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)

Stromelysin-3 (ST3) is an extracellular proteinase predominantly expressed in fibroblasts. The particular structural features and in vitro functions of this molecule suggest it could be the first member of a new subgroup of the matrix metalloproteinase family. ST3 is transiently expressed during mammary gland post-weaning involution, embryonic implantation, various organogeneses, and during amphibian metamorphosis. Moreover, ST3 is expressed in a panel of human invasive carcinomas including breast, colon, and head and neck carcinomas. Almost all ST3-expressing tissues show intense extracellular matrix remodeling activities including the loss of basement membrane integrity. Thus, either directly, or indirectly in association with other proteinases, ST3 might be involved in tissue remodeling processes occurring in both physiological and pathological processes. In vitro and in vivo studies using malignant cells stably transfected in such a way as to modulate their ST3 expression levels indicate that ST3 modifies neither cell proliferation nor invasive properties, but rather favors tumor cell survival in host tissues. This hypothesis is consistent with clinical data showing that ST3 expression could be predictive of tumor progression leading to metastases.
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PMID:Stromelysin-3 in the biology of the normal and neoplastic mammary gland. 1088 96

In recent years significant advances have been made in the treatment of metastatic non-small cell lung cancer. These advances have been due to both the discovery of new, more active drugs and an enhanced understanding of the biology of the disease, which has guided treatment decisions. Today, agents such as paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine are used in combinations that have demonstrated higher overall response rates and longer median overall survival durations than the previous generation of regimens based primarily on cisplatin, etoposide, and vinblastine. Of these new agents, paclitaxel has been the most widely studied and has demonstrated considerable activity when administered in a wide range of doses and schedules. Regimens with significant activity include paclitaxel and carboplatin as well as paclitaxel, carboplatin, and gemcitabine. However, because the optimal doses and schedules have not been clearly elucidated, current research efforts continue to focus on variations of these regimens. Just as advances have been made in the treatment of metastatic disease, it also has been clearly demonstrated that preoperative chemotherapy (+/- radiation) dramatically improves the overall survival for patients with stage III disease. The identification of growth factors, growth factor receptors, oncogenes, and tumor suppressor genes, which influence this disease, is providing new targets for future treatment strategies. Likewise, new therapeutic entities such as antiangiogenesis agents and matrix metalloproteinase inhibitors are being evaluated.
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PMID:Future directions in the treatment of non-small cell lung cancer. 1089 74

We investigated whether the expression of membrane-type-1 matrix metalloproteinase (MT1-MMP), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) was consistent with the proposed roles of these proteins in promoting metastasis in colorectal cancer. The expression of MT1-MMP was significantly more frequent in deeply invasive carcinomas (P = 0.007) and in cases of vascular invasion (P = 0.02). The frequency of detection of MMP-2 in the stroma was much greater in vascular invasion-positive cases (42%) than in negative cases (20%; P = 0.02). The rate of detection of TIMP-2 in tumour cell cytoplasm increased with the depth of invasion (P = 0.03). TIMP-2 in the stroma was found more frequently in tumours with lymphatic invasion and lymph node metastasis (P < 0.05). Significant correlations were found between detection of MT1-MMP and MMP-2 in tumour cell cytoplasm (P < 0.05), of MT1-MMP and TIMP-2 in tumour cell cytoplasm (P < 0.01), and of MMP-2 and TIMP-2 in tumour cell cytoplasm (P < 0.01). Immunohistochemical detection of MT1-MMP and TIMP-2 might be useful for monitoring infiltration in colorectal carcinoma but is not correlated with distant metastases.
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PMID:Immunohistochemical detection of membrane-type-1-matrix metalloproteinase in colorectal carcinoma. 1090 73

