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)

A human rectal adenocarcinoma cell line, RCM-1, secreted some neutral proteinases: metallo-, serine and cysteine proteinases; and trypsin inhibitors into the serum-free conditioned medium (SFCM) in vitro. They were separated by anion-exchange and gel filtration high-performance liquid chromatography. SFCM from the cells of early passage numbers (20-24) contained native activities of serine proteinase and collagenolytic metalloproteinase. However, after several passages the native activities of them were diminished and latent form of metalloproteinase increased. In contrast to the native proteolytic activities, trypsin inhibitory activity was elevated in SFCM from the cells of passages 38-42. It inhibited the serine proteinase secreted by the same cells of early passage numbers. Furthermore, the serine proteinase was able to activate the latent form of metalloproteinase. Cooperative roles of these tumor-secreted proteinases and inhibitors may be important in tumor invasion.
Invasion Metastasis 1989
PMID:Neutral proteinases and inhibitors secreted by human rectal adenocarcinoma cell line (RCM-1). 265 68

Metastases in livers with cirrhosis are a rare event in comparison to metastases in normal livers. This fact is of great importance for clinical differential diagnosis of tumours of the liver. High metalloproteinase inhibitor contents and especially altered lectins or lectin binding sites in cirrhosis of the liver may help to explain the rare event "metastasis in cirrhosis".
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PMID:[Why are metastases in cirrhotic livers so rare?]. 267 14

We review the metalloproteinase/metalloproteinase inhibitor field, past work implicating metalloproteinases in invasion and metastasis, and our research using sense and antisense tissue inhibitor of metalloproteinase (TIMP) RNA to manipulate TIMP expression. Experiments on murine 3T3 cell lines downmodulated for TIMP expression have revealed a role for TIMP in controlling tumorigenesis as well as invasion; in tumors that develop from these cell lines there is an apparent increase in expression of genes encoding metalloproteinases. Growth patterns of cells engineered to produce different levels of TIMP and the characteristics of tumor cell lines derived from cells downmodulated for TIMP expression have been investigated. The evidence that metalloproteinases are an essential contributor to the metastatic process, and that TIMP is a prominent regulator, is quite conclusive.
Invasion Metastasis 1989
PMID:Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. 268 86

In this report we describe the isolation and characterization of a neutral metalloproteinase, from human small cell lung cancer cells, which degrades a wide range of connective tissue proteins. Treatment of tumor cytosol by ammonium sulphate precipitation followed by zinc chelated column chromatography, anion exchange chromatography, and gel filtration chromatography yielded a single enzymatically active protein, which on SDS-PAGE appeared as a diffuse band of 65,000-70,000 daltons. The tumor metalloproteinase, which was inhibited by metal chelators and serum, was able to digest gelatin, type I collagen, type IV collagen, laminin, and fibronectin. We propose that the capacity of this proteinase to degrade both components of blood vessel basement membranes and other connective tissue matrices facilitates the dissemination of human lung cancer cells during the multistep process of metastasis.
Clin Exp Metastasis
PMID:Characterization of a connective tissue degrading metalloproteinase from human small cell lung cancer cells. 283 54

Activated ras oncogene transfection into suitable recipient cells has been shown to induce the metastatic phenotype (Thorgeirsson, et al., Mol. Cell. Biol., 5: 259-262, 1985). We have used this model system to study the correlation of basement membrane collagenolysis with metastatic propensity. The c-Ha-ras oncogene alone, or combined with v-myc, transfected into early passage rat embryo fibroblasts, induce these cells to secrete high levels of type IV collagenolytic metalloproteinase and to concomitantly exhibit a high incidence of spontaneous metastases in nude mice. Cotransfection of c-Ha-ras plus the adenovirus type 2 E1a gene yields cells which are highly tumorigenic but nonmetastatic and fail to produce type IV collagenase. This effect is due to a suppression of collagenase elaboration, not increased production of a collagenase inhibitor, and not decreased production of a collagenase activator. The characteristics of the collagenase are identical to tumor type IV collagenase described previously. The nonmetastatic cells which failed to produce type IV collagenase retain the ability to secrete high levels of plasminogen activator. Transfection with the protooncogenic forms of Ha-ras or mos, or spontaneous transformation of NIH 3T3 cells or chemical transformation of BALB 3T3 cells yields cells which fail to produce collagenase, are tumorigenic, but totally nonmetastatic. These data support a biochemical linkage of type IV collagenase expression with the metastatic phenotype in this rodent system.
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PMID:Secretion of type IV collagenolytic protease and metastatic phenotype: induction by transfection with c-Ha-ras but not c-Ha-ras plus Ad2-E1a. 302 10

Tumor invasion and metastases is the major cause of treatment failure for cancer patients. There is a great need to develop new clinical methods to predict the clinical aggressiveness of a patient's tumor and to identify and eradicate clinically silent micrometastases. Such new methods may be derived from basic research into the biochemical mechanisms of invasion and metastases. We have isolated proteins involved in tumor cell attachment, invasion, and locomotion. The 'laminin receptor' is a tumor cell surface protein which specifically binds laminin, a glycoprotein of basement membranes. The laminin receptor may play a role in tumor cell attachment. 'Type IV collagenase' is a metalloproteinase which cleaves type IV basement membrane collagen but not interstitial collagens. The 'autocrine motility factor' is a secreted protein which binds to the cell surface and profoundly stimulates cell locomotion. All of these proteins appear to be augmented in actively metastatic tumor cells, at least in the models studied. They may provide strategies for diagnosis and therapy of metastases.
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PMID:Biochemical mechanisms of tumor invasion and metastases. 304 Mar 18

