Roles of Matrix Metalloproteinases in Tumor Metastasis and Angiogenesis

Yoon, Sang-Oh; Park, Soo‐Jin; Yun, Chang-Hyun; Chung, An‐Sik

doi:10.5483/bmbrep.2003.36.1.128

Cited by 265 publications

(206 citation statements)

References 70 publications

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“…Most metalloproteinases are regarded as key regulators of tumor cell invasiveness, because they possess proteolytic activities to destruct the ECM and alter the cell-cell attachments and cell-matrix attachments, which are integral to tumor cell migration (38). However, little is known about the involvement of ADAMTS members in cell invasion except for ADAMTS1 and ADAMTS5.…”

Section: Discussionmentioning

confidence: 99%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors.

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Section: Discussionmentioning

confidence: 99%

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

Choi

Wang

et al. 2014

Molecular Cancer Research

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“…Cell migration and invasion are coordinated active processes involving ECM degradation by proteases such as MMPs [19,20]. At baseline we studied the effects of S1P on MMP expression and activity.…”

Section: S1p Regulation Of Dov 13 Invasiveness Correlates With Mmp-2 mentioning

confidence: 99%

“…Plasmin directly degrades various ECM components as well as activating matrix metalloproteinases (MMP's), a family of zinc-dependent endopeptidases capable of degrading virtually all ECM components and correlated with cellular invasiveness [7,[18][19][20]. uPA activity is upregulated by LPA in DOV 13 cells [21]; however, the effect of S1P on uPA activity is unknown.…”

Section: Introductionmentioning

confidence: 99%

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Devine

Smicun

Hope

et al. 2008

Gynecologic Oncology

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OBJECTIVES-We previously demonstrated that sphingosine 1-phosphate (S1P) bimodally regulates epithelial ovarian cancer (EOC) cell invasiveness: low-concentration S1P stimulates invasion similar to lysophophatidic acid (LPA), while high-concentration S1P inhibits invasion. In this study, we investigated the mechanisms through which S1P affects EOC cell proteolysis, invasion, and adhesion in two cultured epithelial ovarian cancer cell lines. METHODS-G-proteinGi was inhibited by pertussis toxin (PTX) and GTP binding protein Rac by NSC23766. S1P conditioned media of DOV13 and OVCA429 cells were evaluated via gel zymography, fluorometric gelatinase assay, urokinase plasminogen activator (uPA) activity assay, and Western Blot for MT1-MMP. Cell invasion was analyzed in Matrigel chambers. Membrane-N-cadherin was localized via fluorescence microscopy.RESULTS-Zymography revealed pro-MMP2 in conditioned media of EOC cells regardless of treatment. Gelatinase activity was increased by low-concentration S1P. In DOV13 cells this effect was Gi and Rac dependent. In all OVCA429 and control DOV13 cells, PTX enhanced gelatinolysis, suggesting an MMP2-inhibitory pathway via Gi. MT1-MMP was decreased Gidependently by high-concentration S1P. Rac inhibition significantly counteracted low-S1P enhancement and high-S1P reduction of DOV13 invasiveness; and uPA activity in conditioned media of invading cells correlated significantly. Immunohistochemistry revealed Gi-dependent clustering of membrane-N-cadherin in DOV13 cells treated with 0.5µM S1P or 10µM LPA.CONCLUSIONS-S1P influences EOC invasion by regulating ECM-proteolysis and cell-cell attachment via MMP2, uPA, and membrane-N-cadherin. Furthermore, this study illustrates that the net effect of S1P on each of these processes reflects a complex interplay of multiple GPCR pathways involving Gi and downstream Rac.

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“…Normally, they are expressed during embryonic stages and during processes of tissue remodeling, such as ovulation, endometrial cycling and wound healing (Nagase and Woessner, 1999;Brinckerhoff and Matrisian, 2002). MMPs are frequently overexpressed in a variety of human tumors (Edwards and Murphy, 1998;Egeblad and Werb, 2002) and are recognized as important players in many steps of the metastatic process (Freije et al, 2003;Yoon et al, 2003;DeClerck et al, 2004). In breast cancer, as well as in many other cancers, increased MMP expression and activation correlates with increased metastatic potential and poor prognosis (Ishigaki et al, 1999;Jones et al, 1999;Duffy et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

et al. 2005

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The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serumfree reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxiainduced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism.

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Roles of Matrix Metalloproteinases in Tumor Metastasis and Angiogenesis

Cited by 265 publications

References 70 publications

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

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