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PubMed2002

Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation.

Vascular endothelial permeability is maintained by the regulated apposition of adherens and tight junctional proteins whose organization is controlled by several pharmacological and physiological mediators. Endothelial permeability changes are associated with: (1) the spatial redistribution of surface cadherins and occludin, (2) stabilization of focal adhesive bonds and (3) the progressive activation of matrix metalloproteinases (MMPs). In response to peroxide, histamine and EDTA, endothelial cells sequester VE-cadherin and alter its cytoskeletal binding. Simultaneously, these mediators enhance focal adhesion to the substratum. Oxidants, cytokines and pharmacological mediators also trigger the activation of matrix metalloproteinases (MMPs) in a cytoskeleton and tyrosine phosphorylation dependent manner to degrade occludin, a well-characterized tight junction element. These related in vitro phenomena appear to co-operate during inflammation, to increase endothelial permeability, structurally stabilize cells while also remodelling cell junctions and substratum.

Animals↗

PubMedDate not supplied

Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers.

Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers.

Biopsy↗

PubMed2000

Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma.

Three different membrane-type matrix metalloproteinases (MT-MMPs) activate in vitro the latent form of matrix metalloproteinase-2 (MMP-2), which is one of the key proteinases in invasion and metastasis of various cancers. We examined the mRNA expression of MT1, 2, and 3-MMPs and MMP-2 in cell lines of head and neck squamous cell carcinoma (HNSCC) and quantitated the relative expression levels in human HNSCC tissues by Northern blotting. The tissue localization of MT1-MMP and MMP-2 was determined by immunohistochemistry and in situ hybridization. Their implications in clinicopathologic factors were statistically evaluated. All cell lines examined consistently expressed MT1-MMP and MMP-2, but not MT2, 3-MMP. In the clinical specimens, there was a significant correlation in coexpression of messenger of RNA (P = .0005) and colocalization by immunohistochemistry (P < .0001) for MT1-MMP and MMP-2. Relative mRNA expression levels of MT1-MMP and MMP-2 in the carcinoma tissues were significantly higher than those of the control tissues (P = .0045 and P = .0122, respectively). Both mRNA expression level and immunopositivity of MT1-MMP significantly correlated with lymph node metastasis (P = .0081 and P = .0193, respectively), which was confirmed by multivariate logistic regression analysis. Immunoreaction of MT1-MMP and its mRNA expression were observed in both carcinoma cells and stromal cells. The localization of MMP-2 closely corresponded to that of MT1-MMP. These observations suggest that MT1-MMP possesses a role as a determinant of lymph node metastasis in HNSCC, and that concurrent expression of MT1-MMP and MMP-2 are involved in progression of HNSCC.

Blotting, Northern↗

PubMed2002

Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer.

Preclinical studies have provided evidence that matrix metalloproteinases (MMPs), a family of zinc-containing proteolytic enzymes, facilitate tumor invasion, the establishment of metastases, and the promotion of tumor-related angiogenesis. Matrix metalloproteinase inhibitors (MMPIs) have been shown to inhibit tumor growth and dissemination in preclinical models. Not all lung cancers express the MMPs believed to be most important in promoting the neoplastic process, and there are conflicting reports regarding the prognostic significance of MMPs in lung cancer. However, it is possible that these observations are because of limitations in the procedures for measuring MMPs. Many investigators believe that MMPs are universally involved in tumor progression; this hypothesis was the basis for initiating seven phase III MMPI trials in lung cancer. Four studies were closed at completion of the predefined accrual goal, and three were closed early. There were no significant differences in survival in a non-small cell lung cancer prinomastat study, and in a small cell lung cancer marimastat trial. The results of the remaining five studies have not been reported. At this point it appears that MMPIs will probably not play a major role in the treatment of advanced lung cancer patients.

