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:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate the association among matrix metalloproteinases (gelatinases A and B, stromelysin-3 (ST3) and matrilysin) mRNAs expressed in primary breast carcinomas and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. ST3, gelatinase A and matrilysin mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of gelatinase B mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of gelatinase A and matrilysin mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of ST3 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of gel B mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of gelatinase A and B mRNAs were inversely associated with the number of survivors. Our findings suggest that measurements of gelatinase A and B mRNAs expression in breast carcinoma may help to identify patients with an aggressive form of the disease.
Clin Exp Metastasis 1998 Oct
PMID:Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. 993 4

Previous studies have shown a correlation between the production of certain matrix metalloproteinases (MMPs), especially the gelatinases, by malignant tumors and the progression of these cancers as they invade and metastasize through the extracellular matrix and basement membranes. However, very few of these studies examined this relationship in human oral cancer in vivo, and none addressed the issue of how combinations of the MMPs may further enhance tumor progression. To determine which MMPs are produced in vivo by human oral cancers, we used specific anti-human-MMP antibodies and immunocytochemistry (ICC) methods to examine oral cancer tissue specimens from 20 surgery patients. The ICC data indicated that 72-kDa (72K-GL) and 92-kDa gelatinases (92K-GL) were produced in vivo by discreet clusters of tumor cells and by stromal fibroblasts, vascular endothelial cells (72K-GL), and PMNs (92K-GL). Some stromal fibroblasts near the tumors also appeared to produce fibroblast-type collagenase (FIB-CL), a finding confirmed by Western blot analysis of media conditioned by oral tumor explant cultures. ICC results indicated that 5 of the 20 tumors coincidentally produced all three MMPs. To examine how the two gelatinases and FIB-CL may interact in vitro to degrade fibrillar type I collagen, a major structural component of the extracellular matrix, we used a modified FIB-CL activity assay. Combinations of the gelatinases and FIB-CL were incubated with a 3H-collagen substrate, with the results compared with the combination of stromelysin-1 (SL-1, a superactivator of FIB-CL) and FIB-CL. 92K-GL caused a nine-fold increase in collagenase activity, equivalent to SL-1, while 72K-GL produced a four-fold increase. These results indicate that human oral cancers produce 92K-GL, 72K-GL, and FIB-CL in vivo and that the gelatinases and FIB-CL cooperate to enhance collagen degradation greatly in vitro.
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PMID:92K-GL (MMP-9) and 72K-GL (MMP-2) are produced in vivo by human oral squamous cell carcinomas and can enhance FIB-CL (MMP-1) activity in vitro. 1040 63

Osteosarcoma cells are useful for investigating bone metabolism as malignant counterpart of osteoblasts. In hematogenous metastases of osteosarcoma cells, the cells need to adjust to various changes in pericellular environment. The changes in pericellular environment may change intracellular environment and consequently the secretion of matrix metalloproteinases (MMPs) which destroy extracellular matrices. In this report, a new cell line, KOS-1, derived from human osteoblastic osteosarcoma was established, and we assumed various culture conditions containing ingredients of the extracellular matrix to make a comparative study on MMPs detected from the culture supernatants. A wide spectrum of MMPs, including MMP-1 and -3 which were increased in the presence of interleukin 1 beta, was detected in this cell line. Production of MMP-1, the enzyme which decomposes types I, II, III and X collagen, by the cells, was increased in the presence of type I collagen. MMP-3 (stromelysin-1) which degrades types III and IV collagen, laminin, fibronectin, proteoglycan, etc. was produced more abundantly in the presence of type IV collagen. MMP-2 (72-kd type IV collagenase/gelatinase A) activity was found to be increased in the presence of gelatin and type IV collagen. The MMPs production in cultured osteosarcoma cells was changed depending on the culture conditions. This indicates that the same osteosarocma cells produce different amounts and kinds of enzymes involved in local infiltration and remote metastases and increase the production of the enzymes most required under a specific environment.
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PMID:Establishment of an osteoblastic osteosarcoma cell line and effects of cell culture conditions on secretion of matrix metalloproteinases from the cultured osteosarcoma cells. 1094 49

Oesophageal adenocarcinoma is believed to arise from metaplastic mucosa in the distal oesophagus, a condition also known as Barrett's oesophagus (BE). BE develops as a result of injury caused by refluxing gastric and duodenal contents and is associated with increased risk of malignant transformation. Matrix metalloproteinases (MMPs) have been implicated in all aspects of tumour progression; tumour growth, basement membrane degradation, invasion and metastatic spread. Using in situ hybridization, we investigated the expression patterns of collagenases-1 and -3, stromelysin-2, matrilysin, metalloelastase and TIMPs-1 and -3 in BE, adenocarcinoma and lymph-node metastases. Matrilysin was expressed abundantly in 12/15 tumours and in 4/6 lymph-node metastases and its expression correlated with the histological aggressiveness of tumour. Matrilysin and metalloelastase were upregulated already in BE. Stromelysin-2 and collagenase-3 expression was detected only in a few tumours. Collagenase-1 was expressed by cancer and stromal cells in 9/15 tumours. Tumour-infiltrating macrophages expressed metalloelastase in 13/15 cancers. TIMPs-1 and -3 were expressed in 12/15 and 11/15 tumours, respectively. Laminin-5 and tenascin were abundantly expressed at the invasive front of poorly differentiated tumours, but not in BE. Our results indicate that matrilysin is the principal MMP expressed by tumour cells in oesophageal adenocarcinoma, and further studies are needed to investigate whether matrilysin or tenascin-C could be used as a predictive marker for progression of BE to cancer.
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PMID:Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. 1148 70

