The Behavior of MMP-2, MMP-7, MMP-9, and Their Inhibitors TIMP-1 and TIMP-2 in Adenoma-Colorectal Cancer Sequence

Abstract

<b><i>Background:</i></b> We and others have previously shown that matrix metalloproteinases (MMPs) play a role in colorectal cancer (CRC) invasion and metastasis. However, the serum changes of various MMPs and their inhibitors (TIMPs) have scarcely been concomitantly investigated in identical blood samples in the normal colon-adenoma-CRC sequence. <b><i>Methods:</i></b> The MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 serum antigen concentrations were determined concomitantly in 19 tumor-free control patients, 19 patients with high-risk colorectal adenoma, and 47 patients with CRC by ELISA technique. The analyzed parameters were also investigated in correlation with CRC stages. Statistical analysis with one-way ANOVA and Student’s <i>t</i> test was performed. <i>p</i> values &#x3c;0.05 were considered significant. <b><i>Results:</i></b> Serum antigen levels of MMPs and TIMPs were significantly increased in patients with CRC and adenomas compared to controls (mean values, ng/mL) (MMP-7: 5.88, 4.44, and 2.89, respectively, <i>p</i> = 0.001; MMP-9: 1,075.81, 999.22, and 845.97, respectively, <i>p</i> = 0.01; TIMP-1: 241.80, 205.98, and 166.53, respectively, <i>p</i> = 0.001; TIMP-2: 83.40, 80.30, and 69.62, respectively, <i>p</i> = 0.01). The elevated serum MMP-7, MMP-9, TIMP-1, and TIMP-2 levels significantly correlated with advanced tumor stages (<i>p</i> &#x3c; 0.05). No statistically significant differences were observed in MMP-2 levels. <b><i>Conclusions:</i></b> We demonstrate that serum antigen concentrations of MMP-7, MMP-9, TIMP-1, and TIMP-2 were significantly increased in patients with CRC and adenomas compared to controls. These results suggest that MMPs and their inhibitors TIMP-1 and TIMP-2 play an important role in CRC invasion; however, they are also activated in premalignant adenomas. Furthermore, MMP-7, MMP-9, TIMP-1, and TIMP-2 may have a potential prognostic impact in CRC.