Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer

Sillanpää, Sari; Anttila, Markku; Voutilainen, Kirsi; Ropponen, Kirsi; Turpeenniemi‐Hujanen, Taina; Puistola, Ulla; Tammi, Raija; Tammi, Markku; Sironen, Reijo; Saarikoski, Seppo; Kosma, Veli‐Matti

doi:10.1016/j.ygyno.2006.09.004

Cited by 70 publications

(72 citation statements)

References 31 publications

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“…Because MMPs resolve ecM, the MMP increase is necessary to acquire a potent invasive potential. among MMP subtypes, MMP-9 is closely associated with poor outcome in ovarian cancer (22) and its expression level is significantly stronger as lesions progressed from a benign tumor to advanced carcinoma (23,24). earlier study showed that MMP-9 overexpression led to a loss of e-cadherin and promoted a migratory and invasive phenotype in ovarian cancer cells (25), supporting the present results.…”

Section: Altered Expression Of Vegf-c E-cadherin and Mmp-9 In The Tsupporting

confidence: 85%

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Osawa

Yokoyama

Shigeto

et al. 2014

International Journal of Oncology

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Abstract. carbonyl reductase 1 (cBr1) expression level is related to tumor progression. Decreased cBr1 expression is associated with poor prognosis in ovarian cancer. We investigated the relationship between cBr1 expression level and malignant potential of ovarian cancer. oVcar-3 cells overexpressing cBr1 or knocked down for cBr1 were obtained by transfecting cBr1 plasmid Dna (pDna) or small interfering rna (sirna) by electroporation. In vitro cell proliferation and invasion were compared between the two cell types. Subcutaneous cBr1-overexpressed oVcar-3 cells (n=10) and wild-type ones (n=5) were injected into nude mice. the cBr1 sirna was then injected twice a week into five of the 10 CBR1-overexpressed OVCAR-3 tumors. Tumor growth and metastatic behavior were observed 3 weeks after cell transplantation. cell proliferation significantly decreased in cBr1-overexpressed cells as compared to the control, whereas cell proliferation and invasion significantly increased in cBr1-suppressed cells as compared to the control. the size of the cBr1 sirna-injected tumors (n=5) increased significantly as compared to the other two groups (n=5 for each group). the number of metastatic foci in the lungs was significantly higher in mice injected with cBr1 sirna (7.0±2.0) compared to cBr1-overexpressed and wild-type tumors (0 and 2.0±2.0, respectively). Western blot analysis showed that, while vascular endothelial growth factor (Vegf)-c expression was stable in the cBr1-sirna-injected tumors, e-cadherin expression was decreased, whereas matrix metalloproteinase (MMP)-9 was increased in cBr1-sirna-injected tumors compared to the other two groups. these results showed that cBr1 decreases promoted tumor proliferation and growth as well as invasion and metastasis, suggesting that cBr1 has potential to become a new candidate for molecular targeting therapy.

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Section: Altered Expression Of Vegf-c E-cadherin and Mmp-9 In The Tsupporting

confidence: 85%

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Osawa

Yokoyama

Shigeto

et al. 2014

International Journal of Oncology

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“…It was previously suggested that the source of protease expression might affect not only the levels of the enzyme per se but also its pro-tumorigenic activity. 8,14 For example, epithelial cancer cell versus stromal cell expression of MMP has differential prognostic correlation with overall survival in cases of epithelial ovarian cancer. 8 The MMP and cathepsin families are joined in a complicated network of protease activity in tissues (for review, see Levicar et al 63 ).…”

Section: Discussionmentioning

confidence: 99%

“…8,14 For example, epithelial cancer cell versus stromal cell expression of MMP has differential prognostic correlation with overall survival in cases of epithelial ovarian cancer. 8 The MMP and cathepsin families are joined in a complicated network of protease activity in tissues (for review, see Levicar et al 63 ). It is apparent that MMP9 and cathepsin B differ in their pro-invasive capacity.…”

Section: Discussionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1b-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumorassociated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.60Keywords: tumor; metalloproteinase; invasion; cathepsin; Myc; interleukin-1b INTRODUCTIONMatrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates. Owing to the role of MMP in extracellular matrix (ECM) re-arrangement (also referred to as remodeling or degradation), and in the promotion of neoangiogenesis, it was anticipated that MMP inhibition in vivo would have an anti-tumorigenic effect. However, phase III clinical trials with an MMP inhibitor (MMPI), combined with standard-of-care chemotherapy, failed to demonstrate clinical benefit for late stage cancer patients and, remarkably, was in some cases worse than the chemotherapyonly control arm. For instance, the use of Bay 12-9566 in treating patients with pancreatic cancer reduced both median progressionfree survival and quality-of-life when compared with standard care gemcitabine.1 In another case, treatment of glioblastoma patients rendered no statistically significant survival benefits.2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely.3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outc...

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“…Duality of tumour MMP-9 levels with respect to survival has been recognised before in immunohistochemistry-based studies. For example, extensive MMP-9 staining in ovarian cancer cells was associated with a longer survival, as opposed to a shorter survival with a higher stromal expression of MMP-9 (Sillanpaa et al, 2007). Earlier morphometric studies indicated that the degree of MMP-9 expression in tumour-associated lymphocytes, macrophages and neutrophils was inversely associated with invasion and metastasis in colorectal cancer (Takeha et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

et al. 2008

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The prognostic significance of single-nucleotide polymorphisms (SNPs) and tumour protein levels of MMP-2 and MMP-9 was evaluated in 215 colorectal cancer patients. Single-nucleotide polymorphism MMP-2 À1306T and high MMP-2 levels were significantly associated with worse survival. Extreme tumour MMP-9 levels were associated with poor prognosis but SNP MMP-9 À1562C4T was not. Tumour MMP levels were not determined by their SNP genotypes.

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Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer

Cited by 70 publications

References 31 publications

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

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