The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

Abstract

Cancer-associated fibroblasts are abundant in the desmoplastic stroma of pancreatic ductal adenocarcinomas and are considered to play important roles in tumor progression. In this study, we investigated the expression status of secreted protein acidic and rich in cysteine, periostin, fibroblast-activated protein, and the newly developed proCOL11A1 antibody in the stroma of surgically resected pancreatic ductal adenocarcinomas and their prognostic implications. Tissue microarrays were constructed from 155 surgically resected pancreatic ductal adenocarcinomas and paired non-neoplastic pancreata and from another independent set of 48 normal/benign pancreata, and immunohistochemical stains were performed for proCOL11A1, fibroblast-activated protein, secreted protein acidic and rich in cysteine, and periostin. The immunohistochemical stain results were correlated with clinicopathological features and survival data. proCOL11A1, fibroblast-activated protein, secreted protein acidic and rich in cysteine, and periostin expression was significantly increased in the intratumoral stroma of pancreatic ductal adenocarcinomas compared to paired non-neoplastic pancreata (proCOL11A1: 145/155 (93.5%) vs 26/154 (16.9%); fibroblast-activated protein: 139/143 (97.2%) vs 82/132 (62.1%); secreted protein acidic and rich in cysteine: 113/150 (75.3%) vs 49/132 (37.1%); periostin: 135/151 (89.4%) vs 45/135 (33.3%); p < 0.001, all). While the four markers were expressed at lower levels in normal/benign pancreata, there were no significant differences in the expression frequencies among normal pancreas, acute pancreatitis, and chronic pancreatitis. Interestingly, on survival analysis, low intratumoral fibroblast-activated protein cancer-associated fibroblast counts (<100/high-power field) were associated with a significantly reduced overall survival compared to those with high fibroblast-activated protein cancer-associated fibroblast counts (p = 0.010; hazard ratio 5.2 (95% confidence interval 1.3-21.3)). Similar patterns were seen for proCOL11A and secreted protein acidic and rich in cysteine and overall and disease-free survival, although not statistically significant. In conclusion, we demonstrate that the presence of cancer-associated fibroblasts in the tumor stroma may not always be associated with a poor prognosis as suggested in many studies; on the contrary, it may even be associated with prolonged survival, supporting the recent experimental findings that tumor stroma may have a protective role rather than enhance aggressive behavior.

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

“…In addition, Rhim et al 76 demonstrated that PDAC tumors exhibited enhanced malignant biological behaviors and increased vascularity through genetic abortion of SHH in mouse models, indicating that stromal components may to some extent restrain the development of PDAC. In accordance with these experimental results, a recent study conducted on 155 surgically resected PDACs and 48 normal/benign pancreas samples, showed that the presence of more FAP + CAFs (>100/high-power field) in the TME correlated with prolonged survival, rather than being a marker of poor prognosis as indicated in most previous studies 115 . Discussion has thus been initiated regarding whether the PDAC stroma represents a 'friend or foe'.…”

Inter‐ and intra‐tumoural heterogeneity in cancer‐associated fibroblasts of human pancreatic ductal adenocarcinoma

“…So far, studies of CAF subpopulations in PDAC and other cancers have been mainly descriptive and relied on previously reported stromal markers [6,7,[46][47][48]. Although IHC analyses, using multiple CAF markers, confirmed the positivity of most PDAC tumour samples for these proteins, these authors did not demonstrate the simultaneous existence of spatially distinct CAF subpopulations (i.e.…”

“…Although IHC analyses, using multiple CAF markers, confirmed the positivity of most PDAC tumour samples for these proteins, these authors did not demonstrate the simultaneous existence of spatially distinct CAF subpopulations (i.e. intra‐tumour heterogeneity) and did not explore their functions . Ikenaga et al showed the presence of two subpopulations of CAFs in human PDAC stroma (CD10‐positive and CD10‐negative), with the former having a more pro‐tumoural role.…”

Higher Tumor Cellularity in Resected Pancreatic Ductal Adenocarcinoma Is a Negative Prognostic Indicator

“… 26 In contrast, our previous study of a subset of PDA cases revealed that high cancer-associated fibroblast (CAF) counts were associated with significantly better survival outcomes, which supports recent experimental findings that the tumor stroma may have a protective role rather than an enhancing role for any aggressive behavior. 27 - 30 Because the influence of PDA tumor cellularity on patient survival and response to chemotherapy is unclear, the present study focused on the epithelial cell compartment of PDA. However, we did not find significant inverse correlations between the expression of CAF-related markers and tumor cellularity (data not shown), which is unsurprising because the tumor microenvironment is a complex network of many cell types (e.g., fibroblasts, endothelial cells, and inflammatory cells) interacting with the extracellular matrix.…”