Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas

Forsyth, Peter; Wong, Howard; Laing, T D; Rewcastle, N. B.; Morris, Donald G.; Muzik, Huong; Leco, Kevin J.; Johnston, Robert Mackenzie; Brasher, Penny; Sutherland, Garnette; Edwards, Dylan R.

doi:10.1038/sj.bjc.6990291

Cited by 263 publications

(131 citation statements)

References 43 publications

(29 reference statements)

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“…28 Secreted MMP-2 (gelatinase A), MMP-9 (gelatinase B), urokinase and other secreted proteases, as well as cell-surface proteases involved in their activation like MT1-MMP or MT2-MMP (membrane type matrix metalloproteinases-1 and -2) seem to play a critical role in this migratory process. [28][29][30][31][32][33] Beside the proteases identified so far, others may be of additional or even similar importance for the invasive process.…”

Section: Discussionmentioning

confidence: 99%

Matrix‐degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas

Held‐Feindt

Paredes

Blömer

et al. 2005

Intl Journal of Cancer

124

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Brain tumors, in particular glioblastomas, have a high morbidity and mortality, mainly due to their invasive nature. A prerequisite for this invasiveness is cell migration based on increased expression of proteases digesting the extracellular matrix. Brevican, an important extracellular proteoglycan that is upregulated in glioblastomas, can be degraded by certain proteases. We demonstrate that in human glioblastomas secretory proteases like ADAMTS4 and ADAMTS5 (aggrecanases 1 and 2; ADAMTS 5 a disintegrin and metalloproteinase with thrombospondin motifs) are expressed on the mRNA and protein levels in considerable amounts. Realtime RT-PCR shows a higher levels of ADAMTS4 and 5 expressions in glioblastomas in situ, compared to cultured human glioblastoma cells. The upregulation of these proteases in vivo by cytokines may explain this difference. In vitro, transforming growth factor-b induces ADAMTS4, but less ADAMTS5, and interleukin1b ADAMTS5, but not ADAMTS4. As demonstrated by immunohistochemistry and confocal microscopy in situ, ADAMTS5 expression is confined to proliferating glioblastoma cells of surgical tumor sections and with lower intensity to astroglial cells in normal brain sections, as opposed to brevican. In vitro, glioblastoma-derived ADAMTS5 degrades recombinant human brevican to several smaller fragments. Our results show that ADAMTS4 and 5 are upregulated on proliferating glioblastoma cells and these proteases may contribute to their invasive potential. ' 2005 Wiley-Liss, Inc.Key words: glioblastoma; invasion; proteases; extracellular matrix; degradation; cytokines High-grade glial tumors (anaplastic astrocytoma and glioblastoma multiforme) are the most frequent brain tumors in adults. 1,2 Despite multimodal therapeutic efforts, the mean survival time is only 9-12 months for glioblastoma multiforme (WHO Grade IV) and 2 years for anaplastic astrocytoma (WHO Grade III). The ability of individual tumor cells to infiltrate brain tissue is the primary reason for this poor prognosis. Individual tumor cells (''guerrilla cells'') can migrate more than 4.0-7.0 cm from the gross tumor into the surrounding normal brain tissue. 3 In part, the migratory and invasive behavior is a consequence of tumor cell interaction with specific components of the extracellular matrix (ECM). Brain ECM components include laminin, collagen IV, tenascin, fibronectin and proteoglycans. 4 The glycosaminoglycan hyaluronic acid (HA) plays a central role in cellular proliferation, differentiation and migration, and may be a key element in tumor spreading. 5 BEHAB (brain enriched hyaluronan binding)/brevican is a recently identified HA binding protein that belongs to the lectican family. 6-9 BEHAB/brevican expression is developmentally regulated in the central nervous system, in particular during periods of glial cell proliferation and migration. 9 Accordingly, BEHAB/brevican is upregulated in the vast majority of surgical glioblastomas, 9-11 and expression levels and proteolytic cleavage of BEHAB/brevican seem to correlate with tumo...

