Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Clin Exp Metastasis 1992 May
PMID:Expression of gelatinase/type IV collagenase in tumor necrosis correlates with cell detachment and tumor invasion. 131 49

Aberrant expression of secreted proteinases and their specific inhibitors is believed to represent an important factor in the pathogenesis of invasion and metastases of malignant neoplasms. Our previous data indicated a link between elevated expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) and the clinical aggressiveness of malignant non-Hodgkin's lymphomas. Further studies are presented on eighteen cases of high grade, large cell immunoblastic lymphoma in which expression at the RNA level of TIMP-1 and the metalloproteinase, 92 kDa gelatinase, were analyzed. Factors that may influence production of 92 kDa gelatinase, such as necrosis, vascularity, proliferative activity, and extranodal extension, as well as clinical parameters, such as age and sex, stage, location, and survival were assessed. Statistical analysis showed that, although clinical stage was the most important predictor of survival, after controlling for age at diagnosis, levels of 92 kDa gelatinase transcripts added to the ability to predict survival.
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PMID:Relationship between the clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinases-1 (TIMP-1) RNAs. 142 16

The invasion and metastasis of cancer cells is a complex multistep process involving destruction of basement membranes as an early event in the metastatic cascade. Recent evidence implicates secreted matrix metalloproteinase enzymes, such as type IV collagenases, as playing a central role in this tumor cell mediated extracellular matrix proteolysis. Two distinct type IV collagenase enzymes are now recognized. Immunohistochemical and biochemical studies of several human tumors show correlations between invasive potential and the 72 kDa type IV collagenase enzyme. Studies in rodent tumor models suggest that the 92 kDa type IV collagenase may play an important role in these models, but data on human tumors and human tumor tissue is lacking. Evidence suggest that the regulation of the 72 kDa type IV collagenase enzyme activity may occur at many levels, including transcriptional mechanisms, extracellular activation of latent enzyme and specific inhibitors of active enzyme. Thus the invasion of human tumor cells through basement membranes may be the result of net type IV collagenolytic activity that is the result of a balance of activated enzyme species and inhibitors.
Cancer Metastasis Rev 1990 Dec
PMID:Type IV collagenases in tumor invasion and metastasis. 196 94

Basement membrane forms widespread barriers to tumor invasion. It has been shown that tumor-secreted, basement membrane-degrading enzymes, namely metalloproteinases (MMPs) play an important role in tumor invasion and metastasis. In this study, we determined the enzymatic activity, content, and mRNA of both the 72 kDa (MMP-2) and 92 kDa (MMP-9) MMPs in primary cultures of human giant-cell tumor of bone (GCT) in vitro and in tissue extracts (in vivo). Gelatin zymography showed the presence of lytic bands at M(r) 121,000, 92,000, and 72,000, and these enzymatic activities were inhibited by EDTA, an inhibitor of MMPs. Western blots with antibodies specific for MMP-2 and MMP-9 confirmed the presence of MMP-2 and MMP-9 both in vitro and in vivo, but GCT cells at late passage showed only MMP-2. Northern blots using labeled cDNA probes specific for these molecules revealed the presence of 3.1 kb transcript for MMP-2 and a 2.9 kb transcript for MMP-9. Using specific antibodies to 72 kDa and 92 kDa type IV collagenases, we studied their cellular distribution by immunohistochemical means. Stronger immunoreactivity was found for 92 kDa type IV collagenase than 72 kDa type IV collagenase in the giant cells. It appears, therefore, that MMP-9 may play an important role in the malignant behavior of GCTs and suggests a potential therapeutic role for protease inhibitors in attempting to minimize the invasive behavior of GCTs.
Clin Exp Metastasis 1995 Nov
PMID:Expression of 72 kDa and 92 kDa type IV collagenases from human giant-cell tumor of bone. 758

The production and local release of various proteolytic enzymes, either by tumor cells or tumor-associated stromal cells, is thought to facilitate the malignant behavior of solid tumors. Human cutaneous melanoma offers an excellent clinical model to study the possible contribution of such proteases to solid tumor progression because melanoma goes through a series of well defined stages in its pathogenesis; moreover, permanent cell lines have been established from these various stages. As a first step to analyzing the gelatinolytic enzymes in melanoma pathology, we examined cell lines derived from early stage primary melanomas in which patients were cured of their disease and compared the results to those obtained with cell lines established from advanced stage primary lesions or metastases (i.e., from patients who eventually succumbed to the disease). We found that 80% of cell lines examined from early stage lesions constitutively produced only the 72-kDa gelatinase A but never the 92-kDa gelatinase B. In contrast, the majority of advanced stage cell lines examined produced both the 72-kDa gelatinase A and the 92-kDa gelatinase B. Advanced stage cell lines that did not constitutively produce the 92-kDa gelatinase B could be induced to do so with transforming growth factor beta, interleukin 1 beta or 12-O-tetradecanoyl-phorbol-13-acetate. In total, 0 of 5 early stage cell lines constitutively expressed the 92-kDa gelatinase B, and only 2 of 5 could be induced to produce this activity. In contrast, all advanced stage cell lines that were evaluated either constitutively or inducibly produced the 92-kDa gelatinase B. To analyze the mechanism by which 92-kDa gelatinase B production is switched on in the advanced stage melanoma cell lines, somatic cell hybrids were constructed using an advanced stage melanoma cell line as one partner and either one of two early stage cell lines as the other. Constitutive production of the 92-kDa gelatinase B in such hybrids was lost and could not be induced in such hybrids. Coculture of the early and advanced stage cell lines failed to recapitulate what was seen after somatic hybridization, and zymographic analysis of lysates from hybrid cell lines demonstrated no 92-kDa gelatinase B activity. Reverse transcription-PCR analysis demonstrated that the loss of 92-kDa gelatinase B production occurred at the level of steady-state mRNA for the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. 766 94

Members of the matrix metalloproteinase (MMP) family have been implicated in the metastasis of tumor cells, but no direct evidence linking any given member of the MMP family to metastatic behavior has been presented. Rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nude mice and release the 92-kDa gelatinase/collagenase (MMP-9), whereas those transformed by Ha-ras plus the adenovirus E1A gene are not metastatic and do not release MMP-9. Here we demonstrate that MMP-9 expression can be induced in these tumorigenic but nonmetastatic rat cells by transfection with an MMP-9 expression vector. Transfection of a MMP-9 expression vector, but not control DNAs, conferred metastatic capacity on the nonmetastatic cells. The majority of colonies isolated after continued passage either in vivo or in vitro had lost the MMP-9 expression vector. However, occasional cells were isolated from metastases which retained MMP-9 expression after passage. These cells retained metastatic capacity. In contrast, cells isolated after losing MMP-9 expression also lost the ability to metastasize. These results provide direct evidence that MMP-9 has a role in tumor metastasis.
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PMID:Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. 818 3

Radiolabeled substrate degradation assays and gelatin zymography are routinely employed to assay 72 kDa gelatinase A (MMP-2) and 92 kDa gelatinase B (MMP-9) in biological fluids. Enzyme-linked immunosorbent assays (ELISA) have recently been developed for the quantitation of these matrix metalloproteinases (MMP). In this study, we have compared ELISA to standard substrate degradation assays for measurement of MMP-2 and MMP-9 in human plasma and tumor-conditioned media. Gelatin Sepharose chromatography and gel filtration chromatography were employed as partial purification procedures for MMP-2 and MMP-9. The ELISA data for MMP-2 and MMP-9 are linear on a log:log regression curve over a wide range of MMP concentrations and are specific for the designated gelatinase, with no overlap detected with related metalloproteinases. The minimum detectable concentrations of MMP-2 and MMP-9 were approximately 0.5 ng/ml and 0.2 ng/ml, respectively, in the ELISA as compared to 4 ng/ml and 3 ng/ml, respectively, in gelatin zymography. The [3H]gelatin degradation assay required a combination of > 50 ng/ml of MMP-2 and MMP-9 for detection. Although gelatin zymography was less sensitive than ELISA (primarily due to the smaller sample volume employed) and was more difficult to quantitate, this procedure offers the important advantage of being able to distinguish between latent and activated gelatinases.
Clin Exp Metastasis 1994 Jan
PMID:Comparison of techniques for measurement of gelatinases/type IV collagenases: enzyme-linked immunoassays versus substrate degradation assays. 828 15

