Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance

Özen, Özlem; Krebs, Bjarne; Hemmerlein, Bernhard; Pekrun, Arnulf; Kretzschmar, Hans A.; Herms, Jochen

doi:10.1158/1078-0432.ccr-0625-03

Cited by 25 publications

(18 citation statements)

References 41 publications

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“…Notably, MMP-9 is not expressed in normal adult tissues but is expressed in invasive tumors and represents a key protein in brain tumor progression. MMP-9, MT1-MMP, and MT2-MMP are often and strongly expressed in classic and desmoplastic medulloblastomas and correlates with prognosis in classic medulloblastomas (14).…”

Section: Introductionmentioning

confidence: 99%

MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway

Rao

Bhoopathi²,

Chetty³

et al. 2007

Cancer Research

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The involvement of matrix metalloproteinases (MMP) has been suggested in cellular mechanisms leading to medulloblastoma, the most common malignant brain tumor in children. A significant association of the expression levels of MMP-9 with survival and M stage suggests that patients with medulloblastoma metastatic disease at diagnosis may benefit from the anti-MMP therapy. Here, we have evaluated the tumorigenicity of medulloblastoma cells after infection with an adenovirus containing a 21-bp short interfering RNA sequence of the human MMP-9 gene (Ad-MMP-9). Infection of Daoy medulloblastoma cells with Ad-MMP-9 reduced MMP-9 activity and protein levels compared with parental and Ad-SV controls. Ad-MMP-9 decreased the number of viable Daoy cells in a concentration-dependent manner. Fluorescence-activated cell sorting analysis indicated that Ad-MMP-9 infection caused a dose-dependent cell cycle arrest in the G 0 -G 1 phase. Ad-MMP-9-induced cell cycle arrest seems to be mediated by the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway and the cell cycle inhibitor p16INK4a and is phenotypically indistinguishable from senescence. Ad-MMP-9 treatment inhibited medulloblastoma tumor growth in an intracranial model and was mediated by up-regulation of p16 expression. These studies validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of medulloblastoma. [Cancer Res 2007;67(10):4956-64]

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Section: Introductionmentioning

confidence: 99%

MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway

Rao

Bhoopathi²,

Chetty³

et al. 2007

Cancer Research

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“…Type IV collagenase matrix metalloproteinases (MMPs), in particular, MMP-2 and MMP-9, gelatinase A and B, respectively, have been found to promote invasion and metastasis of malignant tumors (4,5). Elevated levels of MMP-2 and MMP-9 are often correlated with malignancies of liver (6,7), brain (8), breast (9), prostate (10), cervical (11), ovarian (12) and other cancers. Degradation of the ECM by MMPs and the increased expression of MMPs associated with tumor growth, angiogenesis and metastasis point to MMPs as an attractive target for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of EGCG, green tea and a nutrient mixture on the patterns of MMP-2 and MMP-9 expression in cancer cell lines

Roomi

Monterrey²,

Kalinovsky³

et al. 2010

Oncol Rep

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Abstract. Type IV collagenase matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, have been found to promote invasion and metastasis of malignant tumors. Extracellular matrix (ECM) degradation by MMPs and increased expression of MMPs in cancer cells and tumor microvascular endothelial cells make MMPs an attractive target for cancer. Focused on a common pathomechanism of cancer growth and invasion, the disintegration of connective tissue, we used natural approaches to increase the integrity and strength of connective tissues. Utilizing the principle of nutrition synergy, we developed a novel micronutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract. This study evaluates the potency of the components EGCG and green tea extract independently compared to that of NM on modulation of patterns of MMP-2 and MMP-9 expression in four cancer cell lines expressing MMP-2, MMP-9 or both. Human fibrosarcoma (HT-1080), hepatocellular carcinoma (SKHep-1), glioblastoma (T-98G), uterine leiomyosarcoma (SK-UT-1) cell lines were obtained from ATCC and grown in minimum essential medium (MEM) supplemented with 10% FBS, penicillin (100 U/ml) and streptomycin (100 mg/ml) in 24-well tissue culture plates. At near confluence, the cells were treated with agents dissolved in media and tested at concentrations indicated in triplicate at each dose. Cells were also treated with PMA 100 ng/ml to study enhanced expression of MMP-9. MMP expression was assessed by gelatinase zymography. Fibrosarcoma and hepatocellular carcinoma cells expressed both MMP-2 and MMP-9. Glioblastoma cells expressed MMP-2 and PMA treatment induced MMP-9 expression. Uterine leimyosarcoma cells expressed no MMPs but PMA induced MMP-9. NM was the most potent dosedependent inhibitor of MMPs, followed by green tea extract and EGCG. In conclusion, these results suggest the enhanced efficacy of nutrients working in synergy to modulate complex pathways such as MMP expression.

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“…Matrix metalloproteinases (MMP) have been shown to be associated with glioblastoma (7,8) and medulloblastoma cell invasiveness (9,10). In particular, levels of MMP-9 and membrane type-1 (MT1) -MMP expression were increased in >75% of medulloblastoma tumor tissues (11). Whether the CD133(+)-CSC subpopulation of cells was also targeted remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Tumor Environment Dictates Medulloblastoma Cancer Stem Cell Expression and Invasive Phenotype

Annabi

Rojas-Sutterlin²,

Laflamme

et al. 2008

Molecular Cancer Research

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The neural precursor surface marker CD133 is thought to be enriched in brain cancer stem cells and in radioresistant DAOY medulloblastoma-derived tumor cells. Given that membrane type-1 matrix metalloproteinase (MT1-MMP) expression is a hallmark of highly invasive, radioresistant, and hypoxic brain tumor cells, we sought to determine whether MT1-MMP and other MMPs could regulate the invasive phenotype of CD133(+) DAOY cells. We found that when DAOY medulloblastoma or U87 glioblastoma cells were implanted in nude mice, only those cells specifically implanted in the brain environment generated CD133(+) brain tumors. Vascular endothelial growth factor and basic fibroblast growth factor gene expression increases in correlation with CD133 expression in those tumors. When DAOY cultures were induced to generate in vitro neurosphere-like cells, gene expression of CD133, MT1-MMP, MMP-9, and MDR-1 was induced and correlated with an increase in neurosphere invasiveness. Specific small interfering RNA gene silencing of either MT1-MMP or MMP-9 reduced the capacity of the DAOY monolayers to generate neurospheres and concomitantly abrogated their invasive capacity. On the other hand, overexpression of MT1-MMP in DAOY triggered neurosphere-like formation which was further amplified when cells were cultured in neurosphere medium. Collectively, we show that both MT1-MMP and MMP-9 contribute to the invasive phenotype during CD133(+) neurosphere-like formation in medulloblastoma cells. Increases in MMP-9 may contribute to the opening of the blood-brain barrier, whereas increased MT1-MMP would promote brain tumor infiltration. Our study suggests that MMP-9 or MT1-MMP targeting may reduce the formation of brain tumor stem cells. (Mol Cancer Res 2008;6(6):907 -16)

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Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance

Cited by 25 publications

References 41 publications

MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway

MMP-9 Short Interfering RNA Induced Senescence Resulting in Inhibition of Medulloblastoma Growth via p16INK4a and Mitogen-Activated Protein Kinase Pathway

Comparative effects of EGCG, green tea and a nutrient mixture on the patterns of MMP-2 and MMP-9 expression in cancer cell lines

Tumor Environment Dictates Medulloblastoma Cancer Stem Cell Expression and Invasive Phenotype

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