Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that fibroblasts and invasive human breast carcinoma (HBC) cells specifically activate matrix metalloproteinase-2 (MMP-2) when cultured on 3-dimensional gels of type I collagen but not a range of other substrates. We show here the constitutive expression of membrane-type 1 (MT1)-MMP in both fibroblasts, and invasive HBC cell lines, that have fibroblastic attributes presumably acquired through an epithelial-to-mesenchymal transition (EMT). Treatment with collagen type I increased the steady-state MT1-MMP mRNA levels in these cells but did not induce either MT1-MMP expression or MMP-2 activation in noninvasive breast carcinoma cell lines, which retain epithelial features. Basal MT3-MMP mRNA expression had a pattern similar to that of MT1-MMP but was not up-regulated by collagen. MT4-MMP mRNA was seen in both invasive and noninvasive HBC cell lines and was also not collagen-regulated, and MT2-MMP mRNA was not detected in any of the HBC cell lines tested. These data support a role for MT1-MMP in the collagen-induced MMP-2-activation seen in these cells. In situ hybridization analysis of archival breast cancer specimens revealed a close parallel in expression of both collagen type I and MT1-MMP mRNA in peritumoral fibroblasts, which was correlated with aggressiveness of the lesion. Relatively high levels of expression of both mRNA species were seen in fibroblasts close to invasive tumor nests and, although only focally, in certain areas close to preinvasive tumors. These foci may represent hot spots for local degradation and invasive progression. Collectively, these results implicate MT1-MMP in collagen-stimulated MMP-2 activation and suggest that this mechanism may be employed in vivo by both tumor-associated fibroblasts and EMT-derived carcinoma cells to facilitate increased invasion and/or metastasis.
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PMID:Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. 916 84

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a presumed activator of MMP2, which is one of the major proteinases in tumor cell invasion. In this study, we determined the clinico-pathologic significance of MT1-MMP expression in 68 human gastric carcinomas. The tumor-normal ratio (T/N ratio) of MTI-MMP expression was determined by reverse transcription-polymerase chain reaction analysis. To visualize the localization of MT1-MMP, an immunohistochemical study was performed. In addition, a gelatin zymography was done to examine the activation ratio of MMP2, and a correlation between MT1-MMP expression and activation of MMP2 was studied. The expression of MT1-MMP mRNA was higher in tumor tissue than in corresponding normal tissue in most cases. The mean value of the T/N ratio was 4.8. Twenty cases with T/N > or = 4.8 showed significantly deeper invasion and higher frequency of lymph node metastasis than 48 cases with T/N < 4.8. MT1-MMP expression was an independent factor influencing both tumor invasion of the gastric wall and lymph node metastasis. Although MT1-MMP expression was not an independent prognostic factor, the patients with T/N > or = 4.8 showed a significantly worse prognosis than those with T/N < 4.8. An immunohistochemical study demonstrated that MT1-MMP expression was mainly recognized in the tumor cells. There was a significant correlation between MT1-MMP expression and activation of MMP2. Our findings suggest that: 1) the expression of MT1-MMP may influence prognosis via tumor invasion of the gastric wall and lymph node metastasis, and 2) MT1-MMP activation of MMP2 may be clinically relevant in gastric carcinoma tumors.
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PMID:Analysis of MT1-MMP and MMP2 expression in human gastric cancers. 922 11

Overexpression of the matrix metalloproteinase matrilysin and the absence of beta 4 integrin are two features characteristic of human prostate carcinoma. In the following study we demonstrate that the beta 4 integrin, but not the alpha 6 or beta 1 integrin subunits, is cleaved by matrilysin in vitro. A specific fragment of 90 kDa is generated using matrilysin, which is not observed with other proteases. Two putative cleavage sites for matrilysin within the extracellular domain of the beta 4 integrin at residues 107 (isoleucine, prior to the ligand-binding region) and 417 (leucine, prior to cysteine-rich region) are identified by sequence comparisons with known matrilysin substrates. The selective cleavage of the beta 4 integrin by matrilysin may partly explain the loss of beta 4 integrin expression in invasive prostate carcinoma.
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PMID:Cleavage of beta 4 integrin by matrilysin. 934 15

