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)

Proteases capable of activating procollagenase from gingiva and from fibroblast and macrophage monolayer cultures were harvested from homogenates of canine tumor mast cells. The mast cell proteases lysed casein and Azocoll but not native collagen. In low salt concentrations the enzymes existed at high molecular weight complexes, which were dissociated by increasing the salt concentration above 1.0 M (NaCl, KCl). Gel filtration in 1.4 M KCl separated the protease activity into three peaks, all of which activated procollagenase. Two of the enzymes showed substrate specificities (hydrolysis of p-tosyl-L-arginine methyl ester and benzoyl-tyrosine ethyl ester) and reactive center reactivities similar to pancreatic trypsin and chymotrypsin. Based on gel filtration, apparent molecular weights of 160 000 (p-tosyl-L-arginine methyl ester esterase), 90 000 (main procollagenase activator) and 36 000 benzoyl-tyrosine ethyl ester esterase) were determined. Activation of procollagenase resulted in a 18-20 000 decrease of the molecular weight. The activation was directly related to the amount of activator added within certain limits. Further addition of activator resulted in proteolytic inactivation of collagenase.
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PMID:Activation of fibroblast procollagenase by mast cell proteases. 5 9

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

Uncontrolled expression of matrix metalloproteinases 2, 3 and 9 (MMP-2, -3 and -9) is believed to be a critical part of the invasive potential of tumor cells because of their ability to degrade type IV collagen, a major structural component of basement membranes. Availability of proteolytic activity in the vicinity of the cell surface is further affected by a local balance between the enzymes and their inhibitors produced by the cell. To determine how frequently deregulated expression of the MMPs and tissue inhibitors of metalloproteinases (TIMPs) is associated with tumor cells, 26 human tumor cell lines were examined by Northern blotting. Transcripts for MMP-2 and MMP-9 were more frequently expressed in mesenchymal tumor cells (9/9 for MMP-2 and 6/9 for MMP-9) than in epithelial tumor cells (4/17 for MMP-2 and 2/17 for MMP-9). Although expression of MMP-2 mRNA was clearly cell type-specific, MMP-9 mRNA expression in mesenchymal cells correlated well with the reported tumorigenicity of the cells. Enhanced expression of MMP-9 mRNA was also associated with the tumorigenic transformation of cells by an activated c-H-ras gene in human embryonic fibroblasts. Only 3 of the 26 tumor cells expressed MMP-3 mRNA, and 2 of the 3 were epithelial tumor cells which coordinately expressed MMP-9 and TIMP-1 mRNAs. TIMP-1 mRNA was almost undetectable in 50% of the tumor cells, but TIMP-2 mRNA was expressed in the majority of the cells. These findings provide comprehensive information about mRNA expression of the MMPs and TIMPs in tumor cells, the deregulation of which is thought to be an integral part of the invasive potential of tumor cells.
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PMID:Expression of genes encoding type IV collagen-degrading metalloproteinases and tissue inhibitors of metalloproteinases in various human tumor cells. 131 Oct 64

In basal cell carcinoma, release of proteolytic activity is implicated in extracellular matrix degradation and tumor infiltration. The stromelysin metalloproteinase family is a major candidate for the matrix proteolytic activity in infiltrative tumors. However, in murine models of basal cell carcinoma, neither stromelysin 1 nor 2 appears to play a role in tumor infiltration. We have analyzed the expression of the newly described stromelysin 3 in human basal cell carcinoma using Northern blot analysis and in situ hybridization. In 12 of 14 cases, levels of stromelysin 3 expression were more than tenfold above those observed in normal skin. In one of five cases of squamous cell carcinoma, stromelysin 3 expression was tenfold above levels seen in normal skin. Stromelysin 3 expression was either undetectable or extremely weak in all five cases of infiltrative malignant melanoma. In basal cell carcinoma, stromelysin 3 transcripts were localized by in situ hybridization to the stromal tissue immediately adjacent to basal cell carcinoma, the tumor cells themselves being negative. Therefore, expression of stromelysin 3 in stromal cells may be expected to play a significant role in destruction of the basal membrane zone and extracellular matrix in basal cell carcinoma invasion.
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PMID:Expression of stromelysin 3 in the stromal elements of human basal cell carcinoma. 134 67

The c-ets1 proteins are transcriptional activators expressed within endothelial cells during blood vessel development in chick embryos. The authors show by in situ hybridization that c-ets1 is transcribed in the endothelia during angiogenesis in human embryos, in granulation tissue, and especially during tumor vascularization. c-ets1 mRNAs were also detected in the fibrocytes of tumor stroma and in the spindle cells of Kaposi's sarcomas, regarded as cells of endothelial origin. It has been shown that the c-ets proteins activate transcription through a PEA3 motif that plays a role in the stimulation of transcription of urokinase-type plasminogen-activator (u-PA), stromelysin and collagenase genes. The authors demonstrate in vitro that the angiogenic factor TNF alpha increases transiently the amount of both c-ets1 and u-PA mRNA in confluent human umbilical vein endothelial cells. Therefore, the authors suggest that the c-ets1 proteins might regulate the transcription of the genes coding for matrix-degrading proteases, which are necessary for both angiogenesis and tumor invasion.
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PMID:c-ets1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans. 137 May 94

A recognized model of tumor invasion requires cells to adhere to epithelial basement membrane and extracellular matrix components triggering release of proteases thus allowing cancer cells to invade the substrate. This adhesion is mediated by beta 1 integrins, a family of receptors to substrates such as collagen, laminin, and fibronectin. In order to study tumor invasion in follicular thyroid cancer (FTC), we used cell lines derived from a single patient's FTC primary tumor (FTC-133), neck lymph node metastases (FTC-236), and lung metastases (FTC-238). In vitro invasion as determined by the ability of the tumor cells to penetrate Matrigel was assessed by scanning electron microscopy. FTC-133 did not invade, FTC-236 was moderately invasive, and FTC-238 was highly invasive. Immunoprecipation with a monoclonal antibody to beta 1 integrin subunits and SDS-PAGE showed increased synthesis and flow cytometry showed increased expression of this subunit in FTC-236 and FTC-238 compared to FTC-133. Proteolytic activity was assessed by gelatin zymography. FTC-238 cell extract and conditioned media exhibited a more complex array of proteases consistent with activated type I collagenase and stromelysin compared to the less invasive clones, however 72 and 92 kd gelatinases consistent with type IV collagenases were present in the conditioned media from all three lines. In conclusion, in vitro invasion parallels in vivo metastasis by the source cells in the FTC-133/236/238 cell-lines. The ability to invade basement membrane preparation correlates with increased synthesis and expression of beta 1 integrins and activation of tumor proteases.
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PMID:Invasion by cultured human follicular thyroid cancer correlates with increased beta 1 integrins and production of proteases. 138 45

Matrix metallo-proteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumor development. The distribution of 3 major matrix metallo-proteinases was studied in human mammary pathology: collagenase (MMP1) which degrades fibrillar interstitial collagens, a 72-kDa gelatinase (MMP2) which mainly degrades type IV collagen and denatured collagens, and stromelysin (MMP3) which has a wider range of action, degrading several matrix components including the core proteins of proteoglycans, laminin and non-helical regions of collagens. These MMPs and the MMP tissual inhibitor (TIMP1) were detected by immunohistochemistry in 30 benign and 79 malignant lesions of the breast. MMPs were detected in 1 fibroadenoma (collagenase) and 22 breast carcinomas: collagenase (9 cases), stromelysin (12 cases) and gelatinase (16 cases) with a limited distribution. Tumor cells were preferentially labelled and the localization of gelatinase and stromelysin at the periphery of some non-invasive and well-differentiated clusters supports the role of these enzymes in the breakdown of basement membranes. Only a few stromal cells (fibroblasts) were found to be immunopositive. In contrast, TIMP1 was more frequently detected, and was found in 7 benign lesions and 55 carcinomas out of 79. It was mainly localized at the periphery of the endothelial cells but was occasionally detected in cancer cells and fibroblasts.
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PMID:Immunolocalization of matrix metallo-proteinases and their tissue inhibitor in human mammary pathology. 139 65

