Human matrix metalloproteinases: an ubiquitarian class of enzymes involved in several pathological processes.

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs) We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC) It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC Their diagnostic sensitivity is consistently higher than those of conventional biomarkers The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future

https://www.mdpi.com/1422-0067/13/10/13240/pdf

The Behavior of Matrix Metalloproteinases and Their Inhibitors in Colorectal Cancer

Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7−181A>G. In addition, the genotype distribution of MMP-7−181A>G was associated with Helicobacter pylori status (χ2 7.8, P=0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2303C>T correlated significantly with the WHO classification (χ2 5.9, P=0.03) and also strongly with tumour-related survival (log rank 11.74, P=0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2−1306C>T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7−181A>G and TIMP-2303C>T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7−181A>G and TIMP-2303C>T, may be helpful in identifying gastric cancer patients with a poor clinical outcome.

/pdf/clinical-impact-of-mmp-and-timp-gene-polymorphisms-in-4440o06i51.pdf

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer.

Pancreatic cancer is a serious disease with poor patient outcome, often as a consequence of late diagnosis in advanced stages. This is in large part due to the lack of diagnostic tools for early detection. To address this deficiency, we have investigated novel molecular near-infrared fluorescent (NIRF) in vivo imaging techniques in clinically relevant mouse models of pancreatic cancer. Genome wide gene expression profiling was used to identify cathepsin cystein proteases and matrix metalloproteinases (MMP) as targets for NIRF imaging. Appropriate protease activatable probes were evaluated for detection of early-stage pancreatic cancer in mice with orthotopically implanted pancreatic cancer cell lines. Mice with pancreatitis served as controls. Whole body in vivo NIRF imaging using activatable cathepsin sensitive probes specifically detected pancreatic tumors as small as 1-2 mm diameter. Imaging of MMP activity demonstrated high specificity for MMP positive tumors. Intravital flexible confocal fluorescence lasermicroscopy of protease activity enabled specific detection of pancreatic tumors at the cellular level. Importantly, topical application of NIRF-probes markedly reduced background without altering signal intensity. Taken together, macroscopic and confocal lasermicroscopic molecular in vivo imaging of protease activity is highly sensitive, specific and allows discrimination between normal pancreatic tissue, inflammation and pancreatic cancer. Translation of this approach to the clinic could significantly improve endoscopic and laparoscopic detection of early-stage pancreatic cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.23780

Highly sensitive detection of early-stage pancreatic cancer by multimodal near-infrared molecular imaging in living mice.

Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer initiation and progression. Our previous studies revealed that the -1306C-->T and -735C-->T polymorphisms in MMP2 promoter significantly influence transcriptional activity and their genotypes and haplotypes are associated with susceptibility to several cancers. This case-control study examined the contribution of these two polymorphisms to the risk of developing lung cancer. MMP2 genotypes and haplotypes were determined in 770 cases and 777 controls and the associations with risk of lung cancer were estimated by logistic regression. We observed a 2-fold [odds ratio (OR), 2.12; 95% confidence interval (CI), 1.64-2.72] or 1.6-fold (OR, 1.57; 95% CI, 1.27-1.95) excess risk of developing lung cancer for the -1306CC or -735CC genotype carriers compared with non-carriers, respectively. A greater risk of lung cancer was associated with the C(-1306)-C(-735) haplotype (OR, 5.01; 95% CI, 2.57-9.78) compared with the T(-1306)-T(-735) haplotype, suggesting a synergic effect of these two polymorphisms. Furthermore, a greater than additive joint effect of the polymorphisms and smoking increased an even higher risk of lung cancer. The OR for smokers with the C(-1306)-C(-735) haplotype was 6.24 (95% CI, 4.51-8.64), which was significantly higher than that (OR, 4.10; 95% CI, 2.89-5.81) of smokers with the T(-1306) or T(-735)-containing haplotypes (P < 0.001). These results are consistent with our previous findings and further support the hypothesis that gain-of-function of MMP2 resulting from genetic polymorphisms plays an important role in human carcinogenesis.

/pdf/functional-haplotypes-in-the-promoter-of-matrix-fit4wpbs2w.pdf

Functional haplotypes in the promoter of matrix metalloproteinase-2 and lung cancer susceptibility.

A single nucleotide polymorphism in the matrix metalloproteinase-2 promoter is associated with colorectal cancer.

Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) play an important role in cancer initiation, invasion, and metastasis. The aim of this study was to investigate whether common genetic variants in these two key MMPs are associated with the development and progression of colorectal cancer in a Chinese population. We detected the MMP-2-790T/G, -955A/C, -1575G/A, and MMP-9-1562 C/T polymorphisms in 126 colorectal cancer patients and matched normal controls by PCR-denaturing high-performance liquid chromatography (DHPLC) or PCR-restriction fragment length polymorphism (RFLP), respectively. We found that the G/G genotype in the MMP-2-1575G/A polymorphism was significantly increased in colorectal cancer patients than in the controls (odds ratio (OR), 1.96; 95% CI, 1.06-3.64). Colorectal cancers with G/G genotype were more common with serosa/adventitia layer involvement than those with G/A+A/A genotypes (P<0.05). However, no significant differences were observed in distribution of the MMP-2-790T/G, -955A/C, and MMP-9-1562 C/T polymorphisms or haplotype of MMP-2 SNPs between patients and controls. Our results suggest that the presence of -1575G allele in the MMP-2 promoter region may be of significance in the assessment of colorectal cancer risk and invasive potential.

Association of matrix metalloproteinase-2 and -9 promoter polymorphisms with colorectal cancer in Chinese.

CDX2 has been shown to play an important role in the pathogenesis of colorectal cancer. The aim of this study was to investigate whether genetic variants in CDX2 contributed to the development and progression of colorectal cancer in a Chinese population. We detected the polymorphisms in the CDX2 coding regions in 126 patients with colorectal cancer and matched tumor-free subjects by PCR-based DHPLC. The correlation between the genotypes and clinicopathological parameters among colorectal cancer cases was also investigated. Three SNPs were identified in the coding region of the CDX2 gene. Neither the genotype frequencies nor allele frequencies of CDX2 polymorphisms showed significant difference from those in healthy controls. There were also no significant association between genotypes and clinicopathological features. When we examined the linkage disequilibrium between three SNPs using expectation-maximization algorithm, we found that there is strong linkage disequilibrium among these SNPs, but no significant difference was found in haplotypes distribution. Our present data suggest that the CDX2 polymorphisms may not be used as a useful marker to predicate susceptibility of colorectal cancer in Chinese.

No association between the polymorphisms in CDX2 coding regions and colorectal cancer in Chinese

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A single nucleotide polymorphism in the matrix metalloproteinase-2 promoter is associated with colorectal cancer.

Association of matrix metalloproteinase-2 and -9 promoter polymorphisms with colorectal cancer in Chinese.

No association between the polymorphisms in CDX2 coding regions and colorectal cancer in Chinese