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

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 painrelated 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.

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

“…S6). This observation is in harmony with our previous findings on the decreasing GFAP content of nerves of PDAC patients with pain (8).…”

“…In the present study, we show this chemokine-receptor axis has a role in the activation of peripheral glia, i.e., SC, in the tumor microenvironment, which seems to entail an analgesic effect in the early disease course. Accordingly, we recently demonstrated decreased pain sensation among PDAC patients who bear increased pancreatic gliosis with cellular hypertrophy of pancreatic glia (8). In the light of the previously reported pro-nociceptive roles of CXCR4 and CXCL12, our observations suggest that peripheral and central CXCL12-mediated signaling exert contrasting effects for nociception, i.e., CXCL12 mediating analgesia via modulation of SC activity.…”

“…However, beyond SC biology, CXCL12-CXCR4 interactions regulate multiple aspects of glial biology in general, including astrocytic and microglial migration and survival (36), neural recovery after ischemia or damage (23,37), and neuron-glia communication (23). CXCR4 was further shown to be increasingly expressed on astrocytes after stimulation by interleukin-6 (38), which we recently demonstrated to be a key factor that generates and maintains reactive gliosis in PDAC (8). Therefore, one can assume that all the above attributes of CXCR4 and CXCR7 in glia biology may also influence the extent of nerve-cancer interactions in PDAC.…”

“…Classically, cancer cells are assumed to penetrate into nerves actively and to use them as paths of dissemination (6,7). However, we recently reported that peripheral glia cells, i.e., Schwann cells (SC), become activated in PDAC and suppress pain sensation (8). Importantly, they emerge around the premalignant precursor lesions of different human and murine gastrointestinal cancers and correlate to the frequency of NI (2).…”

Sleeping in on pancreatic cancer pain: Schwann cell secreted IL-6 pushes snooze on the pain alarm

“…Schwann cells initiate and mediate neural interactions with cancer cells, particularly in the early stages of pancreatic cancer. In this issue of Gut , Demir et al 4 undertook a comprehensive investigation of Schwann cell involvement in human and mouse pancreatic cancer which revealed that interleukin-6 (IL-6) secreted by activated Schwann cells inhibits pain signalling in the early stages of pancreatic cancer. This novel mechanism has dire implications, as inhibiting pain signalling would delay treatment seeking behaviour and therefore early detection of cancer.…”