Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer

BACKGROUND: Nerve invasion (N‐inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N‐inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)‐6/gp130 axis was evaluated in this study as a candidate N‐inv stimulator. METHODS: A human pancreatic cancer (PC) cell, Capan‐1, was confirmed to have the stimulant activity of IL‐6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL‐6/gp130 axis was evaluated using tumor‐derived IL‐6 level and intratumoral pSTAT3 expression in N‐inv of murine sciatic nerves by intraneural injection of Capan‐1 cell (N‐inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients. RESULTS: mRNA and protein expressions of IL‐6 and IL‐6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL‐6 promoted migration and chemotaxis of PC cell. Serum IL‐6 and tumoral IL‐6 mRNA levels in N‐inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL‐6 and gp130 on PC cell and administration of an anti‐IL‐6 receptor antibody, tocilizumab, suppressed N‐inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high‐N‐inv group showed poor prognosis (p =0.059) and elevated serum levels of IL‐6 and C‐reactive protein, synthesis of which is promoted by IL‐6, compared to those in the low‐N‐inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N‐inv was higher than that in the primary pancreatic tumor (p = 0.026). CONCLUSION: Biological activity of IL‐6/gp130 axis promoted N‐inv in murine model and was upregulated in PDAC patients with severe N‐inv. This study is the first evidence that the IL‐6/gp130 axis offers a potential therapeutic target in PDAC with N‐inv.