Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP (original) (raw)
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Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored …
Journal of Cell Biology
A independently of plasminogen, the gelatinase A/TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2, or stromelysin-1. In contrast, deleting or suppressing expression of the membrane-tethered MMP, MT1-MMP, in fibroblasts or tumor cells results in a loss of collagenolytic and invasive activity in vitro or in vivo. Thus, MT1-MMP serves as the major cell-associated proteinase necessary to confer normal or neoplastic cells with invasive activity.
Journal of Biological Chemistry, 1999
Along with degradation of type IV collagen in basement membrane, destruction of the stromal collagens, types I and III, is an essential step in the invasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)). Because A2058 melanoma cells produce substantial quantities of MMP-1, we used these cells as models for studying invasion of type I collagen. With a sensitive and quantitative in vitro invasion assay, we monitored the ability of these cells to invade a matrix of type I collagen and the ability of a serine proteinase inhibitor and all-trans-retinoic acid to block invasion. Although these cells produce copious amounts of MMP-1, they do not invade collagen unless they are cocultured with fibroblasts or with conditioned medium derived from fibroblasts. Our studies indicate that a proteolytic cascade that depends on stromal/tumor cell interactions facilitates the ability of A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, particularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10 ؊6 M) suppresses the invasion of tumor cells by several mechanisms that include suppression of MMP synthesis and an increase in levels of tissue inhibitor of metalloproteinases 1 and 2. We conclude that invasion of stromal collagen by A2058 melanoma cells is mediated by a novel host/tumor cell interaction in which a proteolytic cascade culminates in the activation of pro-MMP-1 and tumor cell invasion.
Cancer research, 1998
We assessed the functional significance of tumor cell-associated matrix metalloproteinase (MMP)-2 in extracellular matrix remodeling compared with that of the soluble enzyme by evaluating the contraction of three-dimensional collagen lattices by human glioma U251.3 and fibrosarcoma HT-1080 cell lines. In this model, the constitutive synthesis and activation of the MMP-2 proenzyme were modulated by stable transfections of tumor cells with cDNA encoding membrane type 1-MMP (MT1-MMP). The efficiency of transfected cells in contracting collagen lattices was shown to be dependent on the MT1-MMP-mediated activation of MMP-2 accompanied by cell surface association of activated MMP-2, on the cell-matrix interactions controlled by collagen-specific integrins, and on the integrity of actin and microtubule cytoskeletons. Each one of these mechanisms was essential but was not sufficient by itself in accomplishing gel contraction by MT1-MMP-transfected cells. Both MMP-2 activation and gel contra...
British Journal of Cancer, 1999
The hallmarks of human malignant gliomas are their marked invasiveness and vascularity. Glioma tumour cells invade beyond the main tumour mass at diagnosis (Burger et al, 1983; Kelly et al, 1987) and render these surgically incurable. Since angiogenesis and tumour invasion have been associated with increased extracellular matrix (ECM) degradation in which the matrix metalloproteinase (MMP) family of enzymes plays a critical role, the involvement of MMPs in glioma biology is coming under increasing scrutiny. MMPs are the principal secreted proteinases required for ECM degradation in a variety of physiological and pathological tissue remodelling processes, including wound healing, embryo implantation, tumour invasion, metastasis and angiogenesis (Woessner, 1991; Aznavoorian et al, 1993; Mignatti and Rifkin, 1993). At least 18 MMPs have been described (Pendas et al, 1997; Yong et al, 1998), which are subdivided into the collagenases, stromelysins, gelatinases and membrane-type MMPs (MT-MMPs) (Sato, 1994). Their activities are controlled at the levels of gene transcription, zymogen activation by proteolysis and inhibition of active forms by the tissue inhibitors of metalloproteinases (TIMPs) (Edwards et al, 1996). There is a wealth of evidence for an association between either deregulated MMPs and aggressive/invasive behaviour in human cancers (Davies et al, 1993; Bernhard et al, 1994; Heppner et al, 1996). This is particularly significant for gelatinase-A (MMP-2) and gelatinase-B (MMP-9) since these are critical factors in basement membrane degradation. Gelatinase-A and gelatinase-B are controlled through distinct mechanisms. Progelatinase-A is widely expressed and is activated by a cell surface mechanism involving MT-1,-2 or-3 MMPs (Butler et al, 1997; Murphy and Knauper, 1997; Ueno et al, 1997). In contrast, progelatinase-B is controlled primarily at the level of gene expression, its transcription being activated by mitogens and inflammatory mediators (Azzam et al, 1993; Cornelius et al, 1995; Edwards et al, 1996). Furthermore, it is not activated by MT-MMPs, but is activated more promiscuously by plasmin, stromelysin-1 and gelatinase-A (Murphy and Knauper, 1997). The levels of active, rather than latent, gelatinase-A correlate best with the invasive cancer phenotype (Azzam et al, 1993; Brown et al, 1993); in breast cancer MT1-MMP is its activator (Ueno et al, 1997).
