Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

K-1735 clones 10 and M2 are cell lines cloned from a UV-induced murine melanoma. While both lines are highly tumorigenic, only the M2 cells are highly invasive in vitro and metastatic in vivo. Here we have exposed the clone 10 cells to the synthetic peptide PA22-2, which contains the IKVAV sequence from the A chain of laminin and which, like laminin, induces collagenase IV production and enhances metastasis formation by B16F10 cells. Zymogram analysis of conditioned media from clone 10 cells cultured on the peptide demonstrated a dose-dependent increase in collagenase IV activity. When clone 10 cells were cultured on a reconstituted basement membrane (Matrigel), this peptide caused an invasive phenotype comparable to the M2 cells. The invasive clone 10 cells were, however, unable to form lung colonies in vivo in the presence of this peptide. We conclude that this peptide represents an active site on laminin which is able to stimulate the invasiveness of this tumor cell line, but that this activity is not sufficient to confer metastatic potential.
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PMID:Induction of an invasive phenotype in benign tumor cells with a laminin A-chain synthetic peptide. 129 29

The influence of human recombinant tumor necrosis factor-alpha has been assessed on a cell line (U-251) derived from a human malignant glial tumor. The results of this study demonstrate that tumor necrosis factor-alpha at doses of 50 and 100 ng/ml: 1) did not have cytotoxic or cytostatic effects on the U-251 cell line; 2) significantly increased the intracellular activity of manganese superoxide dismutase but had no effect on copper and zinc superoxide dismutase, catalase, or glutathione peroxidase activity; and 3) did not significantly alter the intracellular or extracellular general protease and collagenase type IV activity of these cells. The resistance of the U-251 cell line to tumor necrosis factor-alpha cytotoxicity may be related in part to the high intrinsic manganese superoxide dismutase activity present in this cell line combined with the ability of this cell line to induce substantial amounts of protective manganese superoxide dismutase activity in response to tumor necrosis factor-alpha.
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PMID:The effect of tumor necrosis factor-alpha on human malignant glial cells. 131 41

General protease and collagenase IV activity are involved in the remodelling of the vascular basement membrane that occurs during tumor-induced angiogenesis. This study has assessed the level of these enzymes in tumor, peritumoral or contralateral cerebral cortex tissue during the growth of C6 astrocytoma in the rat spheroid implantation model. General proteolytic activity was increased in tumor tissue beginning on day 8 following spheroid implantation, then increased to a maximum value on day 11 and decreased to control values on day 18. A similar pattern was seen for collagenase IV activity but maximal activity occurred on day 13. The peritumor and tumor patterns of activity were similar. General protease activity was increased in the hemisphere contralateral to the tumor suggesting that the growth of C6 astrocytoma in rat brain was influencing biochemical events distant from the tumor. C6 astrocytoma cells orchestrate a cascade of proteolytic events which may play a crucial role in angiogenesis associated with tumor growth in the model system studied.
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PMID:Proteolytic activity during the growth of C6 astrocytoma in the murine spheroid implantation model. 131 23

An expression vector was constructed in which TGF-beta 1 was placed under the control of the metallothionein promoter. Cys223 and Cys225 in the TGF-beta 1 propeptide were converted to serines, mutations which result in dissociation of the pro-peptide and secretion of bioactive TGF-beta 1 [Brunner, A.M., Marquardt, H., Malacko, A.R., Lioubin, M.N. and Purchio, A.F. (1989) J. Biol. Chem., 264, 13660-13664]. A fibrosarcoma was transfected with this plasmid and a clone (17.18) was selected in which TGF-beta 1 mRNA was able to be induced six-fold following zinc sulphate treatment. These cells increased the secretion of bioactive TGF-beta 1 14-fold and exhibited a coincidental increase in jun-B mRNA expression, suggesting that secreted TGF-beta 1 was acting to induce this early response gene by autocrine activation. Following zinc sulphate induction, the tumor cells became progressively more motile and able to invade collagen gels. In contrast to parental tumor not bearing the TGF-beta 1 expression vector, zinc sulphate stimulation of clone 17.18 enhanced collagenase IV and procathepsin L mRNA levels and enhanced the secretion of many collagenolytic proteases into the medium. Since the action of TGF-beta generally decreases proteolysis by suppression of protease transcription, we compared the response of normal parental fibroblasts to ras-transformed fibrosarcomas and confirmed that TGF-beta could greatly enhance collagenase IV and procathepsin L mRNA levels while having little effect on non-transformed fibroblasts. These experiments indicate that induction of TGF-beta secretion can enhance motility and protease production through autocrine activation, thus increasing the invasion potential of fibrosarcomas.
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PMID:Autocrine induction of tumor protease production and invasion by a metallothionein-regulated TGF-beta 1 (Ser223, 225). 131 70

