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)

The invasion and metastasis of cancer cells is a complex multistep process involving attachment of tumor cells to the basement membrane, proteolysis of the local connective tissue stroma, and migration through the proteolyzed stroma. Recent evidence implicates metalloproteinases such as type IV collagenase and transin/stromelysin in the proteolytic aspects of this process. Type IV collagenase activity is modulated by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). Immunohistochemical and biochemical studies of several human tumors show correlations between invasive potential and type IV collagenase activity.
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PMID:Metalloproteinases and cancer invasion. 210 92

The effect of the phorbol ester tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) on cell invasion was studied using an in vitro assay for cell invasion through a reconstituted basement membrane matrix (Matrigel). TPA inhibited the invasiveness of malignant human fibrosarcoma HT1080 cells. In contrast, WI-38 lung fibroblasts, which show a very low invasive capacity, were stimulated (3-fold) to invade Matrigel after exposure to TPA for 48 hours. The inhibitory or stimulatory effects of TPA on cell invasion were correlated with a decrease or an increase in cell motility and collagenase IV activity, respectively. Synthetic diacylglycerols partially mimicked the inhibitory action of TPA on HT1080 cells but failed to stimulate WI-38 cell invasion. Immunoblots demonstrated that in both cell lines the alpha and beta isoforms of protein kinase C were equally down-regulated after a 5 hour exposure to TPA despite the basal low level of protein kinase C polypeptide in the malignant cells. Thus, whereas in WI-38 cells induction of an invasive behavior could be observed in the absence of protein kinase C, in the malignant cells disappearance of the kinase was associated with a non-invasive phenotype.
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PMID:Differential effects of phorbol ester on the in vitro invasiveness of malignant and non-malignant human fibroblast cells. 215 89

Tumor cells attach, degrade, and migrate through basement membranes as they metastasize. Laminin, a major glycoprotein of basement membranes, promotes the metastatic activity of tumor cells by stimulating the attachment and migration of the cells and their secretion of collagenase IV. We have identified a synthetic peptide of 19 amino acids (Cys-Ser-Arg-Ala-Arg-Lys-Gln-Ala-Ala-Ser-Ile-Lys-Val-Ala-Val-Ser-Ala-Asp -Arg) from the sequence of the A chain of laminin that increases experimental metastases of the lungs by murine melanoma cells. The peptide is active when injected either intravenously or intraperitoneally. The peptide increased collagenase IV activity, a key enzyme in the breakdown of basement membranes, to the same extent as laminin. This peptide represents an active site on laminin for promotion of the metastatic phenotype and generates a probe for studying the regulation of malignant activities.
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PMID:Identification of an amino acid sequence from the laminin A chain that stimulates metastasis and collagenase IV production. 215 66

Production of type IV collagenase by tumor cells has been linked to their metastatic potential in several experimental models. A possible role for this enzyme in basement membrane type IV collagen turnover has also been suggested. Two recently developed affinity-purified, monospecific antibodies directed against the amino terminus (H1), or an internal active site domain (metal binding region [MBR]) of human type IV collagenase, were employed in the avidin-biotin-immunoperoxidase technique in formalin-fixed, paraffin-embedded breast tissue samples from 55 patients. Intense cytoplasmic immunostaining of myoepithelial cells was found in normal and hyperplastic tissue, and discontinuous staining was noted in intraductal carcinomas. Luminal epithelial cells were negative or weakly positive in large- or medium-sized ducts but reacted frequently in normal terminal ducts and hyperplastic lesions. Epithelial cells in intraductal carcinomas exhibited immunoreactivity in 20 of 23 cases. Invasive carcinomas were positive in 36 of 40 cases, and metastatic cells in lymph nodes stained in 10 of 12 cases. These results support a role for type IV collagenase in the basement membrane remodeling of normal breast. Our findings suggest that myoepithelial cells play a pivotal role in this enzymatic activity. The high percentage of positive cells in invasive carcinomas and the strong immunoreactivity of lymph node metastases support the role of the enzyme in tumor invasion and metastasis and suggest that tumor cells are the essential source of the enzyme in these processes.
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PMID:Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. 215 30

