Serum MMP-8 levels increase in colorectal cancer and correlate with disease course and inflammatory properties of primary tumors

Department of Pathology, Institute of Diagnostics, University of Oulu, Oulu, Finland.
International Journal of Cancer (Impact Factor: 5.09). 08/2012; 131(4):E463-74. DOI: 10.1002/ijc.26435
Source: PubMed


Matrix metalloproteinases (MMPs) form a family of zinc-dependent endoproteases participating in cancer pathogenesis by promoting invasion and regulating growth signaling, apoptosis, angiogenesis and immune responses. MMP-8 is an intriguing MMP with recently discovered antitumor activity and immunoregulatory properties, but its role in colorectal cancer (CRC) has not been studied extensively. Preoperative serum MMP-8 levels (S-MMP-8) of 148 CRC patients and 83 healthy controls were measured using an immunofluorometric assay and related to clinical and pathological parameters. The patients had higher S-MMP-8 than the controls (median 63.0 vs. 17.2 ng/ml, p = 1.5E - 9), and a receiver operating characteristics analysis yielded an area under the curve of 0.751 in differentiating the groups. In univariate analyses, S-MMP-8 correlated positively with disease stage (p = 4.5E - 4), the degree of primary tumor necrosis (p = 0.0024) and blood neutrophil count (Pearson r = 0.523, p = 2.5E - 9). Particular interest was also addressed to the inflammatory properties of the tumors, and both variables studied, peritumoral tumor-destructing inflammatory infiltrate and Crohn's-like lymphoid reaction (CLR), showed a negative correlation with S-MMP-8 (p = 0.041 and p = 0.0057, respectively). In a multiple linear regression analysis, high S-MMP-8 associated with elevated blood neutrophil count, distant metastases, low-grade CLR and low body mass index. Overall, our results indicate that MMP-8 is involved in the course and progression of CRC influencing the immune response against the tumor and contributing to the resolution of necrosis. Serum or plasma MMP-8 may prove to be a worthy biomarker for CRC.

Download full-text


Available from: Tuula Salo, Nov 12, 2014
  • Source
    • "All the cell counts were expressed as cells mm À 2 . The MMR screening status was evaluated by MLH1 and MSH2 immunohistochemistry as described earlier (Väyrynen et al, 2012a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Higher-grade inflammatory infiltrate is a promising marker for better prognosis in colorectal cancer (CRC). However, the knowledge on the interrelationships between different inflammatory cells and classifications is fragmentary. Methods: We analysed the densities of eight types of inflammatory cells in a prospectively recruited group of 117 CRC patients and determined their interrelationships and contributions to Klintrup–Mäkinen (K–M) score of overall peritumoural inflammation. We characterised the inflammatory infiltrate in relation to stage and recurrences in 24-month follow-up. Results: There were high positive correlations between the inflammatory cell densities, with the exception of mast cells and CD1a+ immature dendritic cells. High K–M score associated with high peri- and intratumoural densities of CD3+, CD8+, CD68+, CD83+, and FoxP3+ cells and neutrophils. Advanced stage associated with low K–M score, as well as low CD3+, CD8+, CD83+, and FoxP3+ cell counts, of which low K–M score, low CD3+ T-cell count, and low FoxP3+ T-cell count were linked to higher recurrence rate. Conclusion: The density of CRC inflammatory infiltrate declines as stage advances. Especially, low K–M score and low T-cell counts predict higher recurrence rate. The high positive correlations between the individual inflammatory markers support the value of overall inflammatory reaction scoring.
    Full-text · Article · Sep 2013 · British Journal of Cancer
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphoneuclear leukocytes or neutrophils, a major component of white blood cells, contribute to the innate immune response in humans. Upon sensing changes in the microenvironment, neutrophils adhere to the vascular wall, migrate through the endothelial cell (EC)-pericyte bilayer, and subsequently through the extracellular matrix to reach the site of inflammation. These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes. While primarily mediators of tissue homeostasis, there are an increasing number of studies indicating that neutrophil recruitment and transmigration can also lead to host-tissue injury and subsequently inflammation-related diseases. Neutrophil-induced tissue injury is highly regulated by the microenvironment of the infiltrated tissue, which includes cytokines, chemokines, and the provisional extracellular matrix, remodeled through increased vascular permeability and other cellular infiltrates. Thus, investigation of the effects of matrix proteins on neutrophil-EC interaction and neutrophil transmigration may help identify the proteins that induce pro- or anti-inflammatory responses. This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases. This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. For each disease model, inflammatory molecules released by neutrophils, important regulatory matrix proteins, current anti-inflammatory treatments, and the scope for further research will be summarized.
    Full-text · Article · Jun 2012 · The Yale journal of biology and medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC. Methods: Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland. Results: The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan-Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 (P=0.013 and P=0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio (P=0.004). Conclusion: Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC.
    Full-text · Article · Aug 2013 · Annals of Medicine
Show more