We have previously observed that acellular extracts from necrotic areas (NE) of the non-metastatic murine mammary adenocarcinoma M3, enhance in vitro cell detachment and spontaneous lung metastases. In the present study, using different proteinase inhibitors along with NE, only the calcium chelator EDTA could significantly abrogate the enhanced cell detachment from M3 produced by NE. The typical cleavage products of type IV collagenase were detected inside the tumor necrotic area, mainly in association with necrobiotic cells, as evaluated by Western blot analysis and immunohistochemical assays. Zymography revealed the presence of 72- and 92-kDa gelatinase/type IV collagenase in NE. Moreover, NE increased the in vitro invasive ability of cultured M3 cells. The use of specific antibodies against both 72- and 92-kDa type IV collagenases in the invasion assay showed that only the latter was able to revert the enhanced invasiveness to the baseline. It can be concluded that tumor necrosis is an important source of gelatinase/type IV collagenase, mainly in its 92 kDa form, and plays a major role in tumor invasion.
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PMID:Expression of gelatinase/type IV collagenase in tumor necrosis correlates with cell detachment and tumor invasion. 131 49

SV-40 transformed human lung fibroblasts and HT 1080 fibrosarcoma cells secrete a 92-kDa type IV collagenase (in addition to 72-kDa type IV collagenase identical to that found in macrophages, phorbol ester differentiated U937 cells, and keratinocytes. The expression of this protease is induced by the tumor promoter TPA, and interleukin-1 and was not detected in the parental human lung fibroblast. The 92-kDa preproenzyme has a predicted Mr of 78,426, including a 19 amino acid long hydrophobic signal peptide. The apparent discrepancy between the predicted molecular weight and the molecular weight of the secreted protein is due to a post-translational modification of the enzyme through glycosylation. The 92-kDa type IV collagenase consists of five distinct domains, including a unique 54 amino acid long collagen--like domain, and is a member of the secreted ECM metalloprotease gene family. Both the 72 and 92-kDa type IV collagenase contain a fibronectin-like collagen binding domain. The mosaic structure of the secreted ECM metalloproteases is a result of a recruitment of the functional units from ECM structural macromolecules into an enzyme protein in the process of evolution. The 92-kDa and 72-kDa type IV collagenase proenzymes form a noncovalent complex with inhibitors, which is activatable by APMA, yielding an enzymes with similar if not identical substrate specificity profile. Our results demonstrate that while the 92-kDa type IV collagenase forms a stoichiometric complex with TIMP, the 72-kDa type IV collagenase, purified from the same starting material, contains a novel 24-kDa inhibitor-TIMP-2.
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PMID:Mosaic structure of the secreted ECM metalloproteases and interaction of the type IV collagenases with inhibitors. 133 9

