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PubMed2005

Inhibitory effect of DA-125, a new anthracyclin analog antitumor agent, on the invasion of human fibrosarcoma cells by down-regulating the matrix metalloproteinases.

Matrix metalloproteinases (MMPs), zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. In this study, we examined the influence of DA-125, a new anthracyclin analog, on the gene expression of MMPs (MMP-2, MMP-9 and MT1-MMP), tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases of MMPs and TIMPs mRNA levels were observed in DA-125-treated HT1080 human fibrosarcoma cells detected by reverse transcriptase-polymerase chain reaction. Gelatin zymography analysis also showed a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with DA-125 compared to controls. In addition, DA-125 inhibited the invasion, motility and cell migration, and colony formation of tumor cells. These data, therefore, provide direct evidence for the role of DA-125 as a potential cancer chemotherapeutic agent, which can markedly inhibit the invasive capacity of malignant cells. Further, to clarify the transcriptional regulatory pathway, we primarily investigated the role of nuclear factor-kappaB (NF-kappaB) in the expression of MMPs by DA-125 in HT1080 cells. Electrophoretic mobility shift assay demonstrated that DA-125 modulates the binding activity of NF-kappaB. Using the luciferase reporter gene assay, a dose-dependent down-regulation of NF-kappaB-mediated luciferase expression was also observed. These results suggest that DA-125 down-regulates MMPs expression in HT1080 cells through the NF-kappaB-mediated pathway.

Anthracyclines↗
PubMed2005

Expression and correlation of CD44v6, vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 in Krukenberg tumor.

AIM: To explore the expression and correlation of CD44v6, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and matrix metalloproteinase (MMP)-9 in Krukenberg and primary epithelial ovarian carcinoma. METHODS: The expressions of CD44v6, VEGF, MMP-2 and MMP-9 were detected by immunohistochemical method in 20 cases of normal ovarian tissues, 38 cases of Krukenberg tumor and 45 cases of primary epithelial ovarian carcinoma. RESULTS: The expression of CD44v6 (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: chi(2) = 4.516, P = 0.034; Krukenberg tumor tissue vs normal ovarian tissue: chi(2) = 19.537, P = 0.001) and VEGF (primary epithelial ovarian carcinoma tissue vs normal ovarian tissue: P = 0.026; Krukenberg tumor tissue vs normal ovarian tissue: chi(2) = 22.895, P = 0.001) was significantly higher in primary epithelial ovarian carcinoma tissue and Krukenberg tumor tissue than in normal ovarian tissue. The positive expression rate of MMP-2 and MMP-9 was 0% in the normal ovarian tissue. The positive expression rate of CD44v6 (chi(2) = 10.398, P = 0.001), VEGF (chi(2) = 13.149, P = 0.001), MMP-2 (chi(2) = 33.668, P = 0.001) and MMP-9 (chi(2) = 38.839, P = 0.001) was remarkably higher in Krukenberg tumor than in primary epithelial ovarian carcinoma. The correlation of CD44v6, VEGF, MMP-2, and MMP-9 was observed in primary epithelial ovarian carcinoma and Krukenberg tumor. CONCLUSION: CD44v6, VEGF, MMP-2, and MMP-9 are involved in ovarian carcinoma, gastric cancer and Krukenberg tumor. Detection of CD44v6, VEGF, MMP-2 and MMP-9 may contribute to the diagnosis of ovarian carcinoma, gastric cancer, and Krukenberg tumor.

Adult↗
PubMed1989

Interaction of human rheumatoid synovial collagenase (matrix metalloproteinase 1) and stromelysin (matrix metalloproteinase 3) with human alpha 2-macroglobulin and chicken ovostatin. Binding kinetics and identification of matrix metalloproteinase cleavage sites.

The homologous proteinase inhibitors, human alpha 2-macroglobulin (alpha 2M) and chicken ovostatin, have been compared with respect to their "bait" region sequences and interactions with two human matrix metalloproteinases, collagenase and stromelysin. A stretch of 34 amino acid residues of the ovostatin bait region sequence was determined and the matrix metalloproteinase cleavage sites identified. Collagenase cleaved a X-Leu bond where X was unidentified, whereas the major cleavage site by stromelysin was at the Gly-Phe bond, 4 residues on the COOH-terminal side of the collagenase cleavage site. Collagenase cleaved the alpha 2M bait region at the Gly679-Leu680 bond, and stromelysin at Gly679-Leu680 and Phe684-Tyr685 bonds. Sequence similarity in the bait region of members of the alpha-macroglobulin family is strikingly low. The kinetic studies indicate that alpha 2M is a 150-fold better substrate for collagenase than type I collagen. Structural predictions based on the bait region sequences suggest that a collagen-like triple helical structure is not a prerequisite for the efficient binding of tissue collagenase to a substrate. The binding of stromelysin to alpha 2M is slower than that of collagenase. Stromelysin reacts with ovostatin even more slowly. Despite the preference of chicken ovostatin for metalloproteinases, human alpha 2M, a far less selective inhibitor, reacts more rapidly with collagenase and stromelysin. These results suggest that alpha 2M may play an important role in regulating the activities of matrix metalloproteinases in the extracellular space.

