Expression of Matrix Metalloproteinases and Their Inhibitors in Human Brain Tumors

Béliveau, Richard; Delbecchi, Louis; Beaulieu, Édith; Mousseau, Nathalie; Kachra, Z.; Berthelet, France; Moumdjian, Robert; Maestro, Rolando F. Del

doi:10.1111/j.1749-6632.1999.tb09425.x

Cited by 32 publications

(17 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With respect to gliomas, the upregulation of MMP-2 and MMP-9 has been observed in cell lines and resected specimens (Rutka et al, 1995;Saxena et al, 1995;Sawaya et al, 1996;Forsyth et al, 1998Forsyth et al, , 1999Lampert et al, 1998;Beliveau et al, 1999;Pagenstecher et al, 2001;VanMeter et al, 2001;Wild-Bode et al, 2001). In vivo the expression of MMP-2, determined by in situ hybridization or immunohistochemistry, is principally in glioma cells, whereas MMP-9 expression tends to be predominant in regions of angiogenesis (for review, see Forsyth et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade

et al. 2003

View full text Add to dashboard Cite

The presence of reactive astrocytes around glioma cells in the CNS suggests the possibility that these two cell types could be interacting. We addressed whether glioma cells use the astrocyte environment to modulate matrix metalloproteinase-2 (MMP-2), a proteolytic enzyme implicated in the invasiveness of glioma cells. We found that astrocytes in culture produce significant amounts of the pro-form of MMP-2 but undetectable levels of active MMP-2. However, after coculture with the U251N glioma line, astrocyte pro-MMP-2 was converted to the active form. The mechanism of pro-MMP-2 activation in glioma-astrocyte coculture was investigated and was found to involve the urokinase-type plasminogen activator (uPA)-plasmin cascade whereby uPA bound to uPA receptor (uPAR), leading to the conversion of plasminogen to plasmin. The latter cleaved pro-MMP-2 to generate its active form. Furthermore, key components (i.e., uPAR, uPA, and pro-MMP-2) were contributed principally by astrocytes, whereas the U251N glioma cells provided plasminogen. In correspondence with this biochemical cascade, the transmigration of U251N cells through Boyden invasion chambers coated with an extracellular matrix barrier was increased significantly in the presence of astrocytes, and this was inhibited by agents that disrupted the uPA-plasmin cascade. Finally, using resected human glioblastoma specimens, we found that tumor cells, but not astrocytes, expressed plasminogen in situ. We conclude that glioma cells exploit their astrocyte environment to activate MMP-2 and that this leads to the increased invasiveness of glioma cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade

et al. 2003

View full text Add to dashboard Cite

show abstract

“…PET tracers of MMP activity are currently being developed using 125 I-and 18 Flabelled analogues of the non-peptidyl broad-spectrum MMP inhibitor CGS 27023A [87,88]. Animal studies suggest this preferentially detects activity of MMP-1, -2 and -9 [87], the MMPs with the most important activity in gliomas [89]. Such PET markers may help determine the degree of invasiveness in an individual glioma.…”

Section: Imaging Biomarkers Of Tumour Invasionmentioning

confidence: 99%

Imaging biomarkers of brain tumour margin and tumour invasion

Price

Gillard²

2011

BJR

View full text Add to dashboard Cite

ABSTRACT. Invasion of tumour cells into the normal brain is one of the major reasons of treatment failure for gliomas. Although there is a good understanding of the molecular and cellular processes that occur during this invasion, it is not possible to detect the extent of the tumour with conventional imaging. However, there is an understanding that the degree of invasion differs with individual tumours, and yet they are all treated the same. Newer imaging techniques that probe the pathological changes within tumours may be suitable biomarkers for invasion. Imaging methods are now available that can detect subtle changes in white matter organisation (diffusion tensor imaging), tumour metabolism and cellular proliferation (using MR spectroscopy and positron emission tomography) occurring in regions of tumour that cannot be detected by conventional imaging. The role of such biomarkers of invasion should allow better delineation of tumour margins, which should improve treatment planning (especially surgery and radiotherapy) and provide information on the invasiveness of an individual tumour to help select the most appropriate therapy and help stratify patients for clinical trials.

show abstract

“…5 MMP-2 expression and activation in particular is upregulated in glioblastoma and is associated with its rapid progression to increasing levels of malignancy. 6,7 Cell-mediated pro-MMP-2 activation involves cleavage by MT1-MMP on cell membranes. 8,9 The activity of these MMPs is regulated by the endogenous specific inhibitor tissue inhibitor of metalloproteinases (TIMP)-2, which in excess can bind cell surface MT1-MMP and both latent and active MMP-2 in an inhibitory manner.…”

mentioning

confidence: 99%

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Jong

Rajasekaran

et al. 2003

Lab Invest

View full text Add to dashboard Cite

Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin avb3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.

show abstract

Expression of Matrix Metalloproteinases and Their Inhibitors in Human Brain Tumors

Cited by 32 publications

References 6 publications

Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade

Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade

Imaging biomarkers of brain tumour margin and tumour invasion

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Contact Info

Product

Resources

About