Metalloproteinases are thought to be important for tumor invasion and metastasis. We used in situ hybridization with 35S-labeled cRNA probes to localize sites of expression for 92-kDa type IV collagenase mRNA in sections of nodular basal cell carcinoma. Positive signal for 92-kDa type IV collagenase mRNA was detected in eosinophilic granulocytes within inflammatory infiltrates surrounding the tumor nodules. Eosinophils, however, were not adjacent to tumor cells, suggesting that metalloenzyme production by these granulocytes in this disease may be targeted more to stromal components than to remodeling or destruction of the basement lamina. The identity of the eosinophils was confirmed by cell morphology and specific histochemical staining. No resident or other migratory cells were positive for enzyme mRNA in these samples. Signal specificity for in situ hybridization was shown by a duplication of the results with complementary oligomeric probes and by a lack of signal in sections hybridized with a sense RNA probe or nonspecific oligomer. No signal for 92-kDa type IV collagenase mRNA was detected in circulating eosinophils or in eosinophils associated with Hodgkin's lymphoma. These data suggest that eosinophils migrate into the dermis and express type IV collagenase in response to basal cell carcinoma and that this process may have a role in tumor growth.
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PMID:Expression of 92-kDa type IV collagenase mRNA by eosinophils associated with basal cell carcinoma. 140 8

Human neutrophils were found to release a 91-kDa gelatinase that is serologically related to tumor-derived gelatinolytic enzymes, as evidenced by immunoprecipitation. In order to identify the neutrophil gelatinase, the activity in conditioned medium from human neutrophil suspensions was purified by affinity chromatography on a gelatin substrate. The 91-kDa active enzyme was further separated from other stainable protein bands by classical SDS PAGE and blotting to a solid support. Amino-terminal sequence analysis of blotted proteins showed that the 91-kDa enzyme is a truncated form of tumor-derived 92-kDa gelatinase (type IV collagenase), lacking eight residues at the NH2-terminus. Sequence analysis of enzymatically inactive cleavage products of this neutrophil gelatinase demonstrated that the gelatin-binding part of the molecule is restricted to the amino-terminal third. Exocytosis of gelatinase-containing granules from neutrophils occurred spontaneously within 6 h after neutrophil plating. When the cells were triggered with the phorbol ester phorbol 12-myristate 13-acetate, a strong secretagogue, rapid gelatinase release was observed. When granulocytes were stimulated with the neutrophil-activating peptide interleukin-8, maximal exocytosis occurred within 1 h. The almost immediate release of neutrophil gelatinase after stimulation of the cells with a chemotactic factor might play a key role in remodeling of the extracellular matrix during granulocyte movement in response to chemotactic stimuli.
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PMID:Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8. 164 57

In 187 node-negative breast cancers, the expression of laminin receptors and collagenase IV was directly related in 52% of cases, independently of pathological (tumor size and histology) and biological (estrogen receptors and proliferative activity) features. Moreover, the presence of laminin receptors and collagenase IV did not appear to influence tumor proliferative activity, evaluated as 3H-thymidine labelling index. In this case series, relapse-free survival and overall survival at 6 years were significantly affected by tumor size, hormone receptor status and proliferative activity. Conversely, high levels of laminin receptors and collagenase IV failed to influence relapse-free or overall survival, whereas they were strong indicators of local-regional diffusion of the disease.
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PMID:Laminin receptors, collagenase IV and prognosis in node-negative breast cancers. 164 75

Tumor growth is dependent on the ability of neoplastic cells to induce angiogenesis. Remodelling of blood vessels requires reconstruction of the collagen (type IV) and non-fibrous protein components of basement membrane. This study assessed the general protease and collagenase (IV) activities of C6 astrocytoma cells in monolayer and spheroid culture and C6 astrocytoma spheroids growing in vivo. Extracellular release of non-specific proteases and collagenase IV was maximal during early exponential cell growth. Increased spheroid size resulted in enhanced extracellular activity of both enzyme groups assessed. The size of the implanted spheroid influenced the activity measured in vivo. General proteolytic activity was significantly greater in tumor tissue at all spheroid sizes while only the implantation of 750 microns spheroids resulted in significantly increased collagenase type IV activity. The growth of C6 astrocytoma cells in monolayer and spheroid culture in vitro and in vivo is associated with distinct alterations in intracellular and extracellular activity of the proteolytic enzymes assessed. Increased extracellular release of these enzymes may play important roles in tumor-associated angiogenesis, tumor invasiveness, tumor induced hemorrhage and tumor-associated edema.
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PMID:General protease and collagenase (IV) activity in C6 astrocytoma cells, C6 spheroids and implanted C6 spheroids. 165 4


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