Amino Acid Sequence↗
PubMed1998

Matrix metalloproteinase-2 and matrix metalloproteinase-9 in cholesteatoma and deep meatal skin.

A qualitative and quantitative study of the presence of Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9) in cholesteatoma was performed. Ten cholesteatoma and four deep meatal skin specimens were analysed for gelatinase activity at molecular weights corresponding to MMP-2 and MMP-9 using Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS PAGE) Zymography. Gelatinase activity at 72 kDa and 92 kDa was investigated. Western blotting was employed using primary monoclonal antibodies to provide a qualitative assessment of MMP-2 and MMP-9. Non-parametric data analysis using the Mann-Whitney U test did not show a significant difference in expression of MMP-2 (P = 0.51) or MMP-9 (P = 0.14) between the two tissue types. Western blotting showed the presence of both MMP-2 and MMP-9 in the majority of specimens, both cholesteatoma and deep meatal skin.

Blotting, Western↗
PubMed2005

[Effect of progesterone on the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 in human ectopic endometrial stromal cells].

OBJECTIVE: To determine the effect of progesterone on the secretion of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in ectopic endometrial stromal cells. METHODS: Ectopic endometrial stromal cells were obtained from 17 patients with endometriosis. Endometrial stromal cells were obtained from 12 patients with endometriosis and 14 cases of controls. Ectopic endometrial stromal cells of 15 cases were treated with progesterone. Culture supernatants of these stromal cells were analyzed for MMP-2 and MMP-9 by zymography. RESULTS: Endometriotic stromal cells released significantly higher levels of MMP-2 and MMP-9 than endometrial stromal cells from women with and without endometriosis. Progesterone at 10(-9) mol/L caused endometriotic stromal cells a significant reduction MMP-2 and MMP-9 levels. When progesterone concentration was increased from 10(-9) mol/L to 10(-7) mol/L, the release of MMP-9 was almost completely inhibited, wherease that of MMP-2 was not completely inhibited. CONCLUSION: Progesterone may inhibit the secretion of MMP-2 and MMP-9 in ectopic endometrial stromal cells, especially MMP-9.

Adult↗
PubMed2003

Matrix metalloproteinase-7 and matrix metalloproteinase-9 are associated with unfavourable prognosis in superficial oesophageal cancer.

If oesophageal carcinoma is detected in the superficial stage, the prognosis is better than for advanced oesophageal carcinoma. But the factors which predict the prognosis and treatment policy remain unclear. Matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9) have been reported to have close associations with tumour invasion and metastasis. In this study, we retrospectively studied the relations between MMP-7 and MMP-9 expression in immunohistochemistry, clinicopathologic factors, and prognosis in 55 superficial oesophageal carcinomas. MMP-7 and MMP-9 expression occurred in 23.6% and 47.3% of the patients, respectively. MMP-7 expression was significantly correlated with the presence of nodal metastasis (P=0.004). MMP-9 expression was significantly correlated with the depth of tumour invasion (P=0.004), lymphatic permeation (P=0.001), nodal metastasis (P=0.049), and pathologic differentiation grade (P=0.003). By the log-rank test, MMP-7 expression and MMP-9 expression on the invasive front were related to the prognosis. In multivariate analysis, MMP-9 expression on the invasive front was an independent prognostic indicator. The combined expression of MMP-7 and MMP-9 may be a good marker for the degree of malignancy of oesophageal cancer and for the presence of lymphatic metastasis.

Adenocarcinoma↗
PubMed2004

Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD.