Infiltrative capacity was found to distinguish separate T leukemia cell lines. Of seven T-cell lines four exhibited capacity to infiltrate Matrigel. Analysis of infiltration was performed at the single-cell level throughout the Matrigel using a depth meter. Further, we examined differences in migration capacity and metalloproteinase production between infiltrating and non-infiltrating T-cell lines. The capacity to infiltrate was not directly correlated to the capacity to adhere to the Matrigel or to migrate on/to extracellular matrix components. It is concluded that infiltration capacity does not simply reflect capacity to migrate but represents a distinct functional property. The production of metalloproteinases and their inhibitors by the separate T-cell lines was analyzed using rt PCR, biosynthetic labelling, zymography, immunoprecipitation and ELISA. All T-cell lines with capacity to infiltrate produced matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) while non-infiltrating cell lines did not express MMP-9. Expression of MMP-1, 2, 3, 10, 14 and 17 showed no correlation to capacity to infiltrate. Analysis of infiltration in the presence of a metalloprotease inhibitor showed an increased number of cells within the gel. This enhancement of infiltration suggests that the function of MMPs and/or their inhibitors in lymphocyte infiltration is more complex than previously thought.
Clin Exp Metastasis 1999
PMID:Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). 1091 15

Intrahepatic metastasis is one of the malignant features of hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (u-PA)/plasmin, are known to be associated with the invasive properties of various types of tumor cells. In this study, we examined which proteinases play a role in the metastatic invasion of human HCC cell lines. JHH-5 and JHH-6 cells constitutively expressed mRNAs for both membrane-type 1 matrix metalloproteinase (MT1-MMP) and u-PA and invaded through reconstituted MATRIGEL in vitro, whereas JHH-7 cells expressed u-PA mRNA but not MT1-MMP and did not invade. However, hepatocyte growth factor (HGF) induced MT1-MMP expression on the surface of JHH-7 cells and markedly increased invasiveness of JHH-7 in a concentration-dependent manner. Moreover, cleavage activity for pro-MMP-2 was induced in HGF-treated JHH-7 cells. MMP inhibitor, rather than serine proteinase inhibitor, potently inhibited HCC cell invasion. Intrahepatic injection of HCC cell lines into athymic nude mice caused visible intrahepatic metastases in vivo. Moreover, JHH-7 tumors showed expression of MT1-MMP mRNA, while in vitro cultured JHH-7 cells did not. These findings suggest that MT1-MMP plays an important role in the invasive properties of HCC cells, and that HGF modifies the invasive properties of noninvasive HCC cells.
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PMID:Invasiveness of hepatocellular carcinoma cell lines: contribution of membrane-type 1 matrix metalloproteinase. 1093 57

Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing the catalytic importance of substrate-binding exosites outside the catalytic domain, we screened for extracellular substrates using the gelatinase A hemopexin domain as bait in the yeast two-hybrid system. Monocyte chemoattractant protein-3 (MCP-3) was identified as a physiological substrate of gelatinase A. Cleaved MCP-3 binds to CC-chemokine receptors-1, -2, and -3, but no longer induces calcium fluxes or promotes chemotaxis, and instead acts as a general chemokine antagonist that dampens inflammation. This suggests that matrix metalloproteinases are both effectors and regulators of the inflammatory response.
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PMID:Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. 1094 89

Tumor cell invasion and metastasis formation depend on both adhesive and proteolytic mechanisms. Previous studies have shown that expression of matrix metalloproteinase-2 and integrin alphavbeta3 correlate with melanoma progression. Recently, direct binding of matrix metalloproteinase-2 to alpha(v)beta3 was implicated in presenting activated matrix metalloproteinase-2 on the cell surface of invasive cells. In this study we investigated this, using the highly metastatic, alpha(v)beta3-negative melanoma cell lines MV3 and BLM, their beta3-transfected alpha(v)beta3 expressing counterparts, xenografts derived from these cell lines, and fresh human cutaneous melanoma lesions comprising all stages of melanoma progression. Expression and activation status of matrix metalloproteinase-2 were studied by reverse transcription-polymerase chain reaction, immunohistochemistry, western blotting, and zymographic analysis, respectively. Matrix metalloproteinase-2 protein expression in vitro was similar in both alpha(v)beta3-negative and alpha(v)beta3-positive cell lines Remarkable differences, however, exist in the localization of inactive and active matrix metalloproteinase-2. Soluble active matrix metalloproteinase-2 was detectable only in the conditioned medium of alpha(v)beta3-negative cell lines and undetectable in the alpha(v)beta3-positive cell lines. Conversely, active matrix metalloproteinase-2 was present exclusively on the cell surface of the alpha(v)beta3 expressing transfectants. Western blot analysis of other components that are involved in matrix metalloproteinase-2 activation showed that processing of proMT1-matrix metalloproteinase to the activated form was enhanced in beta3 transfectants, whereas secretion of tissue inhibitor of metalloproteinase-2 was decreased. In vivo, the presence of functionally active matrix metalloproteinase-2 was significantly higher in xenografts derived from the alpha(v)beta3 expressing MV3 and BLM cell lines. In human cutaneous melanoma lesions, neither matrix metalloproteinase-2 nor integrin alpha(v)beta3 is detectable in melanoma in situ as determined by immunohistochemistry. In contrast, the number of matrix metalloproteinase-2-positive and alphavbeta3-positive tumor cells was clearly increased in primary melanomas, and melanoma metastases. Double staining experiments and confocal laser microscopy demonstrated that the percentage of cells coexpressing matrix metalloproteinase-2 and alpha(v)beta3 increased in advanced primary melanomas and melanoma metastases. In addition, zymography showed that functionally active matrix metalloproteinase-2 was frequently present in melanoma metastases. In these lesions a high proportion of matrix metalloproteinase-2- and alphavbeta3-double-positive melanoma cells were detectable. Our study demonstrates that the presence of activated matrix metalloproteinase-2 correlates with expression of alpha(v)beta3 in human melanoma cells both in vitro and in vivo, and also in fresh human melanoma lesions. These findings strongly suggest that co-ordinated expression of both factors may be required for melanoma cell invasion and metastasis formation.
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PMID:Coexpression of integrin alpha(v)beta3 and matrix metalloproteinase-2 (MMP-2) coincides with MMP-2 activation: correlation with melanoma progression. 1099 34

