Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions

Préaux, Anne-Marie; Mallat, Ariane; Nhieu, Jeanne Tran Van; d’Ortho, Marie-Pia; Hembry, Rosalind M.; Mavier, Philippe

doi:10.1002/hep.510300432

Cited by 123 publications

(97 citation statements)

References 51 publications

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“…First, we and others have shown that MMP2 activation depends on collagen I deposition in hepatic stellate cell cultures. 17,39 Second, the efficacy of 3-dimensional gels over coating of dishes with collagen I was reported, suggesting that fibrillar collagen organization is crucial in MMP2 activation. Interestingly, an enhanced expression of lysyl oxidase, the enzyme that initiates the first step of extracellular collagen cross-linking, was shown in early stages of liver fibrosis 40 and was suggested to play a role in the early host defense mechanisms in cancers.…”

Section: Discussionmentioning

confidence: 99%

Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas

Théret¹

2001

Hepatology

183

128

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Matrix metalloproteinase-2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type-matrix metalloproteinase-1 (MT1-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady-state mRNA levels of MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin ␥1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R ‫؍‬ .74, P < .001), MT1-MMP (R ‫؍‬ .65, P < .001) and TIMP2 (R ‫؍‬ 0.61, P < .001). MMP2 activity was correlated with the mRNA expression of collagen I (R ‫؍‬ .45 P < .01), collagen IV (R ‫؍‬ .40, P < .01) and laminin ␥1 (R ‫؍‬ .33, P < .05). Unlike collagen IV and laminin ␥1 mRNAs, MMP2, MT1-MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P < .05). In addition, MMP2 activity was fourfold higher (P < .01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6-and 2.8-fold (P < .05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas. (HEPATOLOGY 2001;34:82-88.)Tumor progression depends on the interplay between transformed cells and their micro-environment, particularly the surrounding extracellular matrix (ECM). 1 The balance between synthesis and degradation of ECM components is indeed a key modulator of tumor growth and metastasis. Among the proteases involved in the turnover of ECM, matrix metalloproteinase 2 (MMP2), the type IV collagenase/gelatinase, was shown to specifically act in the process of basementmembrane remodeling related to tumor progression. 2 MMP2 is secreted as a proenzyme and the critical step of MMP2 activation occurs at the cell surface through the formation of a molecular complex involving MMP2, the membrane-type matrix metalloproteinase MT1-MMP 3 and the tissue inhibitor of MMP2, TIMP2, which promotes the binding of MT1-MMP to MMP2. 4 Thus, TIMP2 plays a dual role by acting at a high concentration as a specific inhibitor of MMP2 activation and at a low concentration as a trigger of MMP2 and MT1-MMP clustering. 5 In human livers, fibrogenesis underlies the development of HCC in at least 90% of cases and HCC is an ominous complication of cirrhosis in 30% of the patients. 6,7 However, direct relationships between fibrosis and the progression of HCC were not shown, so far. Increased expression of MMP2, tissue inhibitors of metalloproteinase (TIMP1 and TIMP2), and MT1-MMP by nonparenchymal cells were reported in fibrosis 8-9 and in HCC. [10][11][12] Indeed, hep...

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Section: Discussionmentioning

confidence: 99%

Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas

Théret¹

2001

Hepatology

183

128

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“…The 90% of the patients without metastasis (showing higher mean value of TIMP-2 in both, serum and primary HCC nodule) was still alive after 18 and 24 months; whereas the percentage of the patients with metastasis (showing lower mean value of TIMP-2 in both, serum and primary HCC nodule) still alive after 18 and 24 months was 40% and less than 30%, respectively. where an over-expression of MT1-MMP and MMP-2 has been reported 23,24 and this could therefore mask differences in MMP-2 or MT1-MMP expression between patients with or without metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…In such an environment, upregulation of MMPs and TIMP-2 has been reported and it is possible they have a role in the rearrangement of the liver tissue architecture. 23,24 There is no BM in the liver, but HCC cancer cells grow surrounded by ECM proteins secreted as a consequence of cirrhosis and therefore proteolytic activity is required to allow HCC cells to penetrate and cross over such tissue boundaries. 21 The goal of our study is to investigate the expression and the clinical role of MMP-2, TIMP-2 and MT1-MMP in patients with HCC.…”

