title: 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.
authors.affiliation: University of Illinois College of Medicine, Champaign, IL, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: DeCant
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Diaz
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Riley J
authors.initials: RJ
authors.lastname: Mangan
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Hwang
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lowy
authors.affiliation: Northwestern Medicine, Central DuPage Hospital, Winfield, IL, USA.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Shetuni
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Bharath K
authors.initials: BK
authors.lastname: Sreekumar
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Faraz
authors.initials: F
authors.lastname: Bishehsari
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005136:Eye Proteins / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015843:Serpins / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000502:physiology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: KRAS; PEDF; fibrosis; inflammation; pancreatic cancer