Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis. Recently, we reported that highly metastatic behavior of human melanoma cells in nude mice correlates with urokinase-type PA (u-PA) expression and activity and with PA inhibitor type 1 and 2 (PAI-1, PAI-2) expression. Here we report on the occurrence of components of the PA system in the various stages of human melanoma tumor progression in situ. We studied the protein distribution on freshly frozen lesions of common nevocellular nevi (n = 25), dysplastic (= atypical) nevi (n = 16), early primary melanomas (n = 8), advanced primary melanomas (n = 11), and melanoma metastases (n = 17). Tissue-type PA was present in endothelial cells in all lesions, whereas in metastases it could be detected in tumor cells in a minority of the lesions. u-PA, its receptor, PAI-1, and PAI-2 could not be detected in benign and in early stages but appeared frequently in advanced primary melanoma and melanoma metastasis lesions. u-PA was detected in stromal cells and in tumor cells at the invasive front, the u-PA receptor and PAI-2 in tumor cells, and PAI-1 in the extracellular matrix surrounding tumor cells. Localization of the corresponding messenger RNAs and enzyme activities revealed a similar distribution. We conclude that plasminogen activation is a late event in melanoma tumor progression.
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PMID:Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. 829 13

Cell interactions with the extracellular matrix play a critical role in regulating complex processes such as terminal differentiation and tumor progression. In these studies we describe a melanoma cell system that should be useful in addressing the regulation of cell-matrix interactions and the roles they play in regulating differentiation and cell invasiveness. CS (suspension)-1 melanoma cells are relatively well differentiated: they are melanotic, responsive to melanocyte-stimulating hormone, and express TA99, a melanosome membrane differentiation marker. Their repertoire of integrin receptors for extracellular matrix ligands is limited; in particular, they lack receptors for vitronectin, accounting for the observation that they are nonadherent when cultured in the presence of serum. CS-1 cells are noninvasive as well, and express low levels of both metalloproteinases and activated plasminogen activators. Treatment of these cells with melanocyte-stimulating hormone causes them to increase melanin production and assume an arborized phenotype, suggesting that it promotes their further differentiation. In contrast, treatment of CS-1 with the thymidine analog 5-bromodeoxyuridine, converts them to a highly invasive cell population (termed BCS-1) that loses its differentiated properties and responsiveness to melanocyte-stimulating hormone, acquires a broad integrin repertoire (including vitronectin receptors), and expresses elevated levels of metalloproteinases and activated urokinase. From these observations and findings of others on BrdU treatment of other developmental lineages, we hypothesize that BrdU both suppresses differentiation and promotes invasiveness of CS-1 cells. The demonstrated manipulability of CS-1 cells should make them extremely useful for studying the regulation of both terminal differentiation and tumor progression in the melanocyte lineage.
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PMID:5-Bromo-2-deoxyuridine regulates invasiveness and expression of integrins and matrix-degrading proteinases in a differentiated hamster melanoma cell. 836 Feb 73

The expression of the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied during breast cancer progression. The ST3 gene is expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting ST3 transcripts correlates with the known risk of these carcinomas to become invasive. ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the neoplastic cells in both primary and metastatic tumors. This expression pattern distinguishes the ST3 gene from other matrix metalloproteinase genes, most notably from the 72-kDa type IV collagenase gene, which can be expressed in fibroblastic cells distributed throughout the stroma of primary breast carcinomas. Furthermore, high levels of 72-kDa type IV collagenase, but not of ST3 transcripts, are detected in benign breast fibroadenomas. Interestingly, the urokinase and ST3 genes exhibit very similar patterns of expression in breast carcinomas, which suggests that their products may cooperate during cancer progression.
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PMID:Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression. 844 98