BACKGROUND: The increased expression of matrix metalloproteinases (MMPs) is considered to be a key factor in the development of COPD. Net MMP activity represents a tightly regulated process, which is not addressed by conventional investigation methods such as messenger RNA or protein expression. Yet, quantitative data on MMP activity in the airways of COPD patients are lacking. METHODS: We used specific immunocapture assays to quantify the activity of MMP collagenase (ie, MMP-1, MMP-8, and MMP-13) and MMP gelatinase (ie, MMP-2 and MMP-9) in the induced sputum of COPD patients (17 patients; FEV(1), 56% predicted) and healthy smokers (17 subjects; FEV(1), 99% predicted). RESULTS: Levels of total and active MMP-8 and MMP-9 were significantly increased in COPD patients vs control subjects, whereas MMP-1 activity levels were similar in both groups. The activity of MMP-2 and MMP-13 remained below the detection threshold of the assays. MMP-8 and MMP-9 activity were strongly related to neutrophilia in both groups, and the results of immunohistochemistry tests on sputum cytospins showed that MMP-9 was expressed in both alveolar macrophages and neutrophils, whereas MMP-8 expression was exclusively observed in neutrophils. A positive correlation was found between sputum MMP-8 and MMP-9 activity and the degree of airflow limitation. CONCLUSION: We demonstrate increased MMP-8 and MMP-9 activity in the airway compartment of patients with mild-to-moderate COPD. This study provides further evidence of an impaired proteinase-antiproteinase balance in COPD patients.

Collagenases↗
PubMed2006

Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction.

BACKGROUND: Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in MMP synthesis by as yet unknown mechanisms. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro has not yet been studied. Thus, we studied EMMPRIN expression on monocytes in acute myocardial infarction (MI) and its potential relevance for MMP activation. METHODS AND RESULTS: In 20 patients with acute MI, surface expression of EMMPRIN was significantly enhanced on monocytes compared with in 20 patients with chronic stable angina. EMMPRIN upregulation was associated with increased expression of the membrane type 1 MMP (MT1-MMP) on monocytes (flow cytometry) as well as MMP-9 activity (gelatin zymography) in the plasma. At 6 months after successful revascularization, EMMPRIN, MT1-MMP, and MMP-9 had normalized. The secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese hamster ovary cells. Moreover, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells. Gene silencing of EMMPRIN by small-interfering RNA hindered lipopolysaccharide-induced monocyte secretion of MMP-9, indicating a predominant role of EMMPRIN in MMP-9 induction. CONCLUSIONS: EMMPRIN and MT1-MMP are upregulated on monocytes in acute MI. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in smooth muscle cells, indicating that EMMPRIN may display a key regulatory role for MMP activity in cardiovascular pathologies.

Adult↗
PubMed1995

Complex regulation of membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation by concanavalin A in MDA-MB-231 human breast cancer cells.

Matrix Metalloproteinase-2 (MMP-2) is secreted as a zymogen, the activation of which has been associated with metastatic progression in human breast cancer (HBC). Concanavalin A (Con A) has been found to induce activation of MMP-2 in invasive HBC cell lines. Con A effects on the expression of mRNA for membrane-type matrix metalloproteinase (MT-MMP), a newly described cell surface-associated MMP, showed a close temporal correlation with induction of MMP-2 activation. It is surprising that MT-MMP mRNA is constitutively present in the uninduced MDA-MB-231 cell, despite a lack of MMP-2 activation. We have used actinomycin D to demonstrate a partial requirement for de novo gene expression in the induction of MMP-2 activation by Con A in MDA-MB-231 HBC cells. Furthermore, this transcriptional response to Con A appeared to require the continued presence of Con A for its manifestation. The nontranscriptional component of the Con A induction manifests rapidly, is quite substantial, and persists strongly despite actinomycin D abrogation of both constitutive and Con A-induced MT-MMP. Cycloheximide analyses suggest that protein synthesis may be involved in this rapid transcription-independent response. These studies suggest that Con A induces MMP-2-activation in part by up-regulation of MT-MMP expression but has a more complicated mode of action, involving additional nontranscriptional effects, which apparently require protein synthesis.

Breast Neoplasms↗
PubMed1996

Computational sequence analysis of matrix metalloproteinases.

Matrix metalloproteinases (MMP) play a cardinal role in the breakdown of extracellular matrix involved in a variety of biological and pathological processes. Research on MMPs has classified and characterized these enzymes according to their matrix substrate specificity, gene and protein domain structure, and regulation of activity and expression. However, the discovery of new MMPs has introduced a need for a more comprehensive and systematic method of classification and quantitative comparison of known and newly discovered members. This study compiles a sequence alignment, constructs a dendrogram, and calculates physical data and homology percentage assignments in order to obtain further insight into MMP structure-function relationships. Thorough analysis of MMP primary sequence domains, physical data patterns, and statistical analysis of sequence homology yields higher resolution in the similarities and differences that group MMP members.