Matrix metalloproteinase (MMP) expression was investigated in patients with prostatic adenocarcinoma and benign prostatic hyperplasia (BPH). Forty-one men were studied: 26 had histologically proven prostate cancer, with 14 (54%) showing metastatic disease; 15 patients had BPH. Prostatic tissue was obtained from transurethral resection and needle core biopsies; gelatinolytic activity was determined by zymography. Seven gelatinolytic bands were detected, with molecular weights ranging from > 100 kilodalton (kDa) to 29 kDa. Nine of 14 patients (64%) with skeletal metastases had 92 kDa activity, present in only two of 12 patients (17%) with a negative bone scan, and absent in BPH. The 92 kDa gelatinolytic activity was expressed in 73% of aneuploid tumours compared with 20% of diploid tumours. A 97 kDa gelatinase was expressed in 80% of BPH samples and 23% of carcinoma patients. Enzyme bands of 72, 66 and 45 kDa were equally expressed in malignant tissue, irrespective of metastatic status, but were expressed in fewer BPH patients. The 97, 92, 66 and 45 kDa enzymes were identified as being pro-MMP-9 sequences by Western blotting, using a specific antibody directed against the pro sequence of the mature protein. MMP activity appeared to be increased in malignant prostatic tissue compared with BPH. Pro-MMP-9, in its 92 kDa form, was shown to be exclusively expressed by malignant prostatic tissue, and in particular by tumours that exhibited the aggressive and metastatic phenotype.
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PMID:Matrix metalloproteinase 9 expression in primary human prostatic adenocarcinoma and benign prostatic hyperplasia. 750 23

We previously found that 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced invasion of Matrigel was associated with augmentation of cell motility but not with metalloproteinase activity in a highly metastatic variant (L-10) of human rectal adenocarcinoma cell line RCM-1. In a two-dimensional cell motility assay, TPA induced active L-10 cell locomotion with characteristic morphology; the cells moved outwards from the cell islands mainly as a localized coherent sheet of cells. The leading cells showed locomotor morphologies with fan-shaped leading lamellae while the following cells had cell contacts on all sides and appeared to lack leading lamellae. In the present ultrastructural study, the following cells frequently showed tapering cytoplasmic protrusions and leading lamella-like processes underlapping a preceding cell, indicating that the locomotion mechanism is almost the same for both the leading and following cells. For this type of locomotion as a coherent sheet we propose that localized modulation of cell-cell adhesion was induced such that wide intercellular gaps occurred at the lower portion of the cells to allow the cells to extend the tapering cytoplasmic processes and leading lamellae while close cell-cell contacts remained at the upper portion of the cells. These TPA-induced changes took place predominantly in the cells at the periphery of the cell islands, while the cells in the middle of the cell islands maintained close cell-cell contacts including complex interdigitation all around the cells, suggesting the modulation of TPA action by cell-cell interaction. Additionally, consistent with the evidence for junctional complexes between the cells moving outwards, the Lucifer-yellow dye transfer studies showed some, limited cell-cell coupling, suggesting the presence of at least some gap junctional intercellular communication in the moving cell sheets.
Clin Exp Metastasis 1995 Nov
PMID:Ultrastructural study of TPA-induced cell motility: human well-differentiated rectal adenocarcinoma cells move as coherent sheets via localized modulation of cell-cell adhesion. 758 8

A conditional expression system was established whereby the human K-ras, v-src, and v-mos genes were cloned into a conditional expression vector downstream of the dexamethasone-inducible mouse mammary tumor virus long terminal repeat. Rat-1 fibroblasts were transfected with these constructs and selected in medium containing G418. Cloned transfectants were isolated and characterized for absolute dependence on dexamethasone for expression of oncogene products and anchorage-independent growth in soft agar. Expression of activated p21K-ras(val12) enabled the fibroblasts to degrade extracellular matrix collagen secreted by murine microvessel endothelial cells. Concurrent with p21K-ras(val12) induction a proteinase with the characteristic size and substrate specificity of transin, the murine homologue of the human matrix metalloproteinase stromelysin, was expressed and secreted. Induction of v-mos and v-src oncogenes resulted in little or no detectable transin expression respectively coinciding with a relative or absolute failure to increase degradation of extracellular matrix collagen. This study suggests that in this system the expression of the ras oncogene can contribute to the in vitro invasive behavior of tumor cells by upregulating the production of a metalloproteinase capable of degrading collagen synthesized by vascular endothelial cells.
Clin Exp Metastasis 1995 Jul
PMID:Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene. 760 86

Studies of tissue inhibitors of metalloproteinases (TIMPs) suggest that one of their main functions is to inhibit metalloproteinase (MMP) activity and thus prevent tumor invasion by preserving extracellular matrix (ECM) integrity. In the present study we examined the distribution of transcripts for TIMP-1, MMP-2 and MMP-9 in monkey hepatocellular carcinoma tissues. In situ hybridization demonstrated elevated levels of TIMP-1 transcripts in fibrous tissue septa, tumor inflammatory infiltrate, tumor blood vessels and in expanded portal areas. However, elevated transcripts for MMP-2 and MMP-9 were found only in tumor inflammatory infiltrate. In lung metastasis high levels of TIMP-1 transcripts were found in the stromal cells surrounding necrotic tumor nodules, in tumor blood vessels, and in mesothelial cells. MMP-9 transcripts were elevated at the periphery of the necrotic tumor nodules. These findings suggest that TIMP-1 and type IV collagenases/gelatinases can be independently regulated in vivo and that TIMP-1 may have functions in ECM remodeling which are unrelated to inhibition of MMP activity.
Clin Exp Metastasis 1995 Sep
PMID:Localization of messenger RNA for tissue inhibitor of metalloproteinases-1 and type IV collagenases/gelatinases in monkey hepatocellular carcinomas. 764 22


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