The expression of matrix metalloproteinase 9 and cathepsin B in gastric carcinoma is associated with lymph node metastasis, but not with postoperative survival.

Czyżewska, Jolanta; Guzińska‐Ustymowicz, Katarzyna; Kemonä, A; Bandurski, Roman

doi:10.2478/v10042-008-0007-6

Cited by 31 publications

(28 citation statements)

References 29 publications

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“…For instance, in the analysis of gastric carcinomas, high expression of cathepsin B, but not MMP9, was a statistically significant parameter in the depth of tumor invasion. 64 Interestingly, there are some indications that success of therapeutic trials targeting MMP activity is linked to the lack of cathepsin B in the tumors. For example, inhibition of MMP activity in renal cell carcinoma, a type of cancer with exceptionally low levels of cathepsin B, 65 was one of the rare MMPI trials where the overall survival of the patients was significantly prolonged.…”

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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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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“…one thousand cells of each section were randomly selected and counted blindly. the positive percentage of counted cells was semi-quantitated according to a 2-tier scoring system: weakly positive, 1-40%; and strongly positive, 41-100% (16). the slides were photographed under a nikon eclipse te2000-s Inverted microscope (magnification, x200).…”

Section: Methodsmentioning

confidence: 99%

“…the correlation between sialic acids content and tumor metastatic potential has been reported in many tumors and has received much attention recently. It has been proven that aberrant expression of terminal sialic acids, and in particular α2,3-sialic acids are related to tumor adhesion and invasion (5,6). High levels of sialylation of cell surface glycoconjugates could significantly increase metastasis of colon carcinoma cells and human melanoma cells (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of the α2,3-sialic acid residues in breast cancer is associated with metastatic potential

Cui

Lin²,

Yue³

et al. 2011

Oncol Rep

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Abstract. Aberrant sialylation is closely associated with the malignant phenotype of cancer cells and metastatic potential. However, the precise nature of the molecules in breast cancers has not been unveiled. In this study, we investigated the expression levels of α2,3-sialic acid residues of 50 primary tumor cases, 50 pair-matched lymph node metastasis tumor samples and in the MDA-MB-231, t-47D and McF-7 breast cancer cell lines with different metastatic potential. the expression of α2,3-sialic acid residues was analyzed by histochemistry, cytochemistry and flow cytometry with Maackia amurensis lectin (MAl). the invasion and migration abilities of cells were examined using cell adhesion and transwell in vitro assays. pair-matched lymph node metastasis tumor samples exhibited higher levels of expression of α2,3-sialic acid residues compared to that of primary tumors (p=0.0432). Furthermore, of 38 tumors cases in t1/t2 stages, 31 (81.58%) had weak staining for MAL, which specifically binds to α2,3-sialic acid residues, whereas of 12 tumor cases in t3/t4 stages, only 1 (8.33%) had weak reactions for MAl. the highly metastatic breast cancer cell line MDA-MB-231 exhibited the strongest binding to MAl and the highest expression levels of α2,3-sialic acid residues among the selected cell lines, depending on mrnA expression levels of α2,3-sialyltransferase gene. the adhesion, invasion and migration activities confirmed that MDA-MB-231 exhibited the greater cell adhesion to, migration toward and invasion to Matrigel. taken together, the high expression of α2,3-sialic acid residues in breast cancer was associated with metastatic potential. this property may be important for developing new therapeutic approaches for breast cancer.

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“…Finally, 11 studies (Sier et al, 1996;Zhang et al, 2003;Wang et al, 2005;Mrena et al, 2006;Zheng et al, 2006;De Mingo et al, 2007;Czyzewska et al, 2008;Chu et al, 2010;Peng et al, 2010;Renet al, 2010;Yang et al, 2010) were eligible for meta-analysis. The main features of the eligible studies for MMP-9 were summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Immunohistochemistry was the mostly common technique used to detect MMP-9 expression with formalinfixed, paraffin-embedded tissue specimens, in two trails (Sier C et al, 1996;De Mingo et al, 2007), authors used ELISA to assess MMP-9. Different antibodies were used to detect MMP-9 expression with immunohistochemistry: three ( (Mrena et al, 2006;Chu et al, 2010) used an anti-rabbit antibody, five (Zhang et al, 2003;Wang et al, 2005;Czyzewska et al, 2008;Peng et al, 2010;Ren et al, 2010) used a monoclonal antibody and two (Mrena et al, 2006;Chu et al, 2010) used an polyclonal antibody. In one trial (Yang et al, 2010), authors evaluated positive expression of MMP-9 mRNA with MMP-9 (MK 1540) nucleotide probe (Boster Biological Technology Limited Company, Wuhan, China) to analyze its prognostic value.…”

Section: Figure 1 Methodological Flow Chart Of the Systematic Reviewmentioning

confidence: 99%

Matrix Metalloproteinase-9 as a Prognostic Factor in Gastric Cancer: A Meta-Analysis

Zhang

Liu²,

Chen³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. Method: We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. Results: A total of 11 studies, covering 1700 patients, were included for metaanalysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). Conclusions: Our findings suggested that MMP-9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics.

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The expression of matrix metalloproteinase 9 and cathepsin B in gastric carcinoma is associated with lymph node metastasis, but not with postoperative survival.

Cited by 31 publications

References 29 publications

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

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

Differential expression of the α2,3-sialic acid residues in breast cancer is associated with metastatic potential

Matrix Metalloproteinase-9 as a Prognostic Factor in Gastric Cancer: A Meta-Analysis

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