Carcinoma, Non-Small-Cell Lung↗

PubMed1997

Post-translational modifications in cartilage oligomeric matrix protein. Characterization of the N-linked oligosaccharides by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

Analysis of the carboxymethylated subunit of human cartilage oligomeric matrix protein (COMP) by matrix-assisted laser desorption time-of-flight mass spectrometry indicated a protonated molecular mass of 86949 +/- 149 Da, compared with 83547.0 Da calculated from the sequence. Treatment with N-glycanase caused a reduction in mass of 3571 +/- 219 Da, but there was no loss of mass after treatment with O-glycanase or neuraminidase. Peptides containing two putative sites of N-glycosylation were purified and characterized. Analysis of the masses of these after N-glycanase treatment indicated that one was substituted at Asn-101 with an oligosaccharide of mass 1847. 2 +/- 6.6 Da, and the other was unsubstituted at Asn-124. The remaining site of attachment, at Asn-721, was, therefore, also substituted with an oligosaccharide of mass 1724 +/- 226 Da. Analysis of the total monosaccharide content by chemical methods indicated that there were no additional oligosaccharide substituents. The MALDI-TOF mass spectra of COMP from bovine fetal and adult cartilage were compared, indicating a more heterogeneous pattern of substitution at Asn-101 in the fetal form. Since COMP is distributed throughout the pericellular and territorial environments in developing cartilage but occupies the interterritorial zone in mature cartilage, these changes in glycosylation may allow for different intermolecular interactions.

Amino Acid Sequence↗

PubMed2001

Authentic matrix vesicles contain active metalloproteases (MMP). a role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-beta.

Matrix vesicles (MV) play a key role in the initiation of cartilage mineralization. Although many components in these microstructures have been identified, the specific function of each component is still poorly understood. In this study, we show that metalloproteases (MMP), MMP-2, -9, and -13 are associated with MV isolated from growth plate cartilage. In addition, we provide evidence that MV contain transforming growth factor-beta (TGF-beta) and that MV-associated MMP-13 is capable of activating latent TGF-beta. To determine whether MMPs are associated directly with MV, vesicles isolated from growth plate cartilage were sequentially treated with hyaluronidase, NaCl, and bacterial collagenase to remove matrix proteins and other components attached to their outer surface. Finally, the vesicles were incubated with detergent to rupture the MV membrane and expose components that are inside the vesicles. Each treated MV fraction was subjected to substrate zymography, immunoblotting, and substrate activity assay. Whereas active MMP-13 was lost after combined treatment with hyaluronidase and NaCl, MMP-2 and -9 activities were still retained in the pellet fraction even after detergent treatment, suggesting that the gelatinases, MMP-2 and -9, are integral components of MV. In addition, MV contain TGF-beta in the small latent complex, and MMP-13 associated with the MV surface was responsible for activation of TGF-beta. Since the amount of TGF-beta activated by hypertrophic chondrocytes increased with mineral appearance in serum-free chondrocyte cultures, a role for active MV-associated MMPs is suggested in activation of TGF-beta seen during late chondrocyte hypertrophy and mineralization of growth plate cartilage.

Cell Membrane↗

PubMed2005

Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages.

COX-2-dependent prostaglandin (PG) E2 synthesis regulates macrophage MMP expression, which is thought to destabilize atherosclerotic plaques. However, the administration of selective COX-2 inhibitors paradoxically increases the frequency of adverse cardiovascular events potentially through the loss of anti-inflammatory prostanoids and/or disturbance in the balance of pro- and anti-thrombotic prostanoids. To avoid these collateral effects of COX-2 inhibition, a strategy to identify and block specific prostanoid-receptor interactions may be required. We previously reported that macrophage engagement of vascular extracellular matrix (ECM) triggers proteinase expression through a MAPKerk1/2-dependent increase in COX-2 expression and PGE2 synthesis. Here we demonstrate that elicited macrophages express the PGE2 receptors EP1-4. When plated on ECM, their expression of EP2 and EP4, receptors linked to PGE2-induced activation of adenylyl cyclase, is strongly stimulated. Forskolin and dibutryl cyclic-AMP stimulate macrophage matrix metalloproteinase (MMP)-9 expression in a dose-dependent manner. However, an EP2 agonist (butaprost) has no effect on MMP-9 expression, and macrophages from EP2 null mice exhibited enhanced COX-2 and MMP-9 expression when plated on ECM. In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208. When compared with COX-2 silencing by small interfering RNA or inhibition by celecoxib, the EP4 antagonist was as effective in inhibiting ECM-induced proteinase expression. In addition, ECM-induced MMP-9 expression was blocked in macrophages in which EP4 was silenced by small interfering RNA. Thus, COX-2-dependent ECM-induced proteinase expression is effectively blocked by selective inhibition of EP4, a member of the PGE2 family of receptors.

Animals↗

PubMed2006

Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells.

Proteolytic shedding is an important step in the functional down-regulation and turnover of most membrane proteins at the cell surface. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a multifunctional glycoprotein that has two Ig-like domains in its extracellular portion and functions in cell adhesion as an inducer of matrix metalloproteinase (MMP) expression in surrounding cells. Although the shedding of EMMPRIN is reportedly because of cleavage by metalloproteinases, the responsible proteases, cleavage sites, and stimulants are not yet known. In this study, we found that human tumor HT1080 and A431 cells shed a 22-kDa EMMPRIN fragment into the culture medium. The shedding was enhanced by phorbol 12-myristate 13-acetate and inhibited by TIMP-2 but not by TIMP-1, suggesting the involvement of membrane-type MMPs (MT-MMPs). Indeed, down-regulation of the MT1-MMP expression in A431 cells using small interfering RNA inhibited the shedding. The 22-kDa fragment was purified, and the C-terminal amino acid was determined. A synthetic peptide spanning the cutting site was cleaved by MT1-MMP in vitro. The cleavage site is located in the linker region connecting the two Ig-like domains. The N-terminal Ig-like domain is important for the MMP inducing activity of EMMPRIN and for cell-cell interactions, presumably through its ability to engage in homophilic interactions, and the 22-kDa fragment retained the ability to augment MMP-2 expression in human fibroblasts. Thus, the MT1-MMP-dependent cleavage eliminates the functional N-terminal domain of EMMPRIN from the cell surface, which is expected to down-regulate its function. At the same time, the released 22-kDa fragment may mediate the expression of MMPs in tumor tissues.

Amino Acid Sequence↗

PubMed2000

Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3.

During tissue-invasive events, migrating cells penetrate type I collagen-rich interstitial tissues by mobilizing undefined proteolytic enzymes. To screen for members of the matrix metalloproteinase (MMP) family that mediate collagen-invasive activity, an in vitro model system was developed wherein MDCK cells were stably transfected to overexpress each of ten different MMPs that have been linked to matrix remodeling states. MDCK cells were then stimulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stroma to determine the ability of MMPs to accelerate, modify, or disrupt morphogenic responses. Neither secreted collagenases (MMP-1 and MMP-13), gelatinases (gelatinase A or B), stromelysins (MMP-3 and MMP-11), or matrilysin (MMP-7) affected SF/HGF-induced responses. By contrast, the membrane-anchored metalloproteinases, membrane-type 1 MMP, membrane-type 2 MMP, and membrane-type 3 MMP (MT1-, MT2-, and MT3-MMP) each modified the morphogenic program. Of the three MT-MMPs tested, only MT1-MMP and MT2-MMP were able to directly confer invasion-incompetent cells with the ability to penetrate type I collagen matrices. MT-MMP-dependent invasion proceeded independently of proMMP-2 activation, but required the enzymes to be membrane-anchored to the cell surface. These findings demonstrate that MT-MMP-expressing cells can penetrate and remodel type I collagen-rich tissues by using membrane-anchored metalloproteinases as pericellular collagenases.

Animals↗

PubMed2001

Processing of beta-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex.

