Circulating midkine in malignant and non-malignant colorectal diseases

•Midkine is higher in CRC than in non-malignant bowel diseases and healthy persons.•Midkine elevation reflects CRC stage, dedifferentiation, and metastasis.•Inflammatory IL-1β and angiogenic PDGF-BB are midkine independent predictors in CRC.•In the population under study, midkine was superior to CEA as CRC marker.•Midkine may contribute to multimarker panels devised for CRC screening and/or surveillance. Midkine is a multifunctional cytokine found to be a promising cancer biomarker, however, its suitability in colorectal cancer (CRC) has not been evaluated yet. We assessed midkine circulating levels immunoenzymatically in 105 CRC patients, 86 individuals with increased risk for CRC (56 with inflammatory bowel disease (IBD) and 30 with adenomas), and 70 healthy controls and compared its performance as CRC biomarker to carcinoembryonic antigen (CEA). Midkine was higher in CRC (807ng/L) than in IBD (477ng/L; 633ng/L in active and 335ng/L in inactive), adenomas (418ng/L) or controls (245ng/L). Its levels increased along with advancing CRC stage, being significantly higher compared to controls already in stage I, and dedifferentiation (higher in grade 3 than 1 and 2). Lymph node or distant metastases were associated with significant midkine elevation as well. Midkine positively correlated with IL-1β, IL-6, IL-8, TNF-α, MCP-1, MIP-1α, G-CSF, GM-CSF, VEGF-A, and PDGF-BB with IL-1β and PDGF-BB explaining 40% in its variability. Midkine was better marker of CRC than CEA with 80% accuracy, 83% sensitivity and 68% specificity as compared to 60%, 37%, and 88% of CEA, also in its early stages (74% vs. 52% accuracy). Midkine better differentiated CRC from inactive while CEA from active IBD. Midkine was included in the multimarker panel and significantly contributed to efficient (Λ=0.16) differentiation of healthy controls, adenomas and CRC. Concluding, midkine may lack sufficient specificity to be a sole CRC marker but seems to constitute a valuable addition to multimarker panels devised for CRC screening and/or surveillance.