2006
We assessed the functional significance of tumor cell-associated matrix metalloproteinase i MMI'i-2 in extracellular matrix remodeling compared with that of the soluble enzyme by evaluating the contraction of threedimensional collagen lattices by human glioma U251.3 and n hrosai-coma HT-1080 cell lines. In this model, the constitutive synthesis and activation of the MMP-2 proenzyme were modulated by stable transfections of tumor cells with cDNA encoding membrane type 1-MMP iMTI-MMI'i. The efficiency of transfected cells in contracting collagen lattices was shown to be dependent on the MTl-MMP-mediated activation of MMP-2 accompanied by cell surface association of activated MMP-2, on the cell-matrix interactions controlled by collagen-specific integrins, and on the integrity of actin and microtubule cytoskeletons. Each one of these mechanisms was essential but was not sufficient by itself in accomplishing gel contraction by MTl-MMP-transfected cells. Both MMP-2 activation and...
Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia
Journal of Cell Science, 2009
When migrating away from a primary tumour, cancer cells interact with and remodel the extracellular matrix (ECM). Matrix metalloproteinases (MMPs), and in particular the transmembrane MT1-MMP (also known as MMP-14), are key enzymes in tumour-cell invasion. Results from recent in vitro studies highlight that MT1-MMP is implicated both in the breaching of basement membranes by tumour cells and in cell invasion through interstitial type-I collagen tissues. Remarkably, MT1-MMP accumulates at invadopodia, which are specialized ECM-degrading membrane protrusions of invasive cells. Here we review current knowledge about MT1-MMP trafficking and its importance for the regulation of protease activity at invadopodia. In invasive cells, endocytosis of MT1-MMP by clathrin- and caveolae-dependent pathways can be counteracted by several mechanisms, which leads to protease stabilization at the cell surface and increased pericellular degradation of the matrix. Furthermore, the recent identification ...
Oncogene, 2008
The substrate of matrix metalloproteinase 11 (MMP11) remains unknown. We have recently shown that MMP11 is a negative regulator of adipogenesis, able to reduce and even to revert mature adipocyte differentiation. Here, we have used mouse 3T3L1 cells and human U87MG and SaOS cells to show that MMP11 cleaves the native a3 chain of collagen VI, which is an adipocyte-related extracellular matrix component. It is known that extracellular proteolytic processing of this chain is required for correct collagen VI folding. Interestingly, MMP11deficient fat tissue is less cohesive and exhibits collagen VI alteration, dramatic adipocyte plasma and basement membrane abnormalities and lipid leakage. MMP11 is thus required for correct collagen VI folding and therefore for fat tissue cohesion and adipocyte function. Both MMP11 and collagen VI favor tumor progression. Similar spatio-temporal overexpression at the adipocyte-cancer cell interface has been reported for the two proteins. MMP11-dependent collagen VI processing might therefore be expected to occur during malignancy. Accordingly, collagen VI no longer delineates adipocytes located at the invasive front of breast carcinomas. In conclusion, the native a3 chain of collagen VI constitutes a specific MMP11 substrate. This MMP11 collagenolytic activity is functional in fat tissue ontogenesis as well as during cancer invasive steps.
Regulation of matrix metalloproteinase expression in tumor invasion
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1999
Degradation of basement membranes and stromal extracellular matrix (ECM) is crucial for invasion and metastasis of malignant cells. Degradation of ECM is initiated by proteinases secreted by different cell types participating in tumor cell invasion, and increased expression or activity of every known class of proteinases (metallo-, serine-, aspartic-, and cysteine) has been linked to malignancy and invasion of tumor cells. Studies performed over the last decade have revealed that matrix metalloproteinases (MMPs) play a crucial role in tumor invasion. Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors including cytokines, growth factors, and cell contact to ECM. This review will summarize the current view on the role of MMPs in tumor growth, invasion, and survival, and focus on the role of mitogen-activated protein kinases and AP-1 and ETS transcription factors in the regulation of MMP gene expression during invasion process.
Type IV Collagen Induces Matrix Metalloproteinase 2 Activation in HT1080 Fibrosarcoma Cells
Experimental Cell Research, 2000
Matrix metalloproteinase 2 (MMP-2) activation has been described as a "master switch" which triggers tumor spread and metastatic progression. We show here that type IV collagen, a major component of basement membranes, promotes MMP-2 activation by HT1080 cells. When plated on plastic, HT1080 cells constitutively processed the 66-kDa pro-MMP-2 into a 62-kDa intermediate activated form, most probably through a membrane type (MT) 1 MMP-dependent mechanism. In the presence of type IV collagen, part of this intermediate form was further processed to fully activated 59-kDa MMP-2. This activation was prevented by tissue inhibitor of MMP (TIMP)-2 and a broad-spectrum hydroxamic acid-based synthetic MMP inhibitor (GI129471). Type IV collagen-mediated pro-MMP-2 activation did not involve either a transcriptional modulation of MMP-2, MT1-MMP, or TIMP-2 expression nor any alteration of MT1-MMP protein synthesis or processing. An inverse relationship between MMP-2 activation and the concentration of secreted TIMP-2 was observed. This is consistent with our previous report that TIMP-2 degradation is probably linked to the MT1-MMP-dependent MMP-2 activation mechanism. Because invasive tumor cells must breach basement membranes at different steps of the metastatic dissemination, the ability of HT1080 cells to activate pro-MMP-2 in the presence of type IV collagen might represent a key regulatory mechanism for the acquisition of an invasive potential. activated form. When present at a sufficiently high concentration on the cell surface, this intermediate is further processed to the fully activated 59-kDa MMP-2 by an intermolecular auto lytic cleavage between Asn 80 and Tyr 81 . Alternatively, this second cleavage can be achieved through the action of plasmin . However, the mechanisms regulating this activation process in vivo remain uncertain.