Stable transfection of human tumor cell lines with the adenovirus-5 E1A gene repressed the expression of the secreted proteases, type IV collagenase, interstitial collagenase and urokinase. In addition, E1A blocked the 12-O-tetradecanoyl phorbol acetate (TPA) induction of interstitial collagenase transcription in HT1080 fibrosarcoma cells. Plasmids bearing the interstitial collagenase or type IV collagenase 5' flanking regions linked to a chloramphenicol acetyl transferase coding sequence were constructed and analysed for expression by transient cotransfections into HT1080 cells. Cotransfection with a plasmid bearing a functional E1A gene repressed transcription of the type IV collagenase promoter and blocked the TPA induction of the interstitial collagenase promoter. Furthermore, E1A repressed transcription from a TK promoter driven by AP-1 complex binding sites (TRE), suggesting that E1A interferes with the AP-1 trans-activation pathway. This effect was not, however, due to the repression of c-jun gene transcription by E1A. In fact, the expression of E1A rendered the c-jun gene hypersensitive to TPA induction. Concomitant with reduction in expression levels of secreted proteases, stable E1A transfectants showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibodies inhibited invasive activity of parental tumor cell lines in the in vitro assay, suggesting a possible causal relationship between the repression of secreted proteases and loss of metastatic properties of the transformants.
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PMID:Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells. 215 83

In order to study the role of both collagenases against type I and type IV collagen (type I and type IV collagenase) with regard to tumor invasion and metastasis, the activities of both collagenases in tissue homogenate in each 40 cases of stomach and lung cancers were investigated. The direct assay method of type IV collagenase in tissue was established through modification of Liotta's method. In stomach cancer, the part of advancing front of cancer showed the highest activity of type I collagenase. The adjacent mucosa to cancer also showed high activity of type IV collagenase. The cancer tissues that had the remarkable finding of vascular invasion of cancer cells showed high activity of type IV collagenase. In lung cancer, the correlation between the size of cancer mass and activity of type I collagenase was shown. Squamous cell carcinoma in comparison to adenocarcinoma had higher activity of type I collagenase and poor activity of type IV collagenase. These results suggested that the activity of type I collagenase might participate in local invasion and the activity of type IV collagenase might be associated with vascular invasion of cancer through disruption of basement membrane and they could be one of the useful biochemical tumor marker to represent the growth and metastatic pattern.
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PMID:[New direct assay method of type IV collagenase in tissue homogenate and biochemical role of collagenase against type I, and IV collagens to the invasion of the stomach and lung cancer]. 215 47

Extracellular matrix metalloproteases are secreted by the resident cells of the tissue in a proenzyme form, and their extracellular activity is regulated at the level of gene expression, proenzyme activation, and interaction with inhibitors. To understand the molecular mechanisms that control the activity of ECM metalloproteases and their effect on the cellular phenotype, we have established cell lines in which the transcription of the protease genes is repressed. We also have undertaken a detailed study of the pathway of extracellular activation of interstitial procollagenase. Stable transfection of three human tumor cell lines--H-ras-transformed bronchial epithelial cells TBE-1, fibrosarcoma cells HT1080, and melanoma cells A2058--with the adenovirus E1A gene dramatically repressed the expression of the secreted proteases, type IV and interstitial collagenases, and urokinase-type plasminogen activator. Concomitantly, E1A-expressing cells showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibody inhibited the invasive activity of parental tumor cell lines in the in vitro system, suggesting a possible causal relationship between the effect of E1A on the expression of secreted proteases and the reduced metastatic potential of the E1A-expressing transformants. We have also studied the mechanism of regulation of metalloprotease activity at the level of extracellular activation by investigating the cascade of proteolytic events that results in the activation of interstitial procollagenase. Cocultivation of the major cellular components of skin, dermal fibroblasts, and epidermal keratinocytes induces activation of interstitial procollagenase and prostromelysin in the presence of plasminogen. This activation occurs through a uPA-plasmin-dependent pathway in which plasmin catalyzes the first step in activation of both collagenase and stromelysin by amino-terminal processing. Activated stromelysin can in turn convert plasmin-activated collagenase into a fully active enzyme by removal of approximately 15 amino acid residues from the carboxyl end of the enzyme. This second step of activation results in a 5-8-fold further increase in specific activity of collagenase. This cascade of proteolytic events may constitute a major physiologic pathway of collagenase activation.
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PMID:Secreted proteases. Regulation of their activity and their possible role in metastasis. 215 52

