Prognostic value of blood-based fibrosis biomarkers in patients with metastatic colorectal cancer receiving chemotherapy and bevacizumab

Abstract

A desmoplastic colorectal cancer stroma, characterized by excess turnover of the cancer-associated fibroblast derived collagens type III and VI, can lead to reduced drug-uptake and poor treatment response. We investigated the association between biomarkers of collagen type III and VI and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Serum samples were collected from 252 patients with mCRC prior to treatment with bevacizumab and chemotherapy. Serum concentrations of biomarkers reflecting formation of collagen type III (PRO-C3) and VI (PRO-C6) and degradation of collagen type VI (C6M and C6Mα3) were determined by ELISA. The biomarkers were evaluated for associations with OS, individually, combined, and after adjusting for carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH) and performance status (PS). High baseline levels (> median) of each collagen biomarker were significantly associated with shorter OS (PRO-C3: HR = 2.0, 95%CI = 1.54–2.63; PRO-C6: HR = 1.6, 95%CI = 1.24–2.11; C6M: HR = 1.4, 95%CI = 1.05–1.78; C6Mα3: HR = 1.6, 95%CI = 1.16–2.07). PRO-C3 and PRO-C6 remained significant after adjustment for CEA, LDH and PS. Weak correlations were seen between the collagen biomarkers (r = 0.03–0.59) and combining all improved prognostic capacity (HR = 3.6, 95%CI = 2.30–5.76). Collagen biomarkers were predictive of shorter OS in patients with mCRC. This supports that collagen- and CAF biology is important in CRC.

Extracellular Matrix Biomarkers in Colorectal Cancer

“…Moreover, among the formation of collagen type III (PRO-C3), VI (PRO-C6), and degradation of collagen type VI (C6M and C6Mα3), PRO-C3 was the most effective in predicting the survival outcome of metastatic colorectal cancer (mCRC) patients regardless of other risk factors [47]. In another study, specific fragments of degraded type I, III, and IV collagen and type III collagen formation in serum showed that stage IV metastatic patients could be distinguished from all other stages [42].…”

Collagen Biomarkers Quantify Fibroblast Activity In Vitro and Predict Survival in Patients with Pancreatic Ductal Adenocarcinoma

“…During the past few years, biomarkers originating from the fibrotic TME have gained more attention [18]. We and others have shown that non-invasive biomarkers measuring ECM turnover products from fibroblast-derived collagens are increased in various cancer types and predictive of survival and treatment response [19][20][21][22][23][24][25]. As an example, PRO-C11-511, a biomarker measuring the pro-peptide of type XI collagen has shown to be increased in serum from patients with PDAC and is predictive of survival [24].…”

“…In addition, C4G, a biomarker measuring granzyme B degraded type IV collagen, assesses T-cell response and can identify patients with malignant melanoma responding to immune checkpoint inhibitors [19]. Fibrillar collagens are the most well-studied collagens, and the two fibrillar fibroblast-derived collagens, type IIIand VI collagen, have shown potential as biomarkers in cancer [19,20,22,23,25,26]. Type III and VI collagens are present in most tissue within the interstitial matrix of the ECM and are augmented in many cancer diseases [20,[27][28][29][30][31][32][33][34].…”

COL6A6 inhibits the proliferation and metastasis of non-small cell lung cancer through the JAK signalling pathway

“…The COL6 family plays a critical role in cell adhesion ( 17 , 18 ), apoptosis, autophagy ( 19 ), and dystrophy ( 20 ). Interestingly, some members are involved in the growth and development of tumors ( 21 , 22 ). In previous studies, COL6A6 has been shown to be a cancer suppressor gene that acts as an independent prognostic marker for pituitary adenomas.…”