Matrix metalloproteinases (MPs) constitute a family of proteolytic enzymes (proteases) that degrade extracellular matrix (ECM) and promote the local or metastatic potential of carcinoma cells, and whose action is restrained by special inhibitors (metalloproteinase inhibitors; MIs). We assessed the role of the MPs stromelysin-3 (STR-3), putative metalloproteinase-1 (PUMP-I), and the gelatinases of molecular weights 72 kDa and 92 kDa, as well as the role of their inhibitors tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, as markers of metastatic potential in 25 fresh biopsies of squamous-cell lung carcinomas (SCLCs). We examined levels of messenger ribonucleic acid (mRNA) expression for these MPs and inhibitors through Northern blot analysis in 10 carcinomas of high-to-moderate differentiation without lymph-node involvement, and in 15 infiltrative carcinomas of moderate-to-low differentiation with lymph-node involvement. Five cases with significant epithelial atypia and five samples with normal mucosa were used as controls. Expression of STR-3 and TIMP-2 was also assessed immunohistochemically with the avidin-biotin-complex (ABC) technique. We noticed a progressive increase in the expression levels of MPs, especially of STR-3, and of TIMP-2, from the stage of epithelial atypia to the detection of carcinoma, finding the highest values of these substances among carcinomas of low differentiation with nodal metastases. These findings were also confirmed with immunohistochemical analysis. Our results suggest that there is a significant association of the expression of MPs and MIs with both the local and metastatic potential and the degree of cellular differentiation of SCLC, and that this association is clinically important because of its prognostic and therapeutic implications.
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PMID:Association of expression of metalloproteinases and their inhibitors with the metastatic potential of squamous-cell lung carcinomas. A molecular and immunohistochemical study. 941 77

To reduce postoperative local recurrence in patients who undergo a nerve preserving operation for rectal carcinoma, preoperative estimation of neural invasion would be desirable. For this purpose we clarified the characteristics of rectal carcinomas with neural invasion and then evaluated the usefulness of matrix metalloproteinase 7 (MMP7) gene as an indicator for neural invasion. The study included 128 patients with primary rectal carcinoma. The histologic examination plus immunohistochemical study for S-100 protein was performed. A reverse transcription-polymerase chain reaction (RT-PCR) study for MMP7 using preoperatively obtained biopsy specimens was also performed in 32 patients. Neural invasion was recognized in 38 (29.7%) of 128 tumors. The tumors with neural invasion were characterized by infiltrative growth pattern, frequent lymphatic and venous permeation, frequent lymph node metastasis, and advanced stage of disease. The cases with neural invasion also showed a higher recurrent rate and worse prognosis. An RT-PCR study demonstrated that a significantly higher expression of MMP7 mRNA was recognized in neural invasion positive cases than in negative ones (p<0.05), indicating that MMP7 may be a good indicator for neural invasion of rectal carcinoma. Neural invasion would be an additional useful factor for providing information on malignant potential. The RT-PCR results of MMP7 gene may be useful for predicting which tumors may develop neural invasion.
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PMID:Preoperative estimation of neural invasion in rectal carcinoma. 945 97

Thyroid cancer can degrade basement membranes and invade tissues. This depends on a cascade of matrix metalloproteinases involving membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9. We analyzed the expression and role of these MMPs and their specific inhibitors TIMP-2 and TIMP-3 in human highly purified thyroid epithelial, C 643, HTh 74, SW 1736, and 8505 C thyroid carcinoma and thyroid-derived fibroblast cell cultures. The effect of phorbol-myristate acetate (PMA), and of the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on MMP and TIMP mRNA levels were monitored by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) including an internal homologous competitor fragment. The highest MT1-MMP mRNA levels were found in thyroid-derived fibroblasts. The MT1-MMP mRNA expression was increased up to 10-fold by PMA, while all other growth factors tested had only negligible effects. The thyroid carcinoma cells themselves did not seem to play a crucial role in the production of MT1-MMP in thyroid tumors. Higher MMP-2 mRNA levels were found in all cell types investigated. The highest MMP-2 mRNA levels were determined in thyroid-derived fibroblasts and HTh 74 cells. We found a lack of MMP-2 response to IL-1, TNF-alpha, and phorbol esters. In unstimulated cells, MMP-9 mRNA was found near the detection limit or at low levels. In nearly all cell types, treatment with PMA, IL-1, and TNF-alpha caused an increase of the MMP-9 mRNA levels. The results of basal and stimulated MMP-2 and MMP-9 mRNA expression were confirmed at the protein level by gelatin zymography. TIMP-2 and TIMP-3 mRNAs were expressed at high levels. In contrast to the basal TIMP-3 mRNA levels, which varied over a great range, there were no striking differences the cell types from analyzing TIMP-2 mRNA. There were no or only slight stimulatory effects on TIMP-2 and TIMP-3 mRNA expression by IL-1, TNF-alpha, and PMA. Taken together, most enzymes of the MT-MMP/MMP class of proteases facilitating invasion of thyroid tumor cells seem to have been produced by fibroblasts, not by the tumor cells themselves. However, some dedifferentiated thyroid tumor cell lines may be capable of secreting some of these enzymes, as in the case of HTh 74 cells.
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PMID:mRNA levels of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 and of their inhibitors TIMP-2 and TIMP-3 in normal thyrocytes and thyroid carcinoma cell lines. 954 6

Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.
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PMID:Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin. 956 Mar 29

We examined the production and tissue localization of matrix metalloproteinase-7 (MMP-7 = matrilysin) in human gastric carcinomas and analyzed the data in connection with the clinicopathological factors. Sandwich-enzyme immunoassay for the zymogen of MMP-7 (proMMP-7) showed enhanced production of MMP-7 in carcinoma tissues compared with control normal gastric mucosa. Immunohistochemical studies demonstrated that MMP-7 is localized predominantly to the carcinoma cells in 71% of the carcinoma samples (30/42 cases). The percentage of immunoreactive carcinoma cells to total carcinoma cells (positive ratio) was significantly higher in intestinal-type carcinomas (26%, median) than in diffuse-type carcinomas (3%, median) (p < 0.05). The positive ratio was markedly higher in carcinoma groups with vascular invasion (28%) or lymphatic permeation (12%) than in those without invasion (6%) or permeation (0%) (p < 0.05). It was also significantly higher in carcinoma groups with liver (49%) or lymph-node metastases (15%) than in those without metastases (6 and 2% respectively) (p < 0.05). Both proMMP-7 of 28 kDa and active MMP-7 of 19 kDa were detected in the carcinoma tissues by immunoblotting. Reverse-transcription-PCR showed specific amplification in 50% of the carcinoma cases (6/12 cases) and 8% of the normal control specimens (1/12 cases). In situ hybridization demonstrated that the carcinoma cells almost selectively express MMP-7 mRNA. These data suggest that enhanced production of proMMP-7 and its activation are implicated in invasion and metastasis of human gastric carcinomas.
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PMID:Expression and tissue localization of matrix metalloproteinase 7 (matrilysin) in human gastric carcinomas. Implications for vessel invasion and metastasis. 958 35

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed both in carcinoma cells and in surrounding stromal fibroblasts. MT1-MMP localizes to the surface of tumor cells and is thought to play an important role in tumor invasion. To analyze the mechanism of MT1-MMP gene expression in epithelial tumor cells, the dog kidney epithelial cell line Madin-Darby canine kidney (MDCK) was transformed by oncogenes, including v-src, and expression of MT1-MMP was examined. Transformation of MDCK cells with v-src resulted in loss of cell-to-cell contacts and morphological change. Expression of MT1-MMP in v-src-transformed cells was identified by Northern and Western blotting. Gelatin zymography analysis showed that progelatinase A in the culture medium was processed from latent to activated form by MDCK cells transformed with v-src. The MDCK cells transformed by v-src were tumorigenic in the subcutis (ectopic) and kidney (orthotopic) of nude mice and spontaneously metastasized to the lung after orthotopic implantation. These results suggest that MT1-MMP induced by v-src transformation may promote invasiveness of transformed cells.
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PMID:Transformation of epithelial Madin-Darby canine kidney cells with p60(v-src) induces expression of membrane-type 1 matrix metalloproteinase and invasiveness. 960 72

Membrane type (MT) 1 matrix metalloproteinase (MMP) activates progelatinase A (pro-MMP-2), a type IV collagenase, on the cell surface of tumors; however, its function in breast cancer progression and metastasis is not fully understood. To examine the expression of MT1-MMP in breast cancer cells and fibroblasts, a specific rabbit antibody (Ab) directed against a unique synthetic peptide derived from the human MT1-MMP catalytic domain was produced, purified, and characterized. This Ab is not likely to cross-react with MT2-, MT3-, or MT4-MMP or any other MMPs. MT1-MMP expression and pro-MMP-2 activation were stimulated by concanavalin A in two human breast carcinoma cell lines (BT549 and MDA-MB-231) and in normal human fetal-lung fibroblasts (HFL-1) and were slightly upregulated by breast cancer cell-fibroblast interactions. Both pro-MT1-MMP in plasma membrane (63.4 kDa) and the soluble forms of the enzyme in culture medium (57.6 and 25-30 kDa) were detected by immunoblot analysis, suggesting that cell-surface MT1-MMP exhibits an active conformation without the removal of its propeptide domain and that the mature enzyme is shed into the medium. In breast cancer cells, MT1-MMP and a recombinant catalytic domain of MT1-MMP were unable to activate pro-matrilysin, indicating that MT1-MMP is not a universal activator of all MMPs. MT1-MMP may play an important role in the invasive growth and spread of breast cancer cells by specifically activating pro-MMP-2 to cleave the connective-tissue barrier. Furthermore, use of the specific Ab may aid in the investigation of the role of MT1-MMP in human tumors.
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PMID:Immunological characterization of cell-surface and soluble forms of membrane type 1 matrix metalloproteinase in human breast cancer cells and in fibroblasts. 965 52


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