Biology and biochemistry of proteinases in tumor invasion

Mignatti, Paolo; Rifkin, Daniel B.

doi:10.1152/physrev.1993.73.1.161

Cited by 1,160 publications

(825 citation statements)

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“…MMP-2 secretion involves the degradation of type IV, V, VII and X collagens and fibronectin (Mullins and Rohrlich, 1983) which are constituents of both the basement membrane and the interstitial stroma (Tryggvason et al, 1987). This degradation facilitates the intrusion of endothelial cells across such structures, an important step for neovessel sprouting (Mullins and Rohrlich, 1983;Tryggvason et al, 1987) and metastasis formation (Tryggvason et al, 1987;Mignatti and Rifkin, 1993). Also, previous results by this group showed the inhibition of mRNAs for MMP-2, specularly to the increase of the mRNA for TIMP-2, to be associated to enhanced deposition of extracellular matrix within the tumour, increased thickness of the capsule surrounding it and appearance of a more defined wall around tumour blood vessels (Sava et al, 1996); all these events were matched to a marked reduction of the formation of spontaneous metastases.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

et al. 2002

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NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours.

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Section: Discussionmentioning

confidence: 99%

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

et al. 2002

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“…The latent form (proenzyme) can be activated, at least "in vitro", by other proteases (e.g., plasmin, plasma kallikrein, tissue plasminogen activator, which are present in the inflammatory micro-environment), as well as by mercurials (e.g., 4-aminophenylmercuric acetate) [6]. MMPs appear to be crucial for connective tissue remodelling in physiologic processes, including wound healing [7], angiogenesis [8], cytotrophoblast implantation [9], embryonic development [10], in the cycling of endometrium [11] and in pathologic conditions, such as tumor invasion and metastasis [12], progressive joint destruction [13], inflammation [14], Alzheimer's disease [15] and atherosclerosis [16]. The source of degradative proteinases may depend on the type of disease: in rheumatoid arthritis enzymes may arise from the pannus that proliferates over the cartilage and from inflammatory cells, such as neutrophils and macrophages, that attack the cartilage surface.…”

Section: Introductionmentioning

confidence: 99%

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

Marini

Fasciglione

Monteleone

et al. 2003

Clinical Biochemistry

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Objective: A novel study has been carried out to characterize the amount and activity levels of metalloproteinases (i.e., MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13) and of their inhibitors (i.e., TIMP-1 and TIMP-2) in synovial fluid from patients (n ϭ 56) with different degrees of either chondral lesions or knee arthritis identified and classified by arthroscopy. Design and methods: Zymographies, Western blotting and ELISA tests have been used to correlate the disease stage, as determined by arthroscopy, and both the amount and the activation state of different MMPs and of their inhibitors. Results: Analysis of data obtained demonstrates that the degree of cartilage degradation, as seen by arthroscopy, is strictly related to the activity of some synovial MMPs, in particular MMP-2 and MMP-13 and on reduced inhibitory effect of MMP-2 by TIMP-2; in addition, a serine protease weighing about 125 kDa appears only in patients with severe cartilage degradation, i.e., with knee arthritis. Conclusions: On the whole, this is the first study in which an analysis of synovial MMPs/other proteinases activity and TIMPs has been strictly related to arthroscopy results in patients with different degrees of osteoarthritis. Results indicate that an imbalance between specific MMP activities and the amount of TIMPs and of its inhibitory efficiency is crucial for the disease evolution and it is related to the disease stage.

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“…Proteolysis of ECMs, and especially basement membranes, is considered a key event during this process [1,2]. Several classes of proteinases, including aspartic-, cysteine-, and serine proteinases as well as matrix metalloproteinases (MMPs) have been implicated in tumor invasion [3].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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Enhanced expression and activation of matrix met-alloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with β-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as 11-1β and TNF-α were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-Spectrum MMPIs.

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Biology and biochemistry of proteinases in tumor invasion

Cited by 1,160 publications

References 0 publications

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

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