Endoscopic mucosal resection, which has been widely accepted for the treatment of intramucosal gastric carcinoma (IMGC) because of the minimal invasiveness of the procedure and the sustained quality of life it provides, can only be used on the premise that the carcinoma has no lymph node metastasis. We evaluated the clinicopathological and biological features of IMGC with lymph node metastases in relation to matrix metalloproteinase (MMP) expression. Fifteen cases of lymph node metastasis-positive [n(+)] IMGC and 59 cases of lymph node metastatic-negative [n(-)] IMGC were obtained. The expression of MMP-2 and MMP-9 was investigated with immunohistochemical methods. Clinicopathologically, n(+)-IMGCs were more likely to be of a larger size, to be of poorly differentiated adenocarcinoma, to have had lymphatic permeation [ly(+)], and to have ulcerations within the lesion compared to n(-)-IMGCs. The incidence of the positive expression of MMP-9 in n(+)-IMGCs (67%) or ly(+)-IMGCs (86%) was significantly higher than that in n(-)-IMGCs (32%) or ly(-)-IMGCs (34%). Even in IMGCs, carcinoma cells may produce MMPs that can degrade the basement membrane, allowing them to permeate the lymph capillary. Ulcerations within the lesion may also facilitate the interchange of lymphatic flow between the mucosa and the submucosa, promoting the development of lymph node metastases.
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PMID:Clinicopathological features and overexpression of matrix metalloproteinases in intramucosal gastric carcinoma with lymph node metastasis. 1099 48

We examined the tumorigenic and metastatic potentials of three human non-small cell lung cancer (NSCLC) cell lines, PC-14, A549 or Lu-99 cell lines suspended in Matrigel-containing phosphate-buffered saline were orthotopically implanted into the lungs of nude mice. The formation of a solitary tumor nodule in the lung was observed after the implantation of all cell lines. Intrapulmonary implantation of PC-14 or Lu-99 cells resulted in spontaneous distant metastases. In contrast, A549 cells caused multiple intrapulmonary metastases to the right and left lobes of the lung without producing visible lymphatic metastasis. We also investigated the expression of matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR) and c-MET in these cell lines in vitro and in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of MMP-2 and membrane-type 1 MMP (MT1-MMP) was elevated in PC-14 as compared with the other two cell lines. In contrast, stronger expression of c-MET was observed in A549 than in PC-14 or Lu-99. These results indicate that differential patterns of metastasis of lung cancer might be associated with differential expression of metastasis-associated molecules. Our orthotopic implantation models display clinical features resembling those of NSCLC, and may provide a useful basis for lung cancer research.
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PMID:Solitary lung tumors and their spontaneous metastasis in athymic nude mice orthotopically implanted with human non-small cell lung cancer. 1100 66

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.
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PMID:Development of matrix metalloproteinase inhibitors in cancer therapy. 1115 86


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