Human mononuclear phagocytes have the capacity to participate directly in extracellular matrix turnover via the secretion of neutral proteinases. These neutral proteinases include the serine proteinases, elastase and cathepsin G and the metalloproteinases, interstitial collagenase, 92 kD type IV collagenase, 72 kD type IV collagenase and stromelysin. Mononuclear phagocytes also produce the counter-regulatory metalloproteinase inhibitor, TIMP (tissue inhibitor of metalloproteinases). We have studied the capacity of normal human mononuclear phagocytes and of the human monocytic tumor line U937 to elaborate proteinases and inhibitors. The serine proteinases, elastase and cathepsin G, are present only at the earliest stages of mononuclear phagocyte differentiation (U937 cells in the basal state, freshly isolated peripheral blood monocytes) and are stored within intracellular granules. As human mononuclear phagocytes differentiate (U937 cells exposed to phorbol esters, human monocytes cultured in vitro), the cellular content of these serine proteinases declines rapidly. Accompanying the acquisition of a more differentiated state, the ability for regulated secretion of the neutral metalloproteinases is attained. This capacity is acquired in a sequential manner, with secretion of the 92 kD type IV collagenase observed at earlier states of differentiation while release of stromelysin requires a fully differentiated and LPS (lipopolysaccharide)-stimulated alveolar macrophage. Interstitial collagenase and 72 kD type IV collagenase are synthesized at intermediate stages of differentiation. In comparison to human fibroblasts, human mononuclear phagocytes produce approximately 10-30% of the interstitial collagenase, 10% of the stromelysin and 1-2% of the 72 kD type IV collagenase on a per cell basis. Synthesis of the 92 kD type IV collagenase is restricted to the inflammatory cell (but also occurs in neutrophils and keratinocytes).
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PMID:Neutral proteinase expression by human mononuclear phagocytes: a prominent role of cellular differentiation. 148 61

Type IV collagenase (gelatinase) is a 70,000 dalton neutral metalloproteinase that specifically cleaves type IV collagen in addition to degrading denatured collagen (gelatin). It is secreted in a latent proenzyme form that is converted proteolytically in the extracellular space to a 62,000 dalton active enzyme. The primary structure, enzymatic properties as well as gene structure, demonstrate that type IV collagenase is closely related with the other well characterized metalloproteinases, interstitial collagenase and stromelysin. However, the structure of type IV collagenase differs from the others in that it is larger and contains three internal repeats that resemble the type II domains of fibronectin. Also, initial characterization of the promoter region of the gene indicates that its regulation differs from the other proteinase genes. Type IV collagenase is presumably required for the normal turnover of basement membranes. Augmented activity is linked with the invasive potential of tumor cells and the enzyme is believed to play a major role in the penetration of basement membranes by metastatic cells. Measurements of enzyme activity and mRNA levels as well as immunostaining of a variety of tumor cells and tissues suggest that assays for the enzyme may have value in the follow-up of malignant growth.
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PMID:70 K type IV collagenase (gelatinase). 148 85

The regulation of urokinase plasminogen activator (uPA) expression was investigated in 2 highly metastatic rat mammary adenocarcinoma cell lines, BC1 and MAT 13762. BC1 cells were observed to synthesize, on average, 10 times less uPA enzyme and mRNA than MAT 13762 cells; however this difference was not accounted for by differences in uPA gene copy number/structure or in the rate of uPA gene transcription in the cell lines studied. Moreover, Northern blot analysis of invasive sub-populations derived in vitro from the BC1 cell line revealed levels of uPA expression similar to those of the parent, but a 3-fold elevation in expression of the metalloprotease gene, transin. Further investigation showed that treatment of BC1 cells with either of the protein synthesis inhibitors, cycloheximide or anisomycin, increased the level of both nuclear and cytoplasmic uPA RNA 6- to 18-fold in 4 hr, whilst inducing a maximum 2.6-fold increase in the rate of uPA gene transcription. This increase in uPA gene expression may therefore reflect, in part, an increase in the stability and/or processing of nuclear uPA transcripts. These results suggest that the degree of uPA gene expression does not correlate directly with BC1 tumor-cell invasion in vitro, and that the uPA gene is down-regulated, at least in part, post-transcriptionally in the nucleus of BC1 mammary tumor cells.
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PMID:Post-transcriptional regulation of urokinase plasminogen activator gene expression occurs in the nucleus of BC1 rat mammary tumor cells. 155 91


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