The dystroglycan complex is a membrane-spanning complex composed of two subunits, alpha- and beta-dystroglycan. alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas beta-dystroglycan is an integral membrane protein which anchors alpha-dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of beta-dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of beta-dystroglycan by the membrane-associated matrix metalloproteinase (MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the dystroglycan complex. Our results indicate that the processing of beta-dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of sarcoglycanopathy.

Animals↗

PubMed1993

Extracellular matrix. 3: Evolution of the extracellular matrix in invertebrates.

Invertebrates comprise about 95% of animal species, yet most studies of extracellular matrices have centered on vertebrates. Comparative studies of invertebrates will enhance comprehension of evolutionary processes and appreciation of the diversity of extracellular matrices. Moreover, new functions and new structures will be revealed over a wide range of organismic needs. Another important perspective is that several invertebrate species have provided insight into developmental processes, and those processes often have direct relevance to vertebrate development. Thus, studies of fruit flies, nematodes, and sea urchins have revealed common features of cell biology, embryonic development, and matrix properties that pertain throughout the animal kingdom. The advantages of invertebrates are their rapid rates of embryonic development, their amenability to genetic manipulation, availability of innumerable mutants, and their ease of study in the laboratory. Extracellular matrices themselves are readily compared. Invertebrates display a wide diversity of such matrices, at the levels of both tissue architecture and molecular anatomy. Knowledge of that diversity leads to an appreciation of evolutionary variety and eventually to comprehension of the organization of extracellular matrices and of the properties of their constituent macromolecules. The expanding knowledge of unique matrix molecules from invertebrates also has economic potential and is beginning to provide new materials for biotechnology.

Animals↗

PubMed2004

Up-regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase-associated lipocalin, and matrix metalloproteinase-9 in familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP) is characterized by extracellular deposition of transthyretin (TTR) aggregates and amyloid fibrils, particularly in the peripheral nervous system (PNS) and is accompanied with changes in connective tissue. Given the invasiveness of nerve biopsy, FAP salivary glands (SGs) were used in microarray analysis; biglycan and neutrophil gelatinase-associated lipocalin (NGAL), two genes related to extracellular matrix (ECM) remodeling were overexpressed in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. Matrix metalloproteinase-9 (MMP-9), which exists as a complex with NGAL, was also increased in FAP and in vitro degraded TTR aggregates and fibrils; however in the presence of serum amyloid P, a universal amyloid component, TTR fibrils became resistant to MMP-9 proteolysis. Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. Given the relationship between inflammation and ECM remodeling, and the increase of proinflammatory cytokines in FAP, IL-10 expression in FAP nerves was investigated; IL-10 increased after fibril deposition, suggesting a balance between proinflammatory and anti-inflammatory mechanisms. Changes in ECM-related proteins and inflammatory events may be relevant for therapy in FAP and other neurodegenerative disorders.

Acute-Phase Proteins↗

PubMed2003

Matrix metalloproteinase activity in urine of patients with renal cell carcinoma leads to degradation of extracellular matrix proteins: possible use as a screening assay.

PURPOSE: Localized renal cell carcinoma is usually curable by nephrectomy. However, a large fraction of patients already present with metastatic disease, which results in a poor outcome. Currently no clinically relevant screening assay is available to detect early stage renal cell carcinoma. We investigated whether urinary extracellular matrix (ECM) proteins and/or matrix metalloproteinase (MMP) activity may be valuable as a noninvasive indicator of early stage renal cell carcinoma. MATERIALS AND METHODS: Urine specimens from preoperative patients with renal cell carcinoma and healthy controls were collected. The urinary excretion of the ECM proteins collagen IV, laminin and fibronectin was investigated by immunoblotting. MMP activity was assessed by gelatin zymography and by a fluorescence based microtiter plate activity assay. RESULTS: The full-length forms of all 3 ECM proteins investigated were significantly decreased or absent in renal cell carcinoma urine. Based on criteria established in this study this finding would lead to the correct detection of 95% of patients with renal cell carcinoma (21 of 22) with a false-positive rate of 4.5% (1 of 22 controls). All 11 nonmetastatic cases of the lowest clinical stage (T1N0M0) were correctly identified. The absence of urinary ECM proteins was due to significantly increased urinary MMP activity. CONCLUSIONS: Analysis of decreased urinary ECM proteins and analysis of increased MMP activity may have value for the development of a sensitive, high throughput molecular screening assay to detect early stage renal cell carcinoma.

