Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a novel murine mammary tumor system with variants representing different stages of tumor progression. The MXT-s parental cell line was established from a urethane-induced and hormone-sensitive mammary tumor. MXT-s parental cells are highly tumorigenic but poorly metastatic. MXT clones and variants were selected by either in vitro or in vivo procedures, and they differ in metastatic ability and 17 beta-estradiol dependency for tumor growth. The MXT-c1.1 and MXT-B2 cell lines produced lung metastasis after intravenous injection into 100% of syngenic mice, but only MXT-c1.1 cells were highly metastatic from intramammary tumors. The fingerprints obtained by arbitrarily primed-polymerase chain reaction demonstrated that the metastatic variants and clones had a common genetic background and resulted from clonal selection from the parental cell line. We studied whether the matrix metalloproteinase (MMP) profile is correlated with tumor progression and metastatic ability in the MXT tumor system. Gelatinases A and B were assayed in the cells, both by enzyme activity and mRNA expression. Gelatinase A was expressed in MXT-c1.1 cells, whereas MXT-B2 cells did not express either MMP. In contrast, the mammary fat pad tumors expressed both gelatinases. Membrane Type 1-MMP transcripts were also detected in MXT cells and tumors. Because the mRNA levels of gelatinase. A were low in MXT-B2 tumors, we suggested that exogenous gelatinase A bound the cell membranes of MXT-B2 cells in vivo. Indirect evidence was obtained in vitro by treatment of MXT-B2 cells with NIH/3T3 fibroblast-conditioned medium. After this treatment, we detected a gelatinolytic activity at M(r) 68,000 in the cell-membrane extract of MXT-B2 cells and an increase in migratory ability through type IV collagen matrices. On the other hand, Ha-ras gene dosage correlated positively with metastatic ability but not with either gelatinase A or gelatinase B expression. No significant differences were observed in the expression of stromelysin-1 and tissue inhibitors of MMP. Thus, in the MXT tumor system, the expression of gelatinase A or its cell association and Ha-ras gene dosage independently contribute to the metastatic phenotype.
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PMID:Metastatic ability of MXT mouse mammary subpopulations correlates with clonal expression and/or membrane-association of gelatinase A. 918 Sep 29

In a comprehensive immunohistochemical study of the expression of ten metalloproteinases (MMPs) and their four inhibitors (TIMPs) in 115 non-small cell lung carcinomas (NSCLCs), the findings have been correlated with the histological and clinical features of the tumours. All MMPs and TIMPs were expressed in tumours, with frequencies ranging from 41% for MMP-2 to 68% for MMP-13. Stromal immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13. In some tumours, an overexpression of these proteins, as revealed by stronger staining in cancer cells than in adjacent normal bronchial epithelium, was also observed. The frequency ranged from 1% for MMP-3 to 28% for MMP-13. Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression positively correlated with more advanced stage disease. None of the MMP or TIMP expression correlated with the ras genotype of the tumours. The higher frequency of MMP overexpression in AdC than in SqCC may relate to the greater tendency of the former for systemic metastasis. The association of TIMP-1 overexpression with more advanced disease may suggest a role in prognosis.
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PMID:Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. 1065 12

Matrix metalloproteinase expression was examined in a series of mammalian cell lines of varying degrees of malignant progression. The expression of MMP-2 and MMP-9 was found to correlate with ras-mediated cellular transformation and as a function of malignant potential. Altered MMP-2 and MMP-9 expression was found to correlate also in other oncogene transformed cell lines and the level of expression of both MMP-2 and MMP-9 correlated with metastatic potential. Increased expression of both MMP-2 and MMP-9 was also found in cells which constitutively over-express MAP kinase kinase suggesting that one of the consequences of the persistent activation of the MAP kinase pathway is elevated expression of MMP-2 and MMP-9. Additionally, this study demonstrated a correlation between the expression of MMP-3 (stromelysin-1) and the level of ras expressed in cells and with the cells' ability to form tumors and with malignant potential. The existence of a novel 80 kDa caseinase activity which correlates with ras expression and the ability of the cell to form tumors was also demonstrated. The growth status of transformed cells was also found to be important in determining the expression of MMP-2 mRNA but not MMP-9 mRNA expression, and this expression was cell-type specific. This study also demonstrates that oncogenes can interact to influence and to determine the nature of the matrix metalloproteinases expressed and that this interaction results in a tumorigenic phenotype and, most importantly, contributes to the metastatic phenotype. Alterations in the expression and the regulation of MMPs, particularly MMP-2 and MMP-9, constitute an integral part of the altered growth regulatory program found within transformed cells and in particular, in transformed cells capable of malignant progression.
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PMID:Altered matrix metalloproteinase expression associated with oncogene-mediated cellular transformation and metastasis formation. 1140 28