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Section: Discussionmentioning

confidence: 99%

Matrix‐degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas

Held‐Feindt

Paredes

Blömer

et al. 2005

Intl Journal of Cancer

124

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“…Consistent with this idea, recombinant or over-expressed TIMP-4 had no effect on cellular viability and proliferation (as measured by 3 H-thymidine incorporation and MTT assays, data not shown), but substantially reduced the invasive capacity of glioma cells through Matrigel. Several MMPs have been linked with the invasive behaviour of malignant gliomas, including MMP-2, MMP-9 and MT1-MMP (Saxena et al, 1995;Sawaya et al, 1996;Uhm et al, 1996;Yamamoto et al, 1996;Deryugina et al, 1998;Lampert et al, 1998;Belien et al, 1999;Forsyth et al, 1999;Price et al, 1999;Raithatha et al, 2000). In particular there is growing evidence for involvement of several other members of the MT-MMP family including MT2-MMP (Nakada et al, 1999), MT5-MMP (Llano et al, 1999) and MT6-MMP (Velasco et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Gelatinase-A (MMP-2) and the MT-MMPs that activate it on the cell surface have been linked with both tumour cell invasion and angiogenesis Hiraoka et al, 1998;Belien et al, 1999;Forsyth et al, 1999;Llano et al, 1999;Nakada et al, 1999;Price et al, 1999;Raithatha et al, 2000).…”

mentioning

confidence: 99%

Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas

Groft¹,

Muzik²,

Rewcastle

et al. 2001

Br J Cancer

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Studies have suggested that an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to the malignant phenotype of gliomas. In this study, we have undertaken a detailed analysis of expression of the TIMP family in normal human brain and malignant gliomas at both the mRNA and protein level. Reverse transcription-PCR (RT-PCR) analyses of total RNA from surgical tumour specimens revealed unique expression patterns for the 4 members of the TIMP family, with TIMP-1 and -4 showing positive and negative correlations, respectively, with glioma malignancy. By RT-PCR, TIMP-2 and TIMP-3 expression did not change with tumour grade. In situ hybridization localized TIMP-1 to glial tumour cells and also to the surrounding tumour vasculature. TIMP-4 transcripts were predominantly localized to tumour cells, though minor expression was found in vessels. Recombinant TIMP-4 reduced invasion of U251 glioma cells through Matrigel, and U87 clones overexpressing TIMP-4 showed reduced invasive capacity in vitro. TIMP-4, but not TIMP-1, blocked Membrane Type-1-MMP-mediated progelatinase-A (MMP-2) activation in human umbilical vein endothelial cells. The differential expression and localization of individual TIMPs may contribute to the pathophysiology of human malignant gliomas, particularly with regard to tumour vascularization. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…The purified proteins were separated on SDSPage and identified by mass spectrometry. Unexpectedly, these studies isolated a protein complex consisting of MT1-MMP, MMP-2 and TIMP-2 (Deshane et al, 2003), which are all involved in the enzymatic degradation of the extracellular matrix (Chen and Wang, 1999;Forsyth et al, 1999). This protein complex is instrumental in facilitating the invasion of glioma cells (Belien et al, 1999;Nakada et al, 2003).…”

Section: A Putative CL − Channel Inhibitor (Cltx) Is Currently In Climentioning

confidence: 99%

A role for ion channels in glioma cell invasion

McFerrin¹,

2005

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Many cells, including neuronal and glial progenitor cells, stem cells and microglial cells, have the capacity to move through the extracellular spaces of the developing and mature brain. This is particularly pronounced in astrocyte-derived tumors, gliomas, which diffusely infiltrate the normal brain. Although a significant body of literature exists regarding signals that are involved in the guidance of cells and their processes, little attention has been paid to cell-shape and cell-volume changes of migratory cells. However, extracellular spaces in the brain are very narrow and represent a major obstacle that requires cells to dynamically regulate their volume. Recent studies in glioma cells show that this involves the secretion of Cl − and K + with water. Pharmacological inhibition of Cl − channels impairs their ability to migrate and limits tumor progression in experimental tumor models. One Cl − -channel inhibitor, chlorotoxin, is currently in Phase II clinical trials to treat malignant glioma. This article reviews our current knowledge of cell-volume changes and the role of ion channels during the migration of glioma cells. It also discusses evidence that supports the importance of channel-mediated cell-volume changes in the migration of immature neurons and progenitor cells during development. New unpublished data is presented, which demonstrates that Cl − and K + channels involved in cell shrinkage localize to lipid-raft domains on the invadipodia of glioma cells and that their presence might be regulated by trafficking of these proteins in and out of lipid rafts.

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Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas

Cited by 263 publications

References 43 publications

Matrix‐degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas

Matrix‐degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas

Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas

A role for ion channels in glioma cell invasion

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