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)

Metalloproteinase inhibitors were surveyed with the culture media of 19 kinds of human tumor cell lines, using transin (rat stromelysin) as the target enzyme. This survey showed that most of the cell lines more or less secreted inhibitor activity, and that a human hepatoma cell line, HLE, secreted an extremely high inhibitor activity into the culture medium. Two kinds of metalloproteinase inhibitors were purified from the serum-free conditioned medium of HLE cells. The major inhibitor, which showed a single protein band with a molecular weight (Mr) of 21,000 (21k) (nonreduced) or 24k (reduced) on SDS-polyacrylamide gel electrophoresis, was identified as TIMP-2 (tissue inhibitor of metalloproteinases-2) by the analysis of its N-terminal amino acid sequence. The other was immunologically identified as TIMP. Purified TIMP-2 inhibited the activities of transin, matrin (pump-1), Mr 72k gelatinase, and interstitial collagenase with 1:1 stoichiometry. When the latent precursor form (Mr 57k) of transin was incubated with p-aminophenylmercuric acetate as an activating reagent, TIMP-2 inhibited the conversion of the intermediate form (Mr 45k) into the mature enzyme (Mr 42k). This indicated that TIMP-2 regulates not only the activity of the mature enzyme but also the autolytic processing of the proenzyme. TIMP-2 also inhibited in vitro tumor invasion through reconstituted basement membrane (matrigel) in chemotaxis chambers, showing that the metalloproteinase inhibitors as well as the extracellular matrix metalloproteinases are involved in tumor invasion through basement membrane and other extracellular matrices.
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PMID:Efficient purification of TIMP-2 from culture medium conditioned by human hepatoma cell line, and its inhibitory effects on metalloproteinases and in vitro tumor invasion. 166 1

Collagenolytic activity, extracted from 55 tumor and healthy corresponding intestinal control samples, was determined by 3 different assays using soluble type I and fibrillar type I and III collagen, respectively, as substrate. The enzyme extracted from tumor-digested collagen type I reconstituted fibrils and yielded the three-quarter segments characteristic for the action of one of the matrix metalloproteinases: MMP-I or mammalian collagenase. Metal-chelating agents such as EDTA and O-phenanthrolin indeed inhibited this activity. Collagenolytic activities were calculated on the basis of wet weight, total DNA and total extracted protein. Correlations were sought between levels of activity and both clinicopathological stage (Dukes' staging) and grade of histological differentiation. In all the assays applied, significant correlations were found between grade of histological differentiation and collagenolytic activity expressed as the tumor/control ratios: poorly differentiated tumors exhibited a higher tumor/control ratio than well-differentiated tumors. Also, tumors penetrating into the serosa showed a higher tumor/control ratio than tumors invading the muscularis propria only. A relation between collagenolytic activity and clinico-pathological stage was observed only if activities were calculated on a DNA basis. These results confirm a relationship between the histological appearance of a tumor and its enzymatic potential to degrade interstitial collagens.
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PMID:Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumors. 216 97

A metalloproteinase with Mr 29,000 was purified to homogeneity as a latent proenzyme from the conditioned medium of a human rectal carcinoma cell line CaR-1. This enzyme hydrolyzed casein more potently than gelatin embedded in polyacrylamide gels in zymography assay. Calcium ion was essential for the activity. It exerted the maximum activity at pH 7-9. Its activity was stimulated by organomercurials, such as p-amino-phenyl mercuric acetate and p-chloromercuric benzoic acid, and was inhibited by 1,10-phenanthroline but was hardly affected by diisopropyl fluorophosphate and pepstatin. When the purified proenzyme was activated by the organomercurials, it effectively hydrolyzed fibronectin, laminin, type IV basement membrane collagen, and several types of gelatins but not interstitial type I and III collagens. The treatment of the purified proenzyme with p-aminophenyl mercuric acetate or trypsin formed an active peptide with Mr 20,000. The structural analysis indicated that it was most likely identical to putative metalloproteinase-1, the complementary DNA of which had been cloned from human tumor mRNAs capable of hybridizing to a rat transin complementary DNA. Based on the fact that this enzyme is secreted extracellularly and degrades the matrix proteins, we propose the name "matrin" for this newly identified enzyme.
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PMID:Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. 225 19

