Systemic Protein Biomarkers, Composite Blood Inflammatory Indices and Cellular Ratios in Metastatic Colorectal Cancer: Potential Therapeutic Targets

Abstract

Background/objectives: Although informative, current insights into the inflammatory nature of colorectal cancer (CRC) have yet to have a meaningful impact on the prevention of, and development of novel therapies for, the treatment of this prevalent and challenging disease. Accordingly, the current study was focused on identifying putative, key, systemic, mostly pro-inflammatory biomarkers of metastatic CRC (mCRC) prognosis and outcome. Methods: Patients with mCRC (n = 38) and matched healthy controls (n = 30) were recruited to the study. A multiplex magnetic bead array system and an ELISA procedure were used to measure the plasma concentrations of selected cytokines (n = 25) and that of C-reactive protein (CRP) by immunonephelometry. Systemic inflammatory indices (n = 5) were derived from the hematological data. Results: Plasma levels of 17/25 of the cytokine biomarkers and CRP were found to be significantly elevated, while the neutrophil/lymphocyte ratio proved to be the most useful of the various inflammatory indices. Subgroup analysis of the data derived from the group of mCRC patients revealed that the intensity of the systemic inflammatory response was mostly unaffected by tumor location, age, gender, and treatment line. The exception was time to progression, with a shorter time (<120 days) being associated with increased levels of IL-6, IL-8 and TNF-α. Hierarchical cluster analysis of the data revealed a possible association with a small group of four cytokines, comprising IL-1β, IL-13, IL-6/CRP and TGF-β1. Conclusions: This study confirms a strong association of established mCRC with cytokine-driven systemic inflammation. Four of these cytokines, IL-1β/IL-13 IL-6/CRP, and TGF-β1, appear prominent and are possibly indicative of novel targetable therapeutic options.