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n = 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n = 18) (median 11.2 vs. 17.0 months, p = 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (> or = 20% positive tumor cells, n = 14) was also significantly shorter compared to patients with lower levels of expression (n = 42) (median 5.1 vs. 14.0 months, p = 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p = 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p = 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p = 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.
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PMID:High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma. 1180 3

Matrix metalloproteinases play an important role in tissue regeneration, wound healing and tumor invasion. Our previous studies have shown a higher motility of HaCaT-ras-transfected cells compared with HaCaT or normal human keratinocytes (NHK) in correlation with a higher secretion of MMP-2 (72 kDa) or MMP-9 (92 kDa), according to the medium used for cell cultures. Presently, the expression and activity of MMPs were investigated in two reconstructed skin models, using a dead de-epidermized dermis (DED) or a dermal substitute including living fibroblasts. In all experiments, MMP-9 was essentially secreted by NHK and to a greater extent by HaCaT cells. Its active form (86 kDa) was only detected in both reconstructed skin models according to keratinocyte differentiation. MMP-2 was mainly secreted by living fibroblasts included in the dermal substitute skin model. In this case, its activation was up-regulated when HaCaT cell lines were seeded onto the dermal substitute according to their culture at air/liquid interface as shown for MMP-9. The collagenase MMP-1 and stromelysin-1 (MMP-3), susceptible to activate pro-MMP-2 and -9, respectively, were detected in their inactive form by ELISA. MMP-1 was expressed in both models but MMP-3 required the presence of living fibroblasts. Their activities were not detected using specific fluorogenic substrates. In the skin equivalent model using HaCaT, the extensive secretion and activation of MMP-2 and MMP-9 could explain the defect observed in basal membrane reconstruction, suggesting a direct interaction of HaCaT with fibroblasts.
Clin Exp Metastasis 2003
PMID:Comparative studies on the secretion and activation of MMPs in two reconstructed human skin models using HaCaT- and HaCaT-ras-transfected cell lines. 1471 2

Utilising archival human breast cancer biopsy material we examined the stromal/epithelial interactions of several matrix metalloproteinases (MMPs) using in situ-RT-PCR (IS-RT-PCR). In breast cancer, the stromal/epithelial interactions that occur, and the site of production of these proteases, are central to understanding their role in invasive and metastatic processes. We examined MT1-MMP (MMP-14, membrane type-1-MMP), MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) for their localisation profile in progressive breast cancer biopsy material (poorly differentiated invasive breast carcinoma (PDIBC), invasive breast carcinomas (IBC) and lymph node metastases (LNM)). Expression of MT1-MMP, MMP-1 and MMP-3 was observed in both the tumour epithelial and surrounding stromal cells in most tissue sections examined. MT1-MMP expression was predominantly localised to the tumour component in the pre-invasive lesions. MMP-1 gene expression was relatively well distributed between both tissue compartments, while MMP-3 demonstrated highest expression levels in the stromal tissue surrounding the epithelial tumour cells. The results demonstrate the ability to distinguish compartmental gene expression profiles using IS-RT-PCR. Further, we suggest a role for MT1-MMP in early tumour progression, expression of MMP-1 during metastasis and focal expression pattern of MMP-3 in areas of expansion. These expression profiles may provide markers for early breast cancer diagnoses and present potential therapeutic targets.
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PMID:Matrix metalloproteinase localisation by in situ-RT-PCR in archival human breast biopsy material. 1766 21

The skeleton is a preferred site of metastasis in patients with disseminated breast cancer. We have used 4T1 mouse mammary carcinoma cells, which metastasize to bone from the mammary fat pads of immunocompetent mice, to identify novel genes involved in this process. In vivo selection of parental cells resulted in the isolation of independent, aggressively bone metastatic breast cancer populations with reduced metastasis to the lung. Gene expression profiling identified osteoactivin as a candidate that is highly and selectively expressed in aggressively bone metastatic breast cancer cells. These cells displayed enhanced migratory and invasive characteristics in vitro, the latter requiring sustained osteoactivin expression. Osteoactivin depletion in these cells, by small interfering RNA, also lead to a loss of matrix metalloproteinase-3 expression, whereas forced osteoactivin expression in parental 4T1 cells was sufficient to elevate matrix metalloproteinase-3 levels, suggesting that this matrix metalloproteinase may be an important mediator of osteoactivin function. Overexpression of osteoactivin in an independent, weakly bone metastatic breast cancer cell model significantly enhanced the formation of osteolytic bone metastases in vivo. Finally, high levels of osteoactivin expression in primary human breast cancers correlate with estrogen receptor-negative status and increasing tumor grade. Thus, we have identified osteoactivin as a protein that is expressed in aggressive human breast cancers and is capable of promoting breast cancer metastasis to bone.
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PMID:Osteoactivin promotes breast cancer metastasis to bone. 1795 1

Under analysis were results of genetic investigations of 105 patients with thyroid cancer (TC) treated from 2004 through 2007 in the St. Petersburg City Center of surgery and oncology of the endocrine system organs. The patients' age was from 17 to 80 years (mean age 51.6 +/- 1.9 years). The influence of functional variants of matrix metalloproteinase genes in TC was determined. A reliable correlation was noted between certain gene markers and TC patients' age. An association was revealed between matrix metalloproteinase-3 5A (more active allele) and size of the tumor. A reliably decreased frequency of hyperactive genotype MMP-1 2G was detected in a group of women with metastatic forms of papillary cancer as compared with patients without metastases. It was shown that MMP genes could be a substantial factor of slowing down the rate of malignant growth and invasive properties of cancer of the thyroid gland.
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PMID:[Clinical significance of functional variants of matrix metalloproteinase genes in thyroid cancer]. 1943 48

Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic injury and its likely involvement in setting the stage for initiating subsequent metastatic disease at later circumstances.
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PMID:Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury. 2244 82


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