mentioning

confidence: 99%

Clinical role of MMP‐2/TIMP‐2 imbalance in hepatocellular carcinoma

Giannelli

Bergamini

Marinosci

et al. 2001

Intl Journal of Cancer

175

121

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An imbalance between the proteolytic activity of matrix metalloproteinase-2 (MMP-2) and the tissue inhibitor of MMP-2 (TIMP-2) is responsible for degradation of extracellular matrix (ECM) components and plays a critical role in tumor invasion and in metastasis formation. The occurrence of intra-hepatic metastasis, which severely affects prognosis and long-term survival, is commonly observed in the course of hepatocellular carcinoma (HCC). We investigated the expression of MT1-MMP in tissues, whereas both MMP-2 and TIMP-2 were evaluated in the sera and tissues (primary and metastatic nodules) of HCC patients with and without metastasis, whose clinical outcome was followed over a 2-year period. MT1-MMP expression was similar among primary nodule tissues of patients with and without metastasis. Serum and tissue levels of MMP-2 were not statistically different between patients with and without metastasis, but MMP-2 was concentrated at the invasive edge of the metastatic tissue. On the contrary, serum and tissue levels of TIMP-2 were significantly higher in HCC patients without metastasis than in those with. This situation was not only observed in the primary HCC tissues, but also in the metastatic nodules. These results correlate with the clinical outcome, because more than 90% of the patients with high levels of TIMP-2 were still alive after 2 years, whereas less than 30% with low levels of TIMP-2 had survived. Furthermore, we found a strict correlation between tissue and serum levels of TIMP-2, this suggesting that a MMP-2/TIMP-2 imbalance and in particular TIMP-2 levels, could represent an important prognostic factor in patients with HCC.

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“…Overexpression of angiopoietin-2 in U87MG glioma cells induces expression and processing of MT1-MMP to the 44-kDa species (47). Primary human hepatic myofibroblasts cultured on collagen I also exhibit enhanced MT1-MMP processing (48). Processing of MT1-MMP to the 44-kDa species was detected in the human microvascular endothelial cell-1 line under unstimulated conditions, but it was enhanced by exposure of the cells to elastinderived peptides (49).…”

Section: Matrix Metalloproteinases (Mmp(s))mentioning

confidence: 99%

Mutational and Structural Analyses of the Hinge Region of Membrane Type 1-Matrix Metalloproteinase and Enzyme Processing

Osenkowski

Meroueh

Pavel

et al. 2005

Journal of Biological Chemistry

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Membrane type 1 (MT1)-matrix metalloproteinase (MMP) is a major mediator of collagen degradation in the pericellular space in both physiological and pathological conditions. Previous evidence has shown that on the cell surface, active MT1-MMP undergoes autocatalytic processing to a major membrane-tethered 44-kDa product lacking the catalytic domain and displaying Gly 285 at its N terminus, which is at the beginning of the hinge domain. However, the importance of this site and the hinge region in MT1-MMP processing is unknown. In the current study, we generated mutations and deletions in the hinge of MT1-MMP and followed their effect on processing. These studies established Gly 284 -Gly 285 as the main cleavage site involved in the formation of the 44-kDa species. However, alterations at this site did not prevent processing. Instead, they forced downstream cleavages within the stretch of residues flanked by Gln 296 and Ser 304 in the hinge region, as determined by the processing profile of various hinge deletion mutants. Also, replacement of the hinge of MT1-MMP with the longer MT3-MMP hinge did not prevent processing of MT1-MMP. Molecular dynamic studies using a computational model of MT1-MMP revealed that the hinge region is a highly motile element that undergoes significant motion in the highly exposed loop formed by Pro 295 -Arg 302 consistent with being a prime target for proteolysis, in agreement with the mutational data. These studies suggest that the hinge of MT1-MMP evolved to facilitate processing, a promiscuous but compulsory event in the destiny of MT1-MMP, which may play a key role in the control of pericellular proteolysis. Matrix metalloproteinases (MMP(s))1 are zinc-dependent endopeptidases that play key roles in normal and pathological conditions because of their ability to degrade extracellular matrix components and a variety of bioactive molecules (1-3). The MMP family comprises secreted and membrane-anchored proteases that are major mediators of pericellular proteolysis. Among the membrane-anchored MMPs, MT1-MMP (MMP-14) is a type I transmembrane protease whose broad range of functions includes pericellular collagenolysis (4 -6), activation of other MMPs, including MMP-2 (7, 8) and MMP-13 (9, 10), and cleavage of growth factors, cytokines, chemokines, cell adhesion receptors, protease inhibitors, and an apoptosis death receptor (11-15). MT1-MMP activity is critical for normal growth and development (16,17), and it is involved in various pathological conditions including cancer metastasis and arthritis (18 -20). Like all MMPs, MT1-MMP is inhibited by the tissue inhibitors of metalloproteinases (TIMPs), with TIMP-2, TIMP-3 and TIMP-4 being high affinity inhibitors and TIMP-1 being a weak inhibitor (21). The TIMP-2⅐MT1-MMP complex, which serves to inhibit catalytic activity, can also recruit pro-MMP-2 to the cell surface, facilitating its activation by a neighboring TIMP-2-free MT1-MMP (7, 8). Active MMP-2 can then activate pro-MMP-9 (progelatinase B) (22) and can also participate in the activati...

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Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions

Abstract: Matrix metalloproteinase-2 (MMP-2) is involved in extra-

Cited by 123 publications

References 51 publications

Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas

Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas

Clinical role of MMP‐2/TIMP‐2 imbalance in hepatocellular carcinoma

Mutational and Structural Analyses of the Hinge Region of Membrane Type 1-Matrix Metalloproteinase and Enzyme Processing

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