Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

Hofmann, U.; Westphal, Johan R.; Waas, Erwin T.; Zendman, Albert J.W.; Cornelissen, Ine M. H. A.; Ruiter, Dirk J.; Muijen, G.N.P. van

doi:10.1038/sj.bjc.6690763

Cited by 140 publications

(126 citation statements)

References 32 publications

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“…Moreover, antisense oligonucleotide-driven inhibition of uPAR expression in human melanoma cells inhibited lung metastases in an experimental model of spontaneous metastasis in nude mice (28). Similar data are available for MMPs (26,27), whose control by genetic (29) and pharmacological means (30) has been shown to inhibit the aggressiveness of experimental melanoma. However, information on the control of these proteases by inflammatory cytokines in tumor cells is still limited, and an inconsistency in the trend is seen in the present information (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Introductionsupporting

confidence: 52%

“…Both systems of proteases are markers of melanoma progression. Indeed, uPA/uPAR and MMP are expressed in advanced stages of primary and metastatic melanoma lesions (25)(26)(27). Moreover, antisense oligonucleotide-driven inhibition of uPAR expression in human melanoma cells inhibited lung metastases in an experimental model of spontaneous metastasis in nude mice (28).…”

Section: Introductionmentioning

confidence: 99%

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Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

et al. 2006

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Abstract. Proteases are crucial for the spread of cancer cells from a primary tumor to the site of secondary growth. This study examined the ability of IFNÁ and TNF· to stimulate a better invasiveness in B16 murine melanoma cells, and investigated whether this enhanced ability was related to a higher expression of protease activities, such as urokinase plasminogen activator (uPA) and its receptor (uPAR), and matrix metalloproteinases 2 and 9 (MMP-2, MMP-9). We found that murine melanoma cells enhanced their lungcolonizing potential in vivo and invasiveness through Matrigel-coated filters upon costimulation with IFNÁ and TNF·; neither IFNÁ nor TNF· alone, at the dose used in the experiments, was able to elicit a change in the invasive/ metastatic efficiency of melanoma cells. The invasive phenotype of murine melanoma cells stimulated with IFNÁ and TNF· was characterized by an enhanced uPA/uPAR and MMP-9 expression: TNF· promoted MMP-9 mRNA expression and pro-MMP-9 protein secretion, and the costimulation with IFNÁ and TNF· was required to potentiate the expression of mRNA and protein for uPAR, and to induce a redistribution of uPA from the soluble to the cell bodyassociated form. Both monoclonal antibodies, anti-uPAR and anti-MMP-9, caused a significant reduction of invasiveness in IFNÁ/TNF·-stimulated melanoma cells. These results indicate that invasiveness in B16 murine melanoma cells can be regulated in a cytokine-specific fashion and is dependent on the synergism between the uPA/uPAR system and MMP-9.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

et al. 2006

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“…Although tumorigenity of tumor cells has long been associated with expression of the gelatinases (9), only some tumor cells were shown to express MMP-2 and MMP-9 in vitro (8,52). Indeed, the L-CI.5s lymphoma cells also express significant amounts of gelatinases only during metastasis, i.e., when they are exposed to host tissue.…”

Section: Discussionmentioning

confidence: 99%

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg

Kopitz²,

Schaten³

et al. 2008

Molecular Cancer Research

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The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell -derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell -derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341 -51)

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“…Gelatin zymography was performed to quantify the presence of both activated and latent forms of the gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in the tissue extracts (Heussen and Dowdle, 1980;Hofmann et al, 1999). Each extract was diluted 1 : 1 with sample buffer (0.125 M Tris-HCl, pH 6.8, 17.4% (w v 71 ) glycerol, 4% sodium dodecylsulphate (SDS) and 0.01% bromophenol blue) and heated at 608C for 20 min.…”

Section: Gelatin Zymographymentioning

confidence: 99%

Tissue levels of active matrix metalloproteinase-2 and -9 in colorectal cancer

Waas

Lomme

DeGroot³

et al. 2002

Br J Cancer

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The bioactivity of matrix metalloproteinases was studied in tissues from colorectal cancer patients by means of both quantitative gelatin zymography and a fluorometric activity assay. Next to paired samples of tumour tissue and distant normal mucosa (n=73), transitional tissue was analysed from a limited (n=33) number of patients. Broad-spectrum matrix metalloproteinase activity and both the active and latent forms of the gelatinases matrix metalloproteinase-2 and -9 were higher in tumour than in normal mucosa. The ratio's between active and latent forms of matrix metalloproteinase-2 and -9 were highest in tumour tissue and normal mucosa, respectively. Matrix metalloproteinase-2 levels, both active and latent forms, correlated inversely with stage of disease, the tumours without synchronous distant metastases containing significantly (P=0.005) more active matrix metalloproteinase-2 than the others. At much lower levels of activity, the same trend was observed in distant normal mucosa. The level of latent form of matrix metalloproteinase-9 in tumour depended on tumour location. Neither the active form of matrix metalloproteinase-9 nor broad-spectrum matrix metalloproteinase activity in tumour tissue did correlate with any of the clinicopathological parameters investigated. The results demonstrate explicit differences between the activity of matrix metalloproteinase-2 and -9, indicating different roles for both gelatinases in tumour progression. Such data are necessary in order to develop rational anti-cancer therapies based on inhibition of specific matrix metalloproteinases.

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Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

Cited by 140 publications

References 32 publications

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Tissue levels of active matrix metalloproteinase-2 and -9 in colorectal cancer

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