Serological Biomarkers Reflecting Collagen Remodeling of the Tumor Microenvironment Are

Serological biomarkers reflecting collagen remodeling of the tumor microenvironment are elevated in metastatic colorectal cancer

Kehlet S.N., Sanz-Pamplona R., Leeming D.J., Karsdal M.A., Moreno V.

Background: The local microenvironment of a tumor plays an important role in colorectal cancer development. One of the hallmarks of colorectal cancer is abnormal remodeling of the extracellular matrix within the tumor microenvironment resulting in increased collagen deposition (desmoplasia) and increased matrix metalloproteinase (MMP) activity. This leads to the release of protein degradation fragments into the circulation.

We investigated the potential of disease relevant fragments of collagen type I, III and IV as novel serological biomarkers for colorectal cancer.

Methods: The level of biomarkers reflecting MMP-mediated degradation of type I (C1M), type III (C3M) and type IV (C4M) collagen and the formation of type III (Pro-C3) collagen were measured in serum from patients diagnosed with colorectal cancer (n=196, stage I-IV), subjects with adenomas (n=99, low risk-high risk) and age matched healthy controls (n=99). The levels of the individual biomarkers were compared using ANCOVA to adjust for age and gender on normalized data. Area under the receiver operating characteristics (AUROC) and logistic regression modeling were carried out to evaluate the discriminative power of the biomarkers.

Results: Circulating levels of C1M, C3M and Pro-C3 were significantly elevated in colorectal cancer patients compared to subjects with adenomas (C1M and Pro-C3: p<0.0001, C3M: p<0.01) and healthy controls (C1M and Pro-C3: p<0.01, C3M: p<0.05). When patients were stratified according to their stage, all four biomarkers were able to differentiate stage IV patients from all other stages, adenomas and healthy controls (p<0.05-0.0001). Pro-C3 and C1M had the highest diagnostic accuracy in relation to identifying metastatic tumors from non-metastatic tumors with an AUROC of 0.80 and 0.78, respectively. When all biomarkers were combined the diagnostic power was improved (AUROC=0.85).

Conclusion: In the present study we showed that specific serum biomarkers, reflecting collagen remodeling in the tumor microenvironment, could separate metastatic colorectal cancer patients from non-metastatic patients with high diagnostic power. This suggests that ECM remodeling is a key event in colorectal cancer development and biomarkers reflecting altered disease pathogenesis may increase the understanding of disease mode of action and provide a clinical tool for stratifying and monitoring patients according to disease severity.