Algorithms↗
PubMedDate not supplied

Activation mechanisms of matrix metalloproteinases.

Matrix metalloproteinases (MMPs), also called matrixins, function in the turnover of extracellular matrix components. These enzymes are considered to play important roles in embryo development, morphogenesis and tissue remodeling, and in diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and in cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes and most of them are secreted from the cells as proenzymes. Thus, the activation of these proenzymes is one of the critical steps that leads to extracellular matrix breakdown. This review describes recent progress made to elucidate the activation mechanisms of pro-matrixins which include extracellular stepwise activation common to most proMMPs, cell surface activation of progelatinase A and procollagenase 3, and intracellular activation of prostromelysin 3 and pro-membrane-type-1 MMP.

Amino Acid Sequence↗
PubMed2006

The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells.

The p75 neurotrophin receptor (p75(NTR)) has been characterized as a metastasis and tumor suppressor in prostate cancer. In order to investigate the mechanism(s) by which the p75(NTR) functions as a metastasis suppressor in prostate cancer cells, we characterized the ectopic expression of p75(NTR) on the urokinase plasminogen activator (uPA) and the type IV collagen matrix metalloproteinases (MMP-2 and MMP-9) in PC-3 human prostate cancer cells. Rank-order expression of p75(NTR) greatly reduced protein levels and enzymatic activities of uPA, MMP-2, and MMP-9 as shown by immunoblot and zymography analyses. Conversely, expression of the MMP-9 antagonist, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) exhibited an increase in protein levels with an increase in p75(NTR) levels, whereas TIMP-2 was not detected. Transient transfection with an inducible dominant negative antagonist Deltap75(NTR) rescued uPA, MMP-2, and MMP-9 protein levels and protease activities, and conversely suppressed TIMP-1 levels. Since p75(NTR) signal transduction occurs via the NFkappaB and JNK pathways, antagonism of signaling intermediates in these pathways, using dominant negative IKKbeta or dominant negative MKK-4, respectively, was shown to further decrease expression of uPA, MMP-2, and MMP-9 protein and enzymatic activity levels, and conversely up-regulate levels of TIMP-1. These results indicate that expression of uPA, MMP-2, MMP-9, and TIMP-1 are directly regulated by expression of p75(NTR) and its downstream signal transduction cascade. These results suggest that the metastasis suppressor activity of p75(NTR) is mediated, in part, by down-regulation of specific proteases (uPA, type IV collagenases) implicated in cell migration and metastasis.

Cell Line, Tumor↗
PubMed1997

Rodent pharmacokinetic and anti-tumor efficacy studies with a series of synthetic inhibitors of matrix metalloproteinases.

Matrix metalloproteinases are a family of zinc-containing proteases that degrade extracellular matrix and basement membranes. These enzymes are thought to play a role in processes essential for tumor growth, invasion, and metastasis. Here we report pharmacokinetic and anti-tumor efficacy studies with a series of structurally related inhibitors of these enzymes that were synthesized at Agouron Pharmaceuticals using protein structure based drug design. The compounds studied were AG3287, AG3293, AG3294, AG3296, AG3319, and AG3340. Rat oral bioavailability ranged from 15 to 68%. Despite similar profiles of enzyme inhibition across the family of enzymes, and similar pharmacokinetics following i.p. administration to mice, efficacy against the Lewis lung carcinoma murine model varied from tumor growth enhancement, to significant reductions in the size of primary tumors and the number of lung metastases. AG3340 was the most efficacious compound against the Lewis lung carcinoma model, resulting in the complete cessation of primary tumor growth throughout the experiment in 4/6 mice treated with daily i.p. injections at a dose of 50 mg/kg. This treatment inhibited the formation of lung metastases greater than 5 mm in diameter by 90%.

Animals↗
PubMed2002

The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis.

Matrix metalloproteinases (MMPs) are a large group of enzymes responsible for matrix degradation. Among them, the family of gelatinases (MMP-2/gelatinase A and MMP-9/gelatinase B) is overproduced in the joints of patients with rheumatoid arthritis. Because of their degradative effects on the extracellular matrix, gelatinases have been believed to play an important role in progression and cartilage degradation in this disease, although their precise roles are yet to be defined. To clarify these roles, we investigated the development of Ab-induced arthritis, one of the murine models of rheumatoid arthritis, in MMP-2 or MMP-9 knockout (KO) mice. Surprisingly, the MMP-2 KO mice exhibited severe clinical and histologic arthritis than wild-type mice. The MMP-9 KO mice displayed milder arthritis. Recovery from exacerbated arthritis in the MMP-2 KO mice was possible by injection of wild-type fibroblasts. These results indicated a suppressive role of MMP-2 and a pivotal role of MMP-9 in the development of inflammatory joint disease.

