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

Camilla Böckelman; Ines Beilmann-Lehtonen; Tuomas Kaprio; Selja Koskensalo; Taina Tervahartiala; Harri Mustonen; Ulf-Håkan Stenman; Timo Sorsa; Caj Haglund

doi:10.1186/s12885-018-4589-x

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

BMC Cancer. 2018 Jun 22;18(1):679. doi: 10.1186/s12885-018-4589-x.

Authors

Camilla Böckelman^{1

2}, Ines Beilmann-Lehtonen³, Tuomas Kaprio^{3

4}, Selja Koskensalo³, Taina Tervahartiala⁵, Harri Mustonen³, Ulf-Håkan Stenman⁶, Timo Sorsa^{5

7}, Caj Haglund^{3

4}

Affiliations

¹ Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland. camilla.bockelman@helsinki.fi.
² Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland. camilla.bockelman@helsinki.fi.
³ Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.
⁴ Research Programs Unit, Translational Cancer Biology, University of Helsinki, P.O. Box 105, Haartmaninkatu 4, Terkon tutkijatilat, 3. krs, FIN-00029 HUS, Helsinki, Finland.
⁵ Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Biomedicum Helsinki, P.O. Box 63, Haartmaninkatu 8, 2nd floor, FIN-00014, Helsinki, Finland.
⁶ Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, P.O. Box 700, FIN-00029 HUS, Helsinki, Finland.
⁷ Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.

Abstract

Background: Almost 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.

Methods: We 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.

Results: Among 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 (r_S = 0.229, P < 0.001), and TIMP-1 (r_S = 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.

Conclusions: MMP-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.

Keywords: Colon cancer; Colorectal cancer; MMP-8; MMP-9; Prognosis; Survival; TIMP-1.

MeSH terms

Aged
C-Reactive Protein / analysis
Colorectal Neoplasms / blood
Colorectal Neoplasms / mortality*
Colorectal Neoplasms / pathology
Female
Humans
Male
Matrix Metalloproteinase 8 / blood*
Matrix Metalloproteinase 9 / blood
Middle Aged
Prognosis
Proportional Hazards Models
Tissue Inhibitor of Metalloproteinase-1 / blood*

Substances

TIMP1 protein, human
Tissue Inhibitor of Metalloproteinase-1
C-Reactive Protein
MMP8 protein, human
Matrix Metalloproteinase 8
Matrix Metalloproteinase 9

Grants and funding

101032/Competitive State Research Financing of the Expert Responsibility Area of Turku University Hospital and Vaasa Central Hospital