The high prevalence of prostatic carcinoma (PRCA) and the limited therapeutic possibilities provide a strong stimulus for exploring new approaches in experimental research that ultimately may lead to improved therapy. Indeed, methods for assessing carcinoma prognosis, such as clinical staging (clinical examination, ultrasound, and plasmatic levels of prostatic acid phosphatase and prostate specific antigen) and histopathological grading according to the Gleason score, usually fail to provide consistent predictive information regarding the clinical outcome of single tumors. Increased plasminogen activator (PA) activities have been associated with high-grade malignancies and with the potential for invasion/metastasis in many tumors. Urokinase-type plasminogen activator (uPA) is present in prostatic secretion, and an increased uPA activity has been noted in human prostatic cell lines with metastatic behavior. Unfortunately, any study of uPA production or gene regulation in primary tumors is complicated by the inherent mixture of host stromal cells, infiltrating macrophages, and subpopulations of tumor cells that may have variable metastatic capacity and ability to synthesize uPA. In short-term tissue culture of prostatic samples, it is possible to grow in vitro cancer prostatic epithelial cells and thus exclude the presence of contaminant cells. We have shown elsewhere that the levels of a type IV collagenase, 92-kDa matrix metalloproteinase, a protease involved in tumor progression and invasion, are increased in PRCA primary cell cultures if compared with benign prostatic hyperplasia (BPH) cell cultures (C. Festuccia et al., manuscript in preparation). Activation of matrix metalloproteinases also can be correlated with uPA expression; therefore we studied the expression of uPA in serum-free culture media of primary cultures of PRCA or BPH tissue samples.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator activities in short-term tissue cultures of benign prostatic hyperplasia and prostatic carcinoma. 855 46

Urokinase plasminogen activator (uPA) and its receptor are key components of a cell surface proteolytic cascade used by tumor cells and capillary endothelial cells for basement membrane invasion, a process required for metastasis and angiogenesis. We have cloned, expressed, and purified the epidermal growth factor-like domain of murine uPA alone and fused it to the Fc portion of human IgG as high-affinity murine urokinase receptor antagonists. These molecules are potent inhibitors of murine urokinase binding to its receptor and inhibit angiogenesis in an in vitro model of capillary tube formation in fibrin gels. In vivo, basic fibroblast growth factor-induced neovascularization and B16 melanoma growth in syngeneic mice are also substantially suppressed by these molecules. Coupled with previous studies showing inhibition of metastasis, these findings suggest that urokinase receptor antagonists may be useful therapeutically as inhibitors of tumor progression.
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PMID:Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. 862 23

We recently found that the proteins of the proteolytic system of plasminogen activation emerge in late stages of melanocytic tumor progression. A large body of evidence suggests a role for two proteins, the low-density lipoprotein receptor-related protein (LRP)/alpha(2)-macroglobulin receptor and its receptor-associated protein (RAP), in the internalization of components of the plasminogen activation system. Here, we present data on the presence of these two proteins in human melanoma cell lines which differ in metastatic capacity, their corresponding xenografts, and in cutaneous melanocytic lesions. With flow cytometry, we found surface expression of LRP to be restricted to urokinase plasminogen activator, producing highly metastatic cell lines. These cell lines also produce higher levels of LRP mRNA, whereas RAP mRNA and protein are expressed at equal levels in all cell lines and not expressed at the cell surface. Xenografts of cell lines producing high levels of LRP remarkably contain only a small fraction of LRP-positive tumor cells. Using immunohistochemistry on frozen sections of 107 human melanocytic lesions comprising the various stages of melanocytic tumor progression, we found that expression of both LRP and RAP decreased in tumor progression. Furthermore, we noted that LRP and RAP are coexpressed within the same lesion. Using immunofluorescence double staining, we found that LRP and RAP colocalize in the same cells in the lesions studied and in the same cell structures in the cell lines studied. In conclusion, our results indicate that LRP and RAP are coordinately expressed in a decreased fashion in melanocytic tumor progression. Based on the staining results in xenografts and in human melanocytic lesions, we conclude that a strong correlation between expression of LRP and urokinase-type plasminogen activator seems not to exist in in vivo melanomas.
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PMID:Decreased expression of both the low-density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor and its receptor-associated protein in late stages of cutaneous melanocytic tumor progression. 864 Aug 36

