scholarly journals The Role of Matrix Metalloproteinases a nd Tissue Inhibitors of Metalloproteinases in the Progression of Astrocytomas

10.5772/21358 ◽  
2011 ◽  
Author(s):  
Fabio Motta ◽  
Renata Canalle ◽  
France Yoshioka ◽  
Giovanny Pinto ◽  
Lucia Harada ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Tissue Inhibitors

scholarly journals Functional Analysis of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Differentially Expressed by Variants of Human HT-1080 Fibrosarcoma Exhibiting High and Low Levels of Intravasation and Metastasis

2007 ◽  
Vol 282 (49) ◽  
pp. 35964-35977 ◽  
Author(s):  
Juneth J. Partridge ◽  
Mark A. Madsen ◽  
Veronica C. Ardi ◽  
Thales Papagiannakopoulos ◽  
Tatyana A. Kupriyanova ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Cancer Cell ◽  
Small Interfering Rna ◽  
Cultured Cells ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Down Regulation ◽  
Primary Tumors ◽  
Tissue Inhibitors ◽  
Interfering Rna

The role of tumor-derived matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) in cancer cell dissemination was analyzed by employing two variants of human HT-1080 fibrosarcoma, HT-hi/diss and HT-lo/diss, which differ by 50-100-fold in their ability to intravasate and metastasize in the chick embryo. HT-hi/diss and HT-lo/diss were compared by quantitative reverse transcription-PCR and Western blot analyses for mRNA and protein expression of nine MMPs (MMP-1, -2, -3, -7, -8, -9, -10, -13, and -14) and three TIMPs (TIMP-1, -2, and -3) in cultured cells in vitro and in primary tumors in vivo. MMP-1 and MMP-9 were more abundant in the HT-hi/diss variant, both in cultures and in tumors, whereas the HT-lo/diss variant consistently expressed higher levels of MMP-2, TIMP-1, and TIMP-2. Small interfering RNA-mediated down-regulation of MMP-2 and TIMP-2 increased intravasation of HT-lo/diss cells. Coordinately, treatment of the developing HT-hi/diss tumors with recombinant TIMP-1 and TIMP-2 significantly reduced HT-hi/diss cell intravasation. However, a substantial increase of HT-hi/diss dissemination was observed upon small interfering RNA-mediated down-regulation of three secreted MMPs, including the interstitial collagenase MMP-1 and the two gelatinases, MMP-2 and MMP-9, but not the membrane-tethered MMP-14. The addition of recombinant pro-MMP-9 protein to the HT-hi/diss tumors reversed the increased intravasation of HT-hi/diss cells, in which MMP-9 was stably down-regulated by short hairpin RNA interference. This rescue did not occur if the pro-MMP-9 was stoichiometrically complexed with TIMP-1, pointing to a direct role of the MMP-9 enzyme in regulation of HT-hi/diss intravasation. Collectively, these findings demonstrate that tumor-derived MMPs may have protective functions in cancer cell intravasation, i.e. not promoting but rather catalytically interfering with the early stages of cancer dissemination.

Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts

2005 ◽  
Vol 288 (2) ◽  
pp. H461-H468 ◽  
Author(s):  
Joshua D. Lovelock ◽  
Andrew H. Baker ◽  
Feng Gao ◽  
Jing-Fei Dong ◽  
Angela L. Bergeron ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Brdu Incorporation ◽  
Traditional Role ◽  
Phenotypic Differentiation ◽  
Tissue Inhibitors

The balance between matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, -2, -3, and -4) provoked a significant ( P < 0.0001) 1.3-fold in increase in bromodeoxyuridine (BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, -2-, -3-, and -4-conditioned medium led to a 1.2-fold increase in BrdU incorporation ( P < 0.0001) that was abolished by pretreatment with anti-TIMP-1, -2, -3, and -4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP-1, -2, -3, and -4 led to a significant increase in α-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP-2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP-3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors.

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