Serum MMP-8 and TIMP-1 predict prognosis in colorectal cancer

Abstract

BackgroundAlmost all of the extracellular matrix (ECM) components can be degraded by the endoproteinases matrix metalloproteinases (MMPs). Important regulators of MMPs, and thereby of the extracellular environment, are tissue inhibitors of metalloproteinases (TIMPs), and especially TIMP-1. Early tumor development, as well as distant metastasis, may be results of an MMP/TIMP ratio imbalance altering the ECM. MMPs are elevated in several inflammatory conditions. Our aim is to investigate the prognostic role of MMP-8, − 9, and TIMP-1 in colorectal cancer (CRC) and their relationship to inflammation.MethodsWe included 337 colorectal cancer patients and 47 controls undergoing surgery at Helsinki University Hospital in Finland, 1998–2011. Serum levels of MMP-8 and plasma levels of C-reactive protein (CRP) were determined with a time-resolved immunofluorometric assay (IFMA), and MMP-9 and TIMP-1 with commercial enzyme-linked immunosorbent assay (ELISA) kits. Association and correlation analyses were performed with the Mann-Whitney U, Kruskal-Wallis, and Spearman rank correlation tests. Survival curves were constructed according to the Kaplan-Meier method and compared with the log-rank test.ResultsAmong patients with advanced disease, serum levels of MMP-8 and TIMP-1 were elevated. CRC patients with high MMP-8 (HR (hazard ratio) 1.72, 95% confidence interval (CI) 1.17–2.52, P = 0.005) and those with high TIMP-1 (HR 1.80, 95% CI 1.23–2.64, P = 0.002) had worse prognoses. MMP-9 level failed to serve as a prognostic factor. In multivariable survival analysis, Dukes stage, and low MMP-9/TIMP-1 molar ratio (HR 0.46, 95% CI 0.33–0.98, P = 0.042) were independently predicted prognosis. A weak correlation between CRP and MMP-8 (rS = 0.229, P < 0.001), and TIMP-1 (rS = 0.280, P < 0.001) was noted. Among patients showing no systemic inflammatory response, MMP-8 (HR 1.66, 95% CI 1.10–2.53, P = 0.017) and TIMP-1 (HR 1.59, 95% CI 1.05–2.42, P = 0.029) were prognostic factors.ConclusionsMMP-8 and TIMP-1 in serum, but not MMP-9, identified CRC patients with bad prognosis. Among patients showing no systemic inflammatory response, MMP-8 and TIMP-1 may associate with poor prognosis.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4589-x) contains supplementary material, which is available to authorized users.

Colorectal Cancer Cells Adhere to Traumatized Peritoneal Tissue in Clusters, An Experimental Study

“…MMP-2 in plasma increases with CRC tumour stage and there is a significantly higher concentration in the plasma of CRC patients compared to healthy controls 102 . Furthermore, the serum concentration of MMP-8 in patients with colorectal cancer has been found to correlate with survival 105,106 . Patients with CRC and a high expression of MMP-1 in tumour-free intestinal mucosa have poorer cancer-specific survival (CCS) compared to patients with low MMP-1 expression 107 .…”

“…In paper III the prognostic value of MMP measured in circulating plasma was evaluated and MMP-1 was found to have an impact of cancer specific survival. MMP concentrations in systemic blood have earlier been studied regarded colorectal cancer survival; this is shown in MMP-2, MMP-7, MMP-8 and MMP-9 where concentrations were measured in serum 101,105,106,139,140 . However, paper III studied levels of MMP in plasma samples that are known to be more stable than, serum 141 .…”

RNA cargos in extracellular vesicles derived from blood serum in pancreas associated conditions

“…While MMP 8 has been implicated in acute pancreatitis 39 its function in PDAC is unclear. A different study suggested that MMP8 could also function as a predictive biomarker in serum for colorectal cancer 40 . Another coding transcript, TBX3 is also highly represented in PDAC exosome compared to healthy and IPMN serum.…”

Identification of hub genes in colon cancer via bioinformatics analysis

“…Tissue inhibitor of metalloproteinases (TIMP-1), one of the most important regulators of matrix metalloproteinases (MMPs), is markedly increased in malignant tissue 18 and expressed in fibroblast-like cells located at the invasive front. 19 TIMP-1 is also associated with poor prognosis in colon cancer patients 20 and positively correlates with lymph node metastasis and Dukes classification. 21 TIMP-1 can promote the migration and invasion of cancer cells via reduction of cell apoptosis and activation of cell growth.…”