title: Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion.
abstract: BACKGROUND
  In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer.
  
  
  METHODS
  Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling.
  
  
  RESULTS
  Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75(NTR)-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase.
  
  
  CONCLUSIONS
  Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves-and not cancer cells-migrate first during NI.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA). ekin.demir@tum.de.
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA). ekin.demir@tum.de.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Boldis
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Paulo L
authors.initials: PL
authors.lastname: Pfitzinger
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Steffen
authors.initials: S
authors.lastname: Teller
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Eva
authors.initials: E
authors.lastname: Brunner
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Natascha
authors.initials: N
authors.lastname: Klose
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Matthias
authors.initials: M
authors.lastname: Maak
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Melanie
authors.initials: M
authors.lastname: Laschinger
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC); Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA).
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D050697:Retinal Dehydrogenase / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology*; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D050697:Retinal Dehydrogenase; D009418:S100 Proteins; D055757:SOXE Transcription Factors; D000099295:Formyltetrahydrofolate Dehydrogenase; C527923:SOX10 protein, human; C527924:Sox10 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse