed (formalin-fixed, paraffin-embedded) tissues. Five to nine antibodies per component were tested and the influence of different antigen retrieval regimens on immunoreactivity was investigated. We studied six different microwave-mediated pretreatments and two pretreatments by proteolytic digestion. First, positive and negative control tissues were stained. Then, frozen and paraffin sections from the same cancer lesions were stained after specific modes of pretreatment and with selected antibodies. For each component, one or a few of the tested Abs gave optimal staining on paraffin sections when combined with a particular tissue pretreatment. For PAI-1, and to a lesser degree also for tPA, an underrepresentation of stromal cell staining in paraffin material was found, whereas tumor cells showed good staining. For uPA, PAI-2, and uPAR, consistent staining results were obtained on paraffin sections.
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PMID:Epitopes of components of the plasminogen activation system are re-exposed in formalin-fixed paraffin sections by different retrieval techniques. 952 92

A novel in vitro invasion assay system was established in this laboratory, in which the invasion of tumor cells after interaction with endothelial cells could be examined. Two variant cell lines (FP-10, FP-21) were established from parental HT1080 cells using this assay system. FP-10 and FP-21 cells had higher invasive and metastatic potential than the parental cells both in vitro and in vivo. The activity of anchorage-independent proliferation and the adhesion to the HUVEC monolayer of FP-10 and FP-21 was greater than the parental cells. The secretion of type IV collagenase (both MMP-2 and MMP-9) was also increased more significantly by the variant cells than by the parental cells, and the expression of uPA mRNA was higher in FP-10 and FP-21. Treatment of variant cells with human TIMP-2 remarkably suppressed the increment of the in vitro invasion to the same level as parental cells. These results suggest that this in vitro transendothelial invasion system accelerates multiple mechanisms of the metastasis by HT1080, especially the production of type IV collagenases. It can thus provide a useful model of tumor metastasis.
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PMID:Enhancement of type IV collagenases by highly metastatic variants of HT1080 fibrosarcoma cells established by a transendothelial invasion system in vitro. 956 44

Following malignant transformation, tumor cells and their surrounding stroma produce a variety of growth factors and proteolytic enzymes to induce new capillary formation (angiogenesis) and matrix degradation to promote tumor development. Two key families of proteases, matrix metalloproteases (MMPs) and urokinase (uPA) are now strongly implicated in this process of angiogenesis and matrix degradation. Both MMPs and uPA are abundantly produced by various tumors where their level of expression can serve as prognostic markers. Using gene transfer techniques, overexpression of these proteases and their receptors enhances the invasive and metastatic potential of tumor cells. Furthermore, blockage of actions of MMPs and uPA by molecular and chemical approaches results in a marked decrease in tumor growth to further validate the significance of these enzymes as targets for anti-cancer therapy.
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PMID:Metalloproteases and urokinase in angiogenesis and tumor progression. 957 35

Ascites and serum of patients with ovarian carcinoma contain a soluble form of urokinase-type plasminogen activator receptor (uPAR). We now report that pro-uPA-Sepharose-purified uPAR from ascites of patients with ovarian carcinoma is the full-length molecule missing the glycosyl-phosphatidylinositol anchor, as determined by its amino acid composition. We next examined the significance of determining serum soluble uPAR (suPAR) levels in ovarian cancer patients using a specific ELISA and compared the results with serum concentrations of CA-125, an established diagnostic marker. Serum from pre- and postoperative ovarian cancer patients was assayed for suPAR and CA-125. The majority of the patients with ovarian cancer had enhanced preoperative serum levels of suPAR compared with healthy controls, but suPAR concentrations decreased after operation. Although uPAR was associated with most ovarian carcinomas, it appeared to be a less specific indicator for ovarian cancer than CA-125. On the other hand, suPAR was more specific for other types of solid tumors. Moreover, we have observed some cases of ovarian cancer that showed increase of suPAR but not of CA-125. The prognostic significance of serum suPAR assay for survival of ovarian carcinoma patients was evaluated using Cox's proportional hazards analysis. Our preliminary data show that high preoperative levels of suPAR were associated with worse survival of the patients, whereas CA-125 had no prognostic implications. This is the first report evaluating the assay of serum suPAR levels in ovarian cancer and analyzing its value as a tumor or prognostic marker.
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PMID:The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. 958 23

Tissue samples were obtained from normal (n = 92), hyperplastic (n = 22) and malignant (n = 35) endometria. Urokinase and tissue plasminogen activators (u-PA, t-PA) were assayed in acetate detergent buffer extracts and their mRNAs quantitated in autoradiograms of Northern blots. The tissue content of u-PA was significantly higher in adenocarcinomas compared to normal and hyperplastic endometria. Tumors with poor differentiation and extensive myometrial invasion had the highest levels. The content of t-PA was increased in hyperplastic endometria but not in adenocarcinomas. The tissue content of t-PA was inversely related to clinical stage and loss of differentiation in malignant tumors. In contrast to the protein data, u-PA mRNA was not higher and t-PA mRNA was much lower in malignant compared to benign tumors. Thus, high tumor tissue content of u-PA does not result from transcriptional regulation, and reduction of t-PA mRNA may indicate down-regulation of transcription or possibly reduced mRNA stability. Furthermore, the discrepancy between protein and mRNA for both activators probably indicates up-regulation of the translation process since decreased degradation of activator proteins is a less likely explanation.
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PMID:Discordant expression of mRNA and protein for urokinase and tissue plasminogen activators (u-PA, t-PA) in endometrial carcinoma. 958 36


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