title: Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia.
abstract: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation.
  
  
  
  Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified.
  
  
  
  Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features.
  
  
  
  Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Tieftrunk
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schorn
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ömer Cemil
authors.initials: ÖC
authors.lastname: Saricaoglu
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Paulo L
authors.initials: PL
authors.lastname: Pfitzinger
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Teller
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Hepatic, Biliary & Pancreatic Surgery, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Waldbaur
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Magdalena U
authors.initials: MU
authors.lastname: Kurkowski
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Sonja Maria
authors.initials: SM
authors.lastname: Wörmann
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Shaw
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Kehl
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Laschinger
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK Liverpool NIHR Pancreas Biomedical Research Unit, Liverpool, UK.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
mesh_terms: D000698:Analgesia; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D000072258:Tumor Hypoxia / Q000235:genetics*
chemical_list: D015850:Interleukin-6
keywords: NERVE - GUT INTERACTIONS; NEUROGASTROENTEROLOGY; PANCREATIC CANCER; VISCERAL NOCICEPTION