Pump-1 cDNA has recently been isolated by screening a human tumor cDNA library with a transin (rat stromelysin) probe under low-stringency hybridization conditions. The cDNA codes for a potential protein with significant sequence similarity to the metalloproteinases collagenase and stromelysin, but which lacks the hemopexin-like domain characteristic of these enzymes. Expression of pump-1 cDNA in cos cells using an expression vector leads to secretion of a protein of Mr 28,000 with latent, organomercurial-activatable proteinase activity. Cos cells transfected with a partial pump-1 cDNA in the vector pPROTA secrete a fusion protein between the IgG-binding domains of staphylococcal protein A and pump-1. The fusion protein binds to IgG-Sepharose, and the bound fusion protein undergoes apparent autocleavage in the presence of 4-aminophenylmercuric acetate with elution of active pump-1 species of Mr 21,000 and 19,000. Active pump-1 degrades casein, gelatins of types I, III, IV, and V, and fibronectin and can activate collagenase. Active pump-1 is inhibited by EDTA, 1,10-phenanthroline, and the tissue inhibitor of metalloproteinases. These results show that, despite the absence of a hemopexin-like domain, pump-1 is a latent secreted metalloproteinase. Postpartum rat uteri contain elevated levels of rat pump-1 mRNA. On the basis of this observation, its size, and its substrate specificity, we suggest that pump-1 might correspond to a previously described uterine metalloproteinase, matrix metalloproteinase 7.
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PMID:Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members. 255 50

Fifteen archival human osteosarcoma specimens were examined by in situ hybridization for the expression of human and mouse transforming growth factor-beta (isoforms 1, 2, and 3), c-fos, and metalloproteinase (stromelysin-3 and matrilysin). Osteosarcoma subtypes were confirmed by review of patients' radiographs, histopathology, and age at diagnosis. The outcome and method of treatment were documented. The subtypes of osteosarcoma consisted of nine conventional osteosarcomas and two each of fibroblastic, telangiectatic, and post-radiation osteosarcomas. Each specimen was histologically examined under light microscopy, and then adjacent paraffin sections were assayed with sense and anti-sense RNA probes by in situ hybridization. The probes localized to the neoplastic cells, confirming the methodology of the technique. Human transforming growth factor-beta 1 had the most uniform binding affinity to the osteosarcomas examined and was more specific in binding than mouse transforming growth factor-beta 1. Specific mRNA encoding for the transforming growth factor-beta s, c-fos, and metalloproteinases are detectable in patterns within osteosarcoma cells, and collectively, their expression parallels the different histopathologic subtypes. The less differentiated subtypes (telangiectatic and post-radiation osteosarcomas) expressed the fewest molecular markers. Osteosarcoma is a heterogeneous tumor. Differential expression of matrilysin in osteosarcoma is the first reported detection of metalloproteinase activity in human skeletal sarcoma.
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PMID:Osteosarcoma oncogene expression detected by in situ hybridization. 747 45

In vitro angiogenesis models suggest that new blood vessel formation requires the induction and secretion by endothelial cells of matrix metalloproteinases. These enzymes assist in the controlled proteolytic degradation of the surrounding extracellular matrix during blood vessel formation. The results of in vitro studies cannot be extrapolated directly to the process of in vivo angiogenesis because the type of matrix employed and the repertoire of enzymes secreted by cells in vivo differ dramatically from in vivo conditions. To investigate the in vivo role of matrix metalloproteinases in blood vessel development, we looked for the presence of these proteinases in endothelial cells involved in fetal angiogenesis and in neovascularization of certain invasive skin tumors using immunofluorescent staining. In fetal tissue, interstitial collagenase was present in both early microvessels developing from undifferentiated mesoderm and in microvessels involved in elongation and sprout formation from preexisting blood vessels. In aggressive skin tumors, i.e., morpheaform and recurrent basal cell carcinomas and squamous cell carcinomas, there was a marked increase in the number of collagenase-containing blood vessels, often extending into the tumor nests. Immunofluorescent staining failed to detect stromelysin, matrilysin, or gelatinase A and B (72- and 92-kDa type IV collagenases, respectively) in fetal or tumor blood vessels. These findings are consistent with the hypothesis that proteolytic degradation of the extracellular matrix is required for the formation of new blood vessels. Interstitial collagenase appears to play an important role in this process.
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PMID:Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. 754 2

Matrilysin is a metalloproteinase expressed in a variety of tumors as well as in some types of normal tissue. In addition to regulating normal tissue remodelling, metalloproteinases are believed to play a role in tumor cell invasion and metastasis by degrading components of the extracellular matrix, for example the highly insoluble fibronectin fibrils found in the interstitial stroma. In this study we examined whether matrilysin can degrade fibronectin fibrils produced by human foreskin fibroblasts and characterized the degradation products of soluble fibronectin. Using indirect immunofluorescence microscopy, we demonstrate for the first time degradation of the fibronectin fibrils upon incubation with 15 nM active matrilysin. Removal of matrilysin resulted in regrowth of the fibrils, suggesting that matrilysin was not cytotoxic. Immunoblotting with specific monoclonal antibodies revealed initial degradation of soluble fibronectin within 1 h. Further degradation occurred over a period of 20 h. Degradation of soluble fibronectin resulted in one fragment of 58 kDa containing the gelatin-binding domain, two fragments of 37 and 38 kDa, which were part of the cell attachment domain, and three fragments of 36, 33, and 30 kDa recognized by an antibody raised against the C-terminal heparin-binding domain. In addition to most of these fragments, several intermediates and unique fragments of 31 and 34 kDa could be found in the conditioned medium of human foreskin fibroblasts treated with matrilysin. Isolation of these fragments may allow further studies to determine their influences on cell migration, attachment, and signal transduction, which are expected to be different from the effects of undegraded fibronectin.
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PMID:Degradation of fibronectin fibrils by matrilysin and characterization of the degradation products. 758 59

Over-production of gelatinase A (MMP-2) or under-production of its inhibitor (TIMP-2) may result in the matrix degradation crucial for metastasis, and early evaluation of their expression in primary tumor would offer important prognostic informations. RT-PCR amplicons of MMP-2 and TIMP-2 mRNA from tissue biopsies of 13 breast carcinomas and one fibrocystic mastopathy were quantitated. In comparison with their normal-tissue counterparts, their expression trends were not uniform: in some cases MMP-2 increased in the tumor without changes in TIMP-2, in others TIMP-2 expression also increased, although to a lesser extent than MMP-2; only in 2 cases was it slightly lower in the tumor tissue. Nevertheless, clearer insights were gained from the comparison of the ratio (R) between MMP-2tumor/normal and TIMP-2tumor/normal: as in the fibrocystic mastopathy, the R in carcinomas without lymph-node involvement (LN-) was usually lower than I in most cases. In contrast, in 5 out of 6 patients with lymph-node metastasis (LN+), the ratio ranged between 2 and 4. While the R magnitude was not related to the frequency of positive lymph nodes out of the total analyzed, nor to relapse status at follow-up (all relapse-free), the clear-cut difference between the LN- and LN+ groups was statistically significant. Results suggest that evaluation of MMP-2/TIMP-2 mRNA balance may constitute an early prognostic approach, which may also be more reliable concerning cancer aggressiveness as compared with the MMP-2 alone, and that boosting TIMP-2 expression may be a therapeutic strategy to prevent metastasis.
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PMID:Gelatinase A/TIMP-2 imbalance in lymph-node-positive breast carcinomas, as measured by RT-PCR. 759 Dec 76

The initiation of the angiogenic process requires a locally confined and time-limited proteolysis of the basement membrane (BM) components at the site of new vessel sprout. Gelatinase A, a member of the matrix metalloproteinase family, degrades BM type IV collagen and is involved in the BM breakdown by migrating tumor cells and endothelial cells (EC). Gelatinase A is synthesized as latent proenzyme and must be activated in order to express its proteolytic activity. A plasma membrane-dependent mechanism of activation has been described for several tumor and transformed cells lines. In the present study, we show that latent (72 kD) and mature (62-59 kD) forms of gelatinase A are present in EC membrane fraction from Triton X-114 extract while only latent form is found in the cytosolic fraction. The incubation of EC membrane fraction with exogenous latent gelatinase A resulted in a significant activation giving rise to 62-59 kD mature forms. 12-O-tetradecanoylphorbol-13-acetate (TPA), a strong potentiator of angiogenesis in vitro and in vivo, increases the amount of both latent and activated forms of gelatinase A in EC membrane fraction as well as the ability of this latter fraction to activate exogenous latent gelatinase A. We show that the mRNA transcript coding for the membrane-integrated MMP, the MT-MMP, previously described as a potential gelatinase A activator in invasive tumor cells is also expressed in vascular EC and is regulated through a TPA sensitive process. This enzyme may be responsible for membrane-dependent gelatinase A activation in normal vascular EC and may therefore be a determinant in the control of BM proteolysis during angiogenesis.
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PMID:Plasma membrane-dependent activation of gelatinase A in human vascular endothelial cells. 759 26

The gene expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was studied in human gliomas in vivo and in vitro to evaluate their roles in glioma invasion. Simultaneous expression of one to four MMP genes and two TIMP genes was found in 17 surgical glioma specimens, and one MMP (gelatinase A) gene and two TIMP genes were simultaneously expressed in tissue of three brains. The concomitant overexpression of gelatinase A, gelatinase B, and occasional matrilysin genes was associated with the malignancy of gliomas and accompanied by overexpression of the TIMP-1 gene. In five human glioma cell lines, gelatinase A, TIMP-1, and TIMP-2 genes were constitutively expressed in alll cell lines: the matrilysin gene in three cell lines; the stromelysin gene in two cell lines; and the interstitial collagenase gene in one cell line. There was a clear difference in the expression of gelatinase B and stromelysin genes between surgical glioma specimens and glioma cell lines: the gelatinase B gene was not expressed constitutively in vitro but was overexpressed in vivo, whereas the stromelysin gene was not expressed in vivo but was expressed in some cell lines. To find the cause of that difference in vivo and in vitro, the transcriptional regulations of MMP and TIMP genes by tumor promoter, growth factors, or cytokines were studied in vitro. Interstitial collagenase, gelatinase B, stromelysin, and TIMP-1 genes were upregulated in many cell lines by phorbol-12-myristate-13-acetate (PMA) and in some cell lines by epidermal growth factor, tumor necrosis factor-alpha, or interleukin-1 beta. Transforming growth factor-beta 1 (TGF beta 1) upregulated gelatinase A and matrilysin genes in some cell lines, and there were no clear responses from any MMP and TIMP genes to interleukin-6. Thus, the transcriptional modulation of MMP genes by these growth factors and cytokines seemed insufficient to explain the difference in gelatinase B and stromelysin gene expressions in vivo and in vitro and was suggestive of the genetic alteration of glioma cells in vitro, the heterogeneous cell population in glioma tissues, or both. Furthermore, the in vitro invasion of glioma cells through Matrigel in response to PMA, TGF beta 1, or TIMP-1 was assessed by chemoinvasion assay. In most cell lines, invasion was significantly stimulated by PMA or TGF beta 1 but suppressed by TIMP-1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. 761 76


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