Matrix metalloproteinases play an important role in tissue regeneration, wound healing and tumor invasion. Our previous studies have shown a higher motility of HaCaT-ras-transfected cells compared with HaCaT or normal human keratinocytes (NHK) in correlation with a higher secretion of MMP-2 (72 kDa) or MMP-9 (92 kDa), according to the medium used for cell cultures. Presently, the expression and activity of MMPs were investigated in two reconstructed skin models, using a dead de-epidermized dermis (DED) or a dermal substitute including living fibroblasts. In all experiments, MMP-9 was essentially secreted by NHK and to a greater extent by HaCaT cells. Its active form (86 kDa) was only detected in both reconstructed skin models according to keratinocyte differentiation. MMP-2 was mainly secreted by living fibroblasts included in the dermal substitute skin model. In this case, its activation was up-regulated when HaCaT cell lines were seeded onto the dermal substitute according to their culture at air/liquid interface as shown for MMP-9. The collagenase MMP-1 and stromelysin-1 (MMP-3), susceptible to activate pro-MMP-2 and -9, respectively, were detected in their inactive form by ELISA. MMP-1 was expressed in both models but MMP-3 required the presence of living fibroblasts. Their activities were not detected using specific fluorogenic substrates. In the skin equivalent model using HaCaT, the extensive secretion and activation of MMP-2 and MMP-9 could explain the defect observed in basal membrane reconstruction, suggesting a direct interaction of HaCaT with fibroblasts.
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PMID:Comparative studies on the secretion and activation of MMPs in two reconstructed human skin models using HaCaT- and HaCaT-ras-transfected cell lines. 1471 2

The analysis of migration and gene expression patterns of normal and Ha-ras transformed rat liver epithelial cells revealed differences of diagnostic relevance. The normal cells are induced to migrate by EGF/TGF alpha and to express a set of secreted proteins including fibronectin, EIP-1/PAI-1, and MEP cathepsin L, which the malignant, constitutively migratory cells express constitutively. Only the transformed cells produce proteins of Mr 58/60,000 identified by peptide sequencing as stromelysin-1. The constitutively migratory cells produce invasive tumors and, after intravenous injection, metastatic colonies in the lung ('experimental metastasis'). The results demonstrate specific differences between the migration/invasion of normal and malignant epithelial cells, with PAI-1 as a general biochemical marker for migration/invasion. Constitutive migration and the described gene expression pattern are proposed as in vitro indicators of an invasive phenotype. EGF inducibility of the transformed cells to maximal migration and to an increased expression of stromelysin indicates susceptibility to a paracrine stimulation of malignancy.
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PMID:Constitutive migration and expression of three protease systems define in vitro the malignant phenotype of Ha-ras transformed rat liver epithelial cells. 2154 65

Interstitial collagenase and stromelysin mRNA expression was examined in six rat cell lines isolated after transfection of embryo fibroblasts with polyomavirus large-T and T24-ras oncogenes. Increased levels of stromelysin mRNA were observed in tumors formed by cells with low levels of stromelysin expression before injection, whereas interstitial collagenase mRNA levels were not elevated in tumors. The lung colonizing - but not the chemoinvasive capacity - of two of these cell lines increased following growth in vivo. The increase in stromelysin expression in tumors was not necessarily paralleled by an increase in ras expression. These findings may be relevant to the phenomenon of clonal dominance of metastatic cells in primary tumors.
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PMID:Increases of stromelysin messenger-RNA expression in ras-transformed ref cells in-vivo. 2156 98

Nine cell lines were isolated after cotransfection of rat embryo fibroblasts with polyomavirus large-T (plt) and T24-ras oncogenes. Five of these lines were highly tumorigenic following subcutaneous injection, but differed in their metastatic and in vitro invasive properties. Two cell lines, expressing low levels of ras mRNA, showed low capacity for experimental metastasis. Three cell lines, expressing high levels of ras mRNA, were tumorigenic and showed high capacity for experimental metastasis. High expression of interstitial collagenase, stromelysin and 92 kDa type IV collagenase was observed in the highly metastatic cell lines. Immunochemical analysis revealed that these cell lines expressed apparently wild-type p53 protein. Furthermore, the level of a 43 kDa/pI 5,44 polypeptide was elevated and the levels of a series of 41 to 43 kDa acidic polypeptides were decreased in the metastatic cells. Within this panel of transformed cell lines, high capacity for experimental metastasis did not correlate with high chemoinvasive capacity in the reconstituted basal membrane assay. The limited invasive propensity could not be attributed to low chemotactic or adhesive capacity. We conclude that in vitro invasion does not correlate with experimental metastasis in this model system.
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PMID:Limited invasive capacity of plt plus ras transformed rat fibrosarcoma cells effective in experimental metastasis. 2157 85


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