Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia

作者：Demir, Ihsan Ekin; Tieftrunk, Elke; Schorn, Stephan; Saricaoglu, Oemer Cemil; Pfitzinger, Paulo L.; Teller, Steffen; Wang, Kun; Waldbaur, Christine; Kurkowski, Magdalena U.; Woermann, Sonja Maria; Shaw, Victoria E.; Kehl, Timo; Laschinger, Melanie; Costello, Eithne; Alguel, Hana; Friess, Helmut; Ceyhan, Gueralp O.^*

来源：Gut, 2016, 65(6): 1001-U148.

DOI：10.1136/gutjnl-2015-309784

• FIBRILLARY ACIDIC PROTEIN
• NEURAL INVASION
• ENTERIC GLIA
• PAIN
• EXPRESSION
• INTERLEUKIN-6
• HYPOXIA
• PROGRESSION
• NEUROPATHY
• INDUCTION

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-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) 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; 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.
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.

• 出版日期2016-6
• 单位北京市肿瘤防治研究所; 北京大学