Adult↗

PubMed2005

Children with stable asthma have reduced airway matrix metalloproteinase-9 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio.

BACKGROUND: Childhood asthma is characterized by inflammation of the airways. Structural changes of the airway wall may also be seen in some children early in the course of the disease. Matrix metalloproteinases (MMPs) are key mediators in the metabolism of the extracellular matrix (ECM). OBJECTIVE: To investigate the balance of MMP-8, MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 in the airways of children with asthma. METHODS: One hundred and twenty-four children undergoing elective surgical procedures also underwent non-bronchoscopic bronchoalveolar lavage (BAL). MMP-8, MMP-9 and TIMP-1 were measured by ELISA. RESULTS: There was a significant reduction in MMP-9 in atopic asthmatic children (n=31) compared with normal children (n=30) [median difference: 0.57 ng/mL (95% confidence interval: 0.18-1.1 ng/mL)]. The ratio of MMP-9 to TIMP-1 was also reduced in asthmatic children. Levels of all three proteins were significantly correlated to each other and to the relative proportions of particular inflammatory cells in BAL fluid (BALF). Both MMP-8 and MMP-9 were moderately strongly correlated to the percentage neutrophil count (r=0.40 and 0.47, respectively, P<0.001). CONCLUSIONS: An imbalance of MMPs and their inhibitors occurs in children with well-controlled asthma, which may indicate early derangement of the metabolism of the ECM.

Adolescent↗

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↗

PubMed2006

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity.

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.

Analysis of Variance↗

PubMed2005

Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases.

Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell-associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.

Animals↗

PubMed2005

Dentin matrix protein 1 enhances invasion potential of colon cancer cells by bridging matrix metalloproteinase-9 to integrins and CD44.

The up-regulation of various matrix metalloproteinases (MMP), certain cell receptors such as integrins and CD44, and the SIBLING family of integrin-binding glycophosphoproteins have been reported separately and in various combinations for many types of tumors. The mechanisms by which these different proteins may be interacting and enhancing the ability of a cancer cell to survive and metastasize have become an interesting issue in cancer biology. Dentin matrix protein 1 (DMP1) has been known for a number of years to bind to CD44 and ArgGlyAsp sequence-dependent integrins. This SIBLING was recently shown to be able to specifically bind and activate proMMP-9 and to make MMP-9 much less sensitive to inhibition by tissue inhibitors of metalloproteinases and synthetic inhibitors. In this study, we used a modified Boyden chamber assay to show that DMP1 enhanced the invasiveness of the MMP-9 expressing colon cancer cell line, SW480, through Matrigel in a dose-dependant manner. DMP1 (100 nmol/L) increased invasion 4-fold over controls (86.1 +/- 13.9 versus 22.3 +/- 9.8, P < 0.001). The enhanced invasive potential required the presence of MMP-9 and at least one of the cell surface receptors, CD44, alpha(v)beta(3), or alpha(v)beta(5) integrin. The bridging of MMP-9 to the cell surface receptors was shown by both pull-down and fluorescence activated cell sorting experiments. Because all of these proteins were also shown by immunohistochemistry to be expressed in serial sections of a colon adenocarcinoma, we have hypothesized that the MMP-9/DMP1/cell surface complexes observed to enhance cell invasion in vitro may be aiding metastatic events in vivo.

Adenocarcinoma↗