Animals↗
PubMed2003

Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells.

Amphiregulin (AR) and epidermal growth factor effects on expression and activity of the extracellular matrix metalloproteinase inducer (EMMPRIN) were examined in NS2T2A1 breast tumor cells. Both growth factors induced mRNA and protein expression of EMMPRIN, and matrix metalloproteinase (MMP) -2 and -9 enzymatic activity. The induction of EMMPRIN by AR was mediated by epidermal growth factor receptor (EGFR) tyrosine kinase activation and inhibited by ZD1839. AR and EGFR antisense (AS) cDNAs inhibited EMMPRIN expression and MMP activity. Coculture of NS2T2A1V expressing AR- or EGFR-AS with fibroblasts and endothelial cells showed a decreased MMP activity. In parallel, nude mice tumors derived from AR and EGFR-AS cells revealed reduced level of EMMPRIN and MMP activity. AR and epidermal growth factor, therefore, regulate EMMPRIN and its MMP-mediated expression, identifying EGFR signaling as critical to this regulation.

Amphiregulin↗
PubMed2005

Increased acinar damage of salivary glands of patients with Sjögren's syndrome is paralleled by simultaneous imbalance of matrix metalloproteinase 3/tissue inhibitor of metalloproteinases 1 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 ratios.

OBJECTIVE: Previous findings in labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS) suggest that increased activity and expression of matrix metalloproteinase 9 (MMP-9) and MMP-3 trigger the destruction of acinar structures in these glands. Tissue inhibitors of matrix metalloproteinases (TIMPs) tightly control MMP activity, and TIMP expression is an important modulator of effects attributed to MMPs. This study was undertaken to investigate the correlation between the balance of MMPs/TIMPs in the LSGs of SS patients and the degree of inflammatory infiltration and acinar structure integrity. METHODS: Three groups of SS patients classified according to focus score and residual tissue were studied. The expression of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 was examined at the messenger RNA and protein levels. The ratio of MMP/TIMP expression (R value) was calculated. Focus score and acinar structure were evaluated by histologic analysis. RESULTS: In SS patients the MMP-3/TIMP-1 ratio was higher than 1 and the MMP-9/TIMP-1 ratio was much higher than 1 whereas the MMP-2/TIMP-2 ratio nearly equaled 1, suggesting elevated proteolytic activity due mainly to MMP-9. R values were independent of the focus score of inflammatory cells, but correlated well with the dramatic changes observed in morphologic integrity of acini, as revealed mainly by the lack of nuclear polarity. Acinar changes were more evident when R values for both MMP-9/TIMP-1 and MMP-3/TIMP-1 were higher. CONCLUSION: This study provides evidence that an altered balance between MMPs and their inhibitors is associated with acinar damage. Since salivary gland acinar cells express both MMPs and TIMPs, these cells may play an important role in extracellular matrix destruction and in the LSG pathophysiology in SS.

Blotting, Western↗
PubMed2006

Ets-1 is up-regulated together with its target gene products matrix metalloproteinase-2 and matrix metalloproteinase-9 in atypical and anaplastic meningiomas.

AIMS: Matrix metalloproteinases (MMPs) are a pivotal enzyme system involved in extracellular matrix (ECM) degradation and are considered to be important in the development and invasion of human tumours. Little is known about the regulation of MMPs in meningioma development and prognosis. The transcription factor Ets-1 is the main regulator of several MMPs, including MMP-2 and -9. The aim of this study was to determine the relationship between the expression of Ets-1, MMP-2 and -9 and the malignant potential of meningiomas. METHODS AND RESULTS: Seventy-four meningiomas of different histological grades were investigated immunohistochemically. Up-regulation of Ets-1, MMP-2 and MMP-9 expression was observed in atypical and anaplastic meningiomas. Invasive meningiomas showed increased immunohistochemical expression of these proteins compared with non-invasive meningiomas. We also observed a correlation between the expression of Ets-1 and of its target genes MMP-2 and MMP-9. CONCLUSIONS: Ets-1 may be involved in the transcriptional regulation of MMP-2 and MMP-9 as well as in the invasive process in meningiomas. Evaluation of these expressions might be of prognostic value for meningiomas.

Adult↗
PubMed1997

Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma.

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.

Breast Neoplasms↗