title: Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma.
abstract: OBJECTIVE
  To further characterize the neurotrophic attributes of pancreatic cancer (PCa).
  
  
  BACKGROUND
  PCa is characterized by neuropathic alterations which are resulting in pancreatic pain. To further characterize pancreatic neuropathy, we aimed: to analyze whether neuropathic alterations in PCa are only limited to the tumor-core or whether they are similarly encountered in neural structures in the noncancerous pancreas, to demonstrate whether PCa features neurotrophic attributes and finally to identify responsible neurotrophic molecules.
  
  
  METHODS
  Nerve density and area were quantified in normal pancreas (NP, n=45), histologically "normal" pancreas next to pancreatic cancer (NNPCa, n=61) and PCa (n=97). Growth-associated protein-43, nerve growth factor (NGF), and Artemin expressions were assessed by Immunohistochemistry, Western-Blot, and quantitative real time polymerase chain reaction-analyses. Isolated myenteric plexus of newborn rats were exposed to NP, NNPCa, and PCa tissue extracts and supernatants of Panc1 and T3M4 cancer cells with or without Artemin and NGF depletion, followed by neurite density analysis.
  
  
  RESULTS
  Dense neural networks and enlarged nerves were not only detected in PCa but were also present in NNPCa. Growth-associated protein-43, NGF, and Artemin expressions were absent/weak in NP, but increased in both NNPCa and PCa and were closely associated with intrapancreatic neuropathy. PCa and NNPCa tissue extracts and Panc1/T3M4 supernatants noticeably increased neurite density in myenteric plexus-cultures, which were attenuated by depletion of NGF and Artemin.
  
  
  CONCLUSIONS
  The neurotrophic effects of PCa extend into the peritumoral "normal" pancreatic areas without neuro-cancer interactions. The neurotrophic characteristics of PCa can be mimicked by in vitro analyses and reveal NGF and Artemin as potential key players in the generation of pancreatic neuropathy in PCa.
authors.affiliation: Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. ceyhan@chir.med.tu-muenchen.de
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
authors.forename: Karl-Herbert
authors.initials: KH
authors.lastname: Schäfer
authors.forename: Annika G
authors.initials: AG
authors.lastname: Kerscher
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rauch
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.forename: Mustafa
authors.initials: M
authors.lastname: Kadihasanoglu
authors.forename: Carolin
authors.initials: C
authors.lastname: Böhm
authors.forename: Michael W
authors.initials: MW
authors.lastname: Müller
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D015746:Abdominal Pain / Q000209:etiology; D000368:Aged; D000818:Animals; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D010179:Pancreas / Q000294:innervation*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D019899:Paracrine Communication / Q000502:physiology*; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: C490886:ARTN protein, human; D019922:GAP-43 Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins