Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-α (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC.MethodsFAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line).ResultsStromal FAP expression was detected in 98 % (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb.ConclusionsThe present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma

“…Interestingly, FAP protease-mediated remodeling of the tumor stroma was shown to promote tumor cell migration (26). Coculture of 3T3 fibroblasts forced to express FAP was demonstrated to increase invasive ability of pancreatic cancer cells (27). Collectively, these data suggest that FAP may regulate early steps of the metastasis cascade, i.e., tumor cell dissemination and/or invasion.…”

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

“…Fibroblast activation protein (FAP, also known as FAPa or seprase) is a 95‐kDa type II integral serine protease on cell surface and was identified in 1986 . FAP belongs to the post‐proline dipeptidyl aminopeptidase family, which have activities of dipeptidyl peptidase and gelatinase and can cleave amino‐terminal dipeptides between proline and other amino acids through formation of 170‐kDa by homodimerization .…”

The role of stromal cancer-associated fibroblasts in pancreatic cancer

“…Kawase et al confirmed the role of FAP in cancer cell invasion and EMT and additionally showed its role in the activation of cell cycle progression by phosphorylation of Rb protein in PDAC cells. They also demonstrated that TGF-β, which has been linked to induction of EMT, induces FAP expression [41]. …”