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Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia
  1. Ihsan Ekin Demir1,
  2. Elke Tieftrunk1,
  3. Stephan Schorn1,
  4. Ömer Cemil Saricaoglu1,
  5. Paulo L Pfitzinger1,
  6. Steffen Teller1,
  7. Kun Wang2,
  8. Christine Waldbaur1,
  9. Magdalena U Kurkowski3,
  10. Sonja Maria Wörmann3,
  11. Victoria E Shaw4,
  12. Timo Kehl1,
  13. Melanie Laschinger1,
  14. Eithne Costello4,5,
  15. Hana Algül3,
  16. Helmut Friess1,
  17. Güralp O Ceyhan1
  1. 1Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  2. 2Key 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
  3. 3Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  4. 4Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK
  5. 5Liverpool NIHR Pancreas Biomedical Research Unit, Liverpool, UK
  1. Correspondence to Professor Güralp O Ceyhan, Department of Surgery, Klinikum rechts der Isar, Technische Universität München Ismaninger Str. 22, München D-81675, Germany; gueralp.ceyhan{at}tum.de

Abstract

Objective 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.

Design 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-KrasG12D/KC interbred with IL6−/− or sgp130tg mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified.

Results 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;sgp130tg (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;sgp130tg: 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.

Conclusions 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.

  • NERVE - GUT INTERACTIONS
  • PANCREATIC CANCER
  • NEUROGASTROENTEROLOGY
  • VISCERAL NOCICEPTION

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