title: Pigment epithelium-derived factor associates with neuropathy and fibrosis in pancreatic cancer.
abstract: OBJECTIVE
  Pigment epithelium-derived factor (PEDF) is a noninhibitory member of the serine protease inhibitor gene family with neuroprotective, neuroproliferative, and anti-angiogenic functions. Its role in pancreatic fibrosis and neuropathy is unknown.
  
  
  METHODS
  The expression and localization of PEDF were assessed by quantitative real-time (RT)-PCR, immunohistochemistry, and quantitative image analysis and correlated with neural and microvessel densities (MVDs) in the normal pancreas (n=20) and pancreatic cancer (n=55). Primary human pancreatic stellate cells (PSCs), mouse neuroblastoma, and human Schwann cells were used for functional experiments. The effect of hypoxia on PEDF production in cancer cell lines and immortalized pancreatic ductal epithelial cells was assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay. The effect of recombinant PEDF on PSCs was assessed by immunoblot analysis.
  
  
  RESULTS
  PEDF expression was homogeneous in epithelial cells of the normal pancreas where some acinar cells consistently displayed stronger staining. A higher expression was found in tubular complexes, PanIN lesions, and inflammatory cells in pancreatic cancer. Cancer cells expressed various levels of PEDF. In cancer cell lines and in human immortalized pancreatic ductal epithelial cells, hypoxia increased PEDF mRNA up to 132-fold. Higher expression of PEDF in cancer cells was significantly correlated with better patient survival (median survival 21.5 months vs. 17.5 months, P=0.043), increased neuropathy (P=0.0251), increased PSC activity, and extracellular matrix protein production.
  
  
  CONCLUSIONS
  PEDF increases PSC activity, thereby contributing to the desmoplasia of pancreatic cancer. PSC overactivation likely leads to periacinar fibrosis and degeneration of fine acinar innervation. Increased focal PEDF expression in cancer cells correlates with neuropathic changes and better patient survival.
authors.affiliation: Department of General Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Samkharadze
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.forename: Carolin
authors.initials: C
authors.lastname: Reiser-Erkan
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D006984:Hypertrophy; D007150:Immunohistochemistry; D008049:Lipase / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D010179:Pancreas / Q000294:innervation / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D010525:Peripheral Nerves / Q000473:pathology; D017474:Receptors, Laminin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor; D000217:Acyltransferases
chemical_list: D005136:Eye Proteins; D008049:Lipase; D009414:Nerve Growth Factors; D017474:Receptors, Laminin; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C494794:PNPLA2 protein, human; D000217:Acyltransferases