Matrix Metalloproteinases and Their Inhibitors in Human Pituitary Tumors

Beaulieu, Édith; Kachra, Z.; Mousseau, Nathalie; Delbecchi, Louis; Hardy, Jules; Béliveau, Richard

doi:10.1097/00006123-199912000-00033

Cited by 46 publications

(29 citation statements)

References 28 publications

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“…Gelatin Zymography-To assess the extent of functional recombinant MT1-MMP expression in transfected U-87 cells, we measured the activation of a latent, exogenous source of proMMP-2 by gelatin zymography as described previously (20,26). Briefly, an aliquot (20 l) of the culture medium was subjected to SDS-PAGE in a gel containing 0.1 mg/ml gelatin.…”

Section: Methodsmentioning

confidence: 99%

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Annabi

Thibeault

Moumdjian

et al. 2004

Journal of Biological Chemistry

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Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesteroldepleting agent ␤-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.The principal molecules that have been identified in the normal brain extracellular matrix (ECM) 1 are hyaluronan (HA; also known as hyaluronic acid, hyaluronate) and chondroitin sulfate (1, 2). HA is an important glycosaminoglycan constituent believed to be implicated in angiogenesis, the formation of new blood vessels from preexisting vasculature. Although the serum level of HA is already used as an indicator of progressive malignant disease (3), its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and have been reported to depend on HA concentration and molecular size (4, 5). Accordingly, whereas high molecular weight HA was shown to inhibit EC functions (6), low molecular weight HA stimulated EC proliferation, tubulogenesis (6, 7), and neovascularization (8). Moreover, small HA polymers efficiently regulated CD44 cell surface functional expression and promoted tumor cell migration (9). Astrocytic tumors of the central nervous system express CD44 among other cell adhesion receptors of the integrin or immunoglobulin superfamily. Although HA is the principal ligand of CD44, other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate, whereas mucosal addressin, serglycin, osteopontin, and the class II invariant chain represent ECM-unrelat...

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Section: Methodsmentioning

confidence: 99%

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Annabi

Thibeault

Moumdjian

et al. 2004

Journal of Biological Chemistry

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“…33 Soluble proteins from concentrated media and cell lysates were separated on 7.5% SDS-polyacrylamide gels containing 0.1% (w/v) gelatin under nonreducing conditions. Activities of tPA and uPA were determined by casein zymography.…”

Section: Gel Zymographymentioning

confidence: 99%

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Desrosiers

Cusson

Turcotte

et al. 2005

Intl Journal of Cancer

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The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 M did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.

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“…Gelatinolytic activity in culture media from monolayer cultures was detected by gelatin zymography as S1P displays antiangiogenic activity in brain A Pilorget et al previously described (Beaulieu et al, 1999). Briefly, an aliquot (20 mL) of the culture medium was subjected to SDS/PAGE using a 7.5% (w/v) acrylamide gel containing 0.1 mg/mL gelatin.…”

Section: Gelatin Zymographymentioning

confidence: 99%

Inhibition of Angiogenic Properties of Brain Endothelial Cells by Platelet-Derived Sphingosine-1-Phosphate

Pilorget

Annabi

Bouzeghrane

et al. 2005

J Cereb Blood Flow Metab

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The platelet-derived lysophospholipid sphingosine-1-phosphate (S1P) is present in blood plasma and is one of the most potent growth factors displaying proangiogenic activity towards endothelial cells (EC) derived from various tissues. The paracrine regulation of brain angiogenesis by plateletderived growth factors is, however, poorly understood. In the present study, we assessed the role of S1P on brain EC migration and tubulogenesis, using rat brain-derived (RBE4) EC as an in vitro model. We show that S1P inhibits brain EC migration and tubulogenesis, while it displays proangiogenic activity towards noncerebral EC. Overexpression of the S1P receptor S1P-1 in RBE4 cells potentiated all of the S1P-mediated events. We also show that the lack of expression of MT1-MMP, a membrane-bound matrix metalloproteinase that is thought to cooperate with S1P in tubulogenic processes, may explain the antiangiogenic activity of S1P on brain vasculature. Altogether our results support the hypothesis of a tissue-specific, antiangiogenic role of S1P in the brain, which may help to stabilize the cerebral vasculature and thus have crucial impact on the setting and regulation of normal brain vascularization.

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Matrix Metalloproteinases and Their Inhibitors in Human Pituitary Tumors

Cited by 46 publications

References 28 publications

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Inhibition of Angiogenic Properties of Brain Endothelial Cells by Platelet-Derived Sphingosine-1-Phosphate

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