Treatment of four A375 human melanoma sublines (A375, A375P, A375P-5, A375M), exhibiting distinct metastatic potentials in vivo, with beta-all-trans-retinoic acid in vitro caused a dose- and time-dependent inhibition of the ability of these cells to penetrate Matrigel-coated filters using a reconstituted basement membrane invasion assay. The possible mechanisms of action responsible for the antiinvasive effect were further investigated, and the data showed that compared with untreated cells the retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes, as demonstrated by a decreased ability of the cells to degrade [3H]proline-labeled type IV collagen substrate and by a reduction in the activity of a secreted Mr 64,000 collagenolytic enzyme detected in type IV collagen-containing polyacrylamide gels; (b) expressed lower levels of the human type IV collagenase mRNA (except in the A375P cells), as detected by Northern blot analysis; (c) exhibited decreased levels of tissue plasminogen activator activity, as demonstrated by a chromogenic assay; (d) were 10-40% less adhesive to a reconstituted basement membrane matrix, as determined by a 60-min Na2(51)CrO4-labeled cell attachment assay; (e) exhibited an increase in the high affinity metastasis-associated cell surface laminin receptor, as determined by flow cytometry after binding of fluorescently labeled laminin receptor antibody; and (f) expressed decreased amounts of gp78, a cell surface receptor for motility factor, demonstrated by immunoblotting and immunofluorescence. Collectively, these data suggest that retinoic acid inhibits tumor cell invasion through a basement membrane-like matrix by suppressing matrix degradation and by altering cell surface receptors.
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PMID:Retinoic acid inhibition of human melanoma cell invasion through a reconstituted basement membrane and its relation to decreases in the expression of proteolytic enzymes and motility factor receptor. 216 53

A Mr 92,000 metalloprotease, originally observed in neutrophils, has been found to be secreted by various normal and malignant cells of fibroblastic, hematopoietic, and epithelial origin. The responsiveness of the various cell types to the tumor promoter phorbol ester (phorbol myristate acetate) to secrete this enzyme and a corresponding Mr 72,000 gelatinase has been determined using gelatin zymograms. The latent zymogen form of the Mr 92,000 enzyme has been purified from phorbol myristate acetate-stimulated HT1080 human fibrosarcoma cells using sequential gelatin-Sepharose affinity chromatography and gel filtration. Selective elution from gelatin-Sepharose allows for a distinct separation of the Mr 92,000 gelatinase from the Mr 72,000 gelatinase. A fraction of the tumor cell derived latent Mr 92,000 enzyme is isolated as an apparent complex with human tissue inhibitor of metalloproteases, which is partially dissociated in sodium dodecyl sulfate and completely dissociated upon reduction of disulfide bonds and upon p-aminophenylmercuric acetate treatment. Organomercurial treatment rapidly allows for autoactivation of the proenzyme to active Mr 83,000 and Mr 75,000 species. At physiological pH, the enzyme rapidly degrades gelatin into small fragments and slowly cleaves native type V collagen at an apparent single site. Native type IV collagen is degraded to a much lesser extent. The NH2-terminal amino acid sequence of the Mr 92,000 proenzyme has been determined and is distinct from the Mr 72,000 gelatinase/type IV collagenase which is constitutively produced by fibroblasts. The Mr 92,000 enzyme is also immunologically distinct from the Mr 72,000 enzyme but immunologically cross-reactive with the neutrophil, high molecular weight gelatinase. The Mr 92,000 enzyme constitutes a distinct member of the matrix metalloprotease family. Its substrate specificity implies a broad physiological role, acting on basement membrane type V collagen as well as on denatured (gelatinized) collagens and thus may be involved in the invasive and migratory phenotype of human cells.
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PMID:Tumor promoter-stimulated Mr 92,000 gelatinase secreted by normal and malignant human cells: isolation and characterization of the enzyme from HT1080 tumor cells. 216 35

Proteolysis by type IV collagenase (T4) has been implicated in the process of tumor metastasis. The T4 gene is expressed in fibroblasts, but not in normal epithelial cells, and its expression is specifically repressed by the E1A oncogene of adenovirus. We present an investigation of the transcriptional elements responsible for basal, E1A-repressible, and tissue-specific expression. 5'-Deletion analysis, DNase I footprinting, and gel mobility shift assays revealed a strong, E1A-repressible enhancer element, r2, located about 1,650 bp upstream of the start site. This enhancer bound a protein with binding specificity very similar to that of the transcription factor AP-2. A potent silencer sequence was found 2 to 5 bp downstream of this enhancer. The silencer repressed transcription from either r2 or AP-1 enhancer elements and in the context of either type IV collagenase or thymidine kinase (tk) gene core promoters; enhancerless transcription from the latter core promoter was also repressed. Comprising the silencer were two contiguous, autonomously functioning silencer elements. Negative regulation of T4 transcription by at least two factors was demonstrated. mcf-7 proteins specifically binding both elements were detected by gel mobility shift assays; a protein of approximately 185 kDa that bound to one of these elements was detected by DNA-protein cross-linking. The silencer repressed transcription, in an r2 enhancer-tk promoter context, much more efficiently in T4-nonproducing cells (mcf-7 or HeLa) than in T4-producing cells (HT1080), suggesting that cell type-specific silencing may contribute to the regulation of this gene.
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PMID:Positive and negative transcriptional elements of the human type IV collagenase gene. 217 9


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