Different roles of cancer-associated fibroblasts in pancreatic cancer and biliary tract cancers cancer-associated fibroblasts as a tumor suppressor in biliary tract cancers

Background and aims: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and can exhibit cancer-promoting functions; however, recent studies indicate that CAFs can also inhibit cancer growth and progression. In this study, we identified CAFs that act in an inhibitory manner in biliary tract cancer and elucidated their mechanisms. Materials and Methods: We retrospectively evaluated alpha-smooth muscle actin (alphaSMA) expression in CAFs from 114 cases of pancreatic ductal carcinoma (PDAC) and 154 cases of biliary tract cancers (BTCs) who underwent surgical treatment at our institution from 1996 to 2017. The BTC cell lines, PDAC cell lines, and CAFs were isolated from resected specimens of BTC and PDAC were used to evaluate the proliferative potential of cancer cells. Conditioned media (CM) were prepared from CAFs (CM-CAF). Protein array analysis of CM-CAFs was conducted to identify candidate factors responsible for growth suppression. Results: PDAC patients with positive alphaSMA expression showed significantly shorter overall survival and recurrence-free survival than alphaSMA-negative patients (p = 0.003, p = 0.009, respectively). On the other hands, BTC patients with positive alphaSMA expression showed better recurrence-free survival than alphaSMA-negative patients (p = 0.03). CM-CAF suppressed the proliferation of cancer cells only in BTC cancer cell lines, not in PDAC cell lines. Protein arrays of CM-CAFs revealed that IL-6 and IL-8 were key suppressive factors on BTC cancer cell proliferation. The inhibitory effects on BTC cell proliferation were abolished upon neutralization of IL-6 and IL-8. Conclusions: CAFs serve as a favorable prognostic factor in BTC but not in PDAC. We demonstrated the presence of tumor-suppressive CAFs in BTC, which exert their anti-proliferative effects through the secretion of IL-6 and IL-8. These findings suggest a novel, context-dependent role for CAFs in the tumor microenvironment of biliary tract cancers.