Noninvasive prognostic biomarker potential of quantifying the propeptides of Type XI collagen alpha‐1 chain (PRO‐C11) in patients with pancreatic ductal adenocarcinoma

Abstract

Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the circulation after proteolytic processing at either amino acid 253 or 511. This allows for a noninvasive biomarker approach to quantify Type XI collagen production. We developed two ELISA‐based biomarkers, targeting the two enzymatic cleavage sites (PRO‐C11‐253 and PRO‐C11‐511). In a discovery cohort including serum from patients with PDAC (n = 39, Stages 1‐4), chronic pancreatitis (CP, n = 12) and healthy controls (n = 20), PRO‐C11‐511, but not PRO‐C11‐253, was significantly upregulated in patients with PDAC and CP compared to healthy controls. Furthermore, PRO‐C11‐511 levels >75th percentile were associated with poor overall survival (OS) (HR, 95% CI: 3.40, 1.48‐7.83). The PRO‐C11‐511 biomarker potential was validated in serum from 686 patients with PDAC. Again, high levels of PRO‐C11‐511 (>75th percentile) were associated with poor OS (HR, 95% CI: 1.68, 1.40‐2.02). Furthermore, PRO‐C11‐511 remained significant after adjusting for clinical risk factors (HR, 95% CI: 1.50, 1.22‐1.86). In conclusion, quantifying serum levels of Type XI collagen with PRO‐C11‐511 predicts poor OS in patients with PDAC. This supports that Type XI collagen is important for PDAC biology and that PRO‐C11‐511 has prognostic noninvasive biomarker potential for patients with PDAC.

The Functional Role of Extracellular Matrix Proteins in Cancer

“…Its alpha 1 chain (COL11A1) has been found to be upregulated in a variety of cancers [ 123 , 124 , 125 , 126 , 127 , 128 ] and is supposed to promote proliferation, angiogenesis, invasion and drug resistance of cancer cells [ 129 , 130 , 131 , 132 ]. Proteolytic products of type XI collagen released into the circulation can be used as predictive markers for patients with pancreatic ductal adenocarcinoma [ 133 ]. Type V collagen, another minor fibril-forming collagen, was also shown to be upregulated in squamous cell carcinoma, colorectal, gastric and breast cancer and associated with poor prognosis [ 134 , 135 , 136 , 137 ].…”

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].…”

“…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].…”

The role of network‐forming collagens in cancer progression

“…Previous studies have demonstrated that fibril-forming collagens, such as type I/III/XI collagens, can promote tumor progression and serve as prognostic markers. [9][10][11][12] Network-forming collagens, such as type IV, type VIII, and type X collagen, belong to the nonfibrillar collagens. These collagens can aggregate linearly and associate laterally to form open networks rather than fibers.…”