Matrix metalloproteinases play an important regulatory role in tissue morphogenesis, cell differentiation and motility, and tumor cell invasiveness. We have recently demonstrated elevated activity of the 92 kDa type IV collagenase (MMP-9) in human glioblastoma and in the present study examine the relative amounts of MMP-9 protein and mRNA in human gliomas and as well as the distribution of MMP-9 in human glioma tumors in vivo. Using an enzyme-linked immunosorbent assay for the quantitative determination of MMP-9 protein, we found that levels were significantly higher in malignant astrocytomas, especially in glioblastoma multiforme, than in normal brain tissues and low-grade gliomas. In addition, the amount of MMP-9 mRNA, as determined by northern blot analysis was higher in anaplastic astrocytomas and glioblastoma multiforme than in normal brain tissue and low-grade gliomas. Immunocytochemical staining for MMP-9 showed strong cytoplasmic immunoreactivity in the tumor cells and the proliferating endothelial cells of glioblastoma multiforme and anaplastic astrocytomas. The staining intensity was lowe in low-grade astrocytomas, and was undetectable or very low in normal brain astrocytes. The results indicate that expression of MMP-9 is dramatically upregulated in highly malignant gliomas and correlates with the highly malignant progression of human gliomas in vivo, and support a role for the MMP-9 in facilitating the invasiveness seen in malignant gliomas in vivo.
Clin Exp Metastasis 1996 Jan
PMID:Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. 852 11

Tumor-stromal interactions appear to play an important role in the induction of metalloproteinase expression in malignant tumors. We describe a tissue culture system in which expression of MMP-9 (gelatinase B or the 92 kDa type IV collagenase/gelatinase) was induced by co-cultivation of fibroblasts with breast cancer cell lines. While neither the breast cancer cells nor the normal rat embryo fibroblasts made MMP-9 alone in culture, human MMP-9 was made in the co-cultures. The MMP-9 was secreted in a latent form. The induction occurred at least in part through increases in the MMP-9 mRNA levels in the breast cancer cells. These increases did not appear to require protein synthesis. Conditioned medium from the fibroblasts could duplicate the induction of MMP-9 in the breast cancer cell lines. The active factor in the medium was inactivated by heat or by trypsin suggesting that it was a protein. This protein was in the size range of 30-100 kDa. Thus, fibroblasts could secrete a factor which was able to regulate the expression of MMP-9 in breast cancer cells.
Clin Exp Metastasis 1996 May
PMID:Induction of matrix metalloproteinase 9 expression in breast carcinoma cells by a soluble factor from fibroblasts. 867 73

Tumor cells degrade extracellular matrix components (ECM) to invade surrounding tissues. Cancer cells are known to produce various ECM-degrading enzymes including matrix metalloproteinases (MMPs), serine proteinases and cathepsins. Type IV collagen is one of the major components of the basement membrane, and it composes the structural scaffold of these specialized sheets of the ECM. The enzymatic degradation of type IV collagen is initiated by MMPs, in particular MMP-2 (a 72 kDa type IV collagenase) and MMP-9 (a 92 kDa type IV collagenase) which play a key role in cancer invasion and metastasis. In this study, we investigated MMP-2 concentrations and the activity of type IV collagenase in cancer tissue homogenate in 21 cases with head and neck carcinomas and 6 cases with normal mucosa. MMP-2 concentrations did not differ between normal mucosa and tumor tissue without lymphnode metastases. Type IV collagenase activity in normal mucosa was below the detection limit. MMP-2 concentrations had no relation to tumor size, however MMP-2 concentrations in tumor tissue with lymphnode metastases were higher than that in cases without lymphnode metastasis (35.8 +/- 20.5, 20.0 +/- 9.7 ng/mg protein, respectively). However, there was no correlation between MMP-2 concentrations and type IV activity in tumor tissues. These results suggest that MMP-2 plays an important role in tumor invasion and metastasis, so MMP-2 could be a useful biological tumor marker for metastasis and prognosis.
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PMID:[Matrix metalloproteinase-2 concentrations in squamous cell carcinoma of the head and neck and its clinical significance]. 885 35


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