In order to invade and spread cancer cells must degrade extracellular matrix proteins. This degradation is catalysed by the concerted action of several enzymes, including the serine protease plasmin. Several experimental studies have shown that inhibition of plasmin formation reduces cancer cell invasion and metastasis, indicating a critical role of this proteolytic pathway in these processes. In order to further study the role of plasmin in cancer progression, we have characterized urokinase-type plasminogen activator (uPA) mediated plasmin formation in three human breast cancer cell lines. Using monoclonal antibodies against uPA and its receptor uPAR, we have investigated the contribution of uPA and uPAR to invasive capacity in an in vitro invasion assay. MDA-MB-231 BAG cells were found to express high protein levels of uPA, uPAR and PAI-1. MDA-MB 435 BAG cells produced low amounts of uPA, PAI-1 and moderate amounts of uPAR, whereas MCF-7 BAG cells showed low levels of uPA, uPAR and PAI-1 protein. In a plasmin generation assay MDA-MB-231 BAG cells were highly active in mediating plasmin formation, which could be abolished by adding either an anticatalytic monoclonal antibody to uPA (clone 5) or an anti-uPAR monoclonal antibody (clone R3), which blocks binding of uPA to uPAR. The two other cell lines lacked the capacity to mediate plasmin formation. In the Matrigel invasion assay the cells showed activity in this order: MCF-7 BAG < MDA-MB-435 BAG < MDA-MB-231 BAG. Testing MDA-MB-231 BAG cells in the Matrigel invasion assay revealed that invasion could be inhibited in a dose-dependent manner either by the clone 5 uPA antibody or by the clone R3 uPAR antibody, suggesting that the cell surface uPA system is actively involved in this invasive process. It is concluded that these three cell lines constitute a valuable model system for in vitro studies of the role of cell surface uPA in cancer cell invasion and has application in the search for novel compounds which inhibit mechanisms involved in uPA-mediated plasmin generation on cancer cells.
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PMID:Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness. 867 84

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
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PMID:Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. 868 34

8701-BC cells, derived from a primary carcinoma of the breast, constitutively express mRNA for urokinase-type plasminogen activator (uPA). In this paper, we demonstrated the presence of uPA in the conditioned medium, and of uPA-receptor (uPAR) on the cell surface of 8701-BC cells, which therefore have the potential for an autocrine mechanism of uPA-mediated stimulation. We examined whether exogenous addition of either intact uPA, or its amino-terminal fragment (uPA-ATF), which lacks catalytic activity but retains the uPAR binding site and a growth factor-like domain, or immunoneutralisation of endogenous uPA-uPAR interactions could exert any effect on the proliferative and invasive behaviour of 8701-BC cells. The data demonstrate that, while uPA promotes growth and invasion of 8701-BC cells, its effect reversed by blocking uPA-uPAR interactions, uPA-ATF not only fails to impart growth factor-like signals, but also restrains cell invasion in vitro. In the light of these and other data, an active participation of ATF in the complex cell-ECM network of interactions underlying cancer progression can be postulated. In addition, it appears worth considering the possibility of testing the effect of this uPA fragment in vivo for the therapy of breast (and possibly other) human invasive carcinomas.
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PMID:In vitro anti-proliferative and anti-invasive role of aminoterminal fragment of urokinase-type plasminogen activator on 8701-BC breast cancer cells. 869 76

We have examined the role of urokinase receptor (uPAR) in tumor invasion and metastasis by developing a homologous model of uPAR overexpression in a rat breast cancer cell line (Mat B III) using gene transfer technique. Control (pRc-CMV) and experimental plasmid (pRc-uPAR-S) were transfected into Mat B III cells by using Lipofectin reagent. Levels of uPAR production were accessed by Northern blotting, immunofluorescence, receptor binding and ELISA. At least 3 experimental clones (pRc-uPAR-S), expressing 3- to 5-fold higher levels of uPAR than control (pRc-CMV), were selected for further analysis. Experimental cells overexpressing uPAR showed a 4-to 5-fold higher invasive capacity compared with control cells in a Boyden chamber invasion assay. Both control and experimental cells (1 x 10(6) cells) were injected into the mammary fat pad of syngeneic female Fischer rats. Animals were sacrificed at timed intervals and evaluated for the development of tumor growth and metastasis. Animals receiving cells overexpressing uPAR had significantly larger tumor volume and weight throughout our study. Furthermore, due to increased uPAR expression, experimental animals developed large metastatic lesions in liver, spleen and lymph nodes. Our results therefore demonstrate the role of uPAR in tumor progression, due to its ability to localize uPA within the tumor cell milieu.
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PMID:Overexpression of urokinase receptor in breast cancer cells results in increased tumor invasion, growth and metastasis. 870 19


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