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Introduction: Diagnosis and monitoring of metastatic colorectal cancer (mCRC) depend on diagnostic imaging. Circulating carcinoembryonic antigen (CEA) can be analyzed but no optimal, non-invasive biomarker exists. Circulating collagen IV (COL IV) is a promising biomarker in patients with colorectal liver metastases (CLM). This study aimed to evaluate COL IV and other cancer-related and stroma-derived proteins as biomarkers for mCRC.

Materials & methods: Plasma COL IV and 10 other proteins were analyzed with ELISA and Luminex multiplex assays.

Results: mCRC patients have elevated levels of circulating COL IV, CEA, interleukin-8 (IL-8), hepatocyte growth factor (HGF), cytokeratin-19 fragments (CYFRA 21-1), osteopontin (OPN), and migration inhibitory factor (MIF) compared to primary CRC (pCRC) patients. COL IV is elevated in mCRC patients compared to healthy individuals. Levels of COL IV, CEA, OPN, CYFRA 21-1, IL-8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were dependent on the metastatic site. OPN, CEA, and HGF are very good at discriminating between mCRC patients and pCRC controls. COL IV is very good at distinguishing between mCRC patients and healthy controls. The combination of OPN + CEA is superior at detecting mCRC than CEA alone. High HGF and COL IV levels correlate to poor prognosis.

Conclusion: OPN, CEA, and HGF are potential biomarkers for mCRC. COL IV is a potential biomarker for CLM. The combination of OPN with CEA is superior to CEA alone in detecting mCRC. Levels of circulating proteins depend on metastatic localization, implying that a combination of markers is better than single markers in detecting mCRC disease. High levels of COL IV and HGF have potential prognostic value.