Overexpression of COL11A1 by Cancer-Associated Fibroblasts: Clinical Relevance of a Stromal Marker in Pancreatic Cancer

Abstract

BackgroundThe collagen11A1 (COL11A1) gene is overexpressed in pancreatic cancer. The expression of COL11A1 protein could be involved in desmoplastic events in pancreatic cancer, but an antibody that specifically stains the COL11A1 protein is not currently available.Methods and findingsA total of 54 pancreatic ductal adenocarcinomas (PDAC), 23 chronic pancreatitis (CP) samples, and cultured peritumoral stromal cells of PDAC (passages 3-6) were studied. Normal human pancreas tissue samples were obtained through a cadaveric organ donation program.1) Validation of COL11A1 gene overexpression by q-RT-PCR. Findings: the expression of COL11A1 gene is significantly increased in PDAC samples vs. normal and CP samples.2) Analysis of COL11A1 by immunohistochemistry using highly specific anti-proCOL11A1 antibodies. Findings: anti-proCOL11A1 stains stromal cells/cancer-associated fibroblasts (CAFs) of PDAC but it does not stain chronic benign condition (chronic pancreatitis) stromal cells, epithelial cells, or normal fibroblasts.3) Evaluation of the discrimination ability of the antibody. Findings: anti-proCOL11A1 immunostaining accurately discriminates between PDAC and CP (AUC 0.936, 95% CI 0.851, 0.981).4) Phenotypic characterization of proCOL11A1+ stromal cells co-staining with mesenchymal, epithelial and stellate cell markers on pancreatic tissue samples and cultured peritumoral pancreatic cancer stromal cells. Findings: ProCOL11A1+ cells present co-staining with mesenchymal, stellate and epithelial markers (EMT phenotype) in different proportions.Conclusions/SignificanceDetection of proCOL11A1 through immunostaining with this newly-developed antibody allows for a highly accurate distinction between PDAC and CP. Unlike other available antibodies commonly used to detect CAFs, anti-proCOL11A1 is negative in stromal cells of the normal pancreas and almost absent in benign inflammation. These results strongly suggest that proCOL11A1 is a specific marker for CAFs, and thus, anti-proCOL11A1 is a powerful new tool for cancer research and clinical diagnostics.

Tumor matrix protein collagen XIα1 in cancer

“…ColXIα1 was found to be more highly expressed by TAFs isolated from HNSCC explants than in normal fibroblasts derived from cancer-free patients 40 . Immunohistochemical studies in pancreatic cancer have also suggested that colXIα1 may be a marker capable of differentiating TAFs from normal activated fibroblasts, a distinction which has been elusive so far 47 . In ovarian cancer studies, colXIα1 expression was mainly confined to stromal cells, specifically to the intra/peritumoral stromal cells, and not expressed >1 mm from epithelial tumor cells, indicating again that colXIα1 is a specific marker for TAFs, and potentially for malignant cells undergoing EMT 30 .…”

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

“…Collagens are the major structural component of the tumor microenvironment and have emerged as an important contributor to cancer cell chemoresistance. Collagen type XI alpha 1 (COL11A1), a minor fibrillar collagen crucial for skeletal development and collagen fiber assembly, is a novel biomarker associated with poor survival and chemoresistance in several cancer types including ovarian cancer [25][26][27][28][29] . COL11A1 expression is increased during ovarian cancer progression with the highest expression in cisplatin-resistant recurrent tumors 27 .…”

“…COL11A1 expression is increased during ovarian cancer progression with the highest expression in cisplatin-resistant recurrent tumors 27 . COL11A1 is expressed and secreted by a subset of cancer-associated fibroblasts (CAFs) adjacent to tumor cells and a small number of cancer cells including A2780cis cisplatin-resistant ovarian cancer cell line [25][26][27]30 . We have previously shown that COL11A1 confers cisplatin resistance by engaging α1β1 integrin and Discoidin domain receptor 2 (DDR2) on ovarian cancer cells to activate c-Src-Akt-NFkB signaling to induce inhibitor of apoptosis proteins (IAPs) 31 .…”

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

“…5,6 Within this intra-tumor microenvironment compartment, non-cellular components such as extracellular matrix (ECM), to which both tumor cells and stroma contribute, are largely described and correlate with tumor aggressiveness and tumor cell abilities. 7,8 ECM proteins, such as hyaluronic acid, were shown to act as a barrier to perfusion because of compression of pancreatic tumor blood vessels limiting the amount of drug reaching the tumor cells. 9 Among these ECM proteins, the transforming growth factor-β (TGF-β) acts in PDA as a potent tumor suppressor and tumor promoter in a contextdependent manner.…”