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Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.

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.

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.

p< 0.001, Fig 1B) and not to culture drain fluid (91.5% vs. 67.1%, p < 0.001, Fig 1C). Conclusions: Our survey evaluated a wide range of practice patterns regarding the Whipple procedure. Large variations exist amongst NA and European members including decreased intraoperative bile culture and postoperative drain amylase measurement, and more compliance with prophylactic antibiotics. Further studies are warranted to evaluate if these variations translate into impacts upon surgical outcomes on patients undergoing Whipple operation.