Opposing prognostic roles of tumor-associated and circulating MMP8 in colorectal cancer

Local and systemic inflammation play key roles in colorectal cancer (CRC). Matrix metalloproteinase 8 (MMP8), an enzyme involved in extracellular matrix remodeling, has been linked to both inflammatory processes and cancer progression. This study investigates MMP8 serum concentration and MMP8 expression within the tumor microenvironment, and their relationship with tumor characteristics, inflammation, and survival. The study included 776 stage I-IV CRC patients. MMP8+ cell densities within tumors were analyzed using immunohistochemistry combined with digital image analysis, while preoperative serum MMP8 levels were analyzed using an immunofluorometric assay. Survival analyses were performed using the Kaplan-Meier method and Cox regression models. Correlations with systemic inflammatory markers and immune cell densities were assessed using linear regression models. We found that MMP8 was predominantly expressed by CEACAM8+ granulocytes. High MMP8+ cell density within tumors was associated with favorable prognostic factors, including low disease stage, absent lymphovascular invasion, and mismatch repair (MMR) deficiency, but also with improved cancer-specific survival independent of these factors. The multivariable HR for low (vs. high) MMP8+ cell density was 1.76 (95%CI 1.18–2.60). MMP8+ cell density positively correlated with T-cell densities, but not with serum MMP8 levels or conventional systemic inflammation markers. In contrast, high serum MMP8 levels were associated with systemic inflammation and worse survival, but did not remain an independent prognostic factor in multivariable models. In conclusion, serum MMP8 levels do not correlate with MMP8 expression in the tumor microenvironment, suggesting distinct roles for circulating and tumor-associated MMP8 in CRC progression. High MMP8+ cell densities within tumors are associated with better prognosis and local immune activity, while elevated serum MMP8 levels indicate systemic inflammation and advanced disease.