PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction

Abstract

Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known about the mechanisms by which PEDF limits pancreatic tumorigenesis. We therefore employed human specimens, as well as mouse and in vitro models, to explore the effects of PEDF upon the pancreatic microenvironment. We found that PEDF expression is decreased in human pancreatic cancer samples compared to non-malignant tissue. Furthermore, PEDF-deficient patients displayed increased intratumoral inflammation/fibrosis. In mice, genetic ablation of PEDF increased cerulein-induced inflammation and fibrosis, and similarly enhanced these events in the background of oncogenic KRAS. In vitro, recombinant PEDF neutralized macrophage migration as well as inhibited macrophage-induced proliferation of tumor cells. Additionally, recombinant PEDF suppressed the synthesis of pro-inflammatory/pro-fibrotic cytokines both in vivo and in vitro, and reduced collagen I deposition and TGFβ synthesis by pancreatic stellate cells, consistent with reduced fibrosis. Combined, our results demonstrate that PEDF limits pancreatic cancer progression by attenuating the fibro-inflammatory reaction, and makes restoration of PEDF signaling a potential therapeutic approach to study in pancreatic cancer.