Association of the neurokinin-1R/substance P pathway with intraoperative tumor cell mobilization and early postoperative metastasis in pancreatic cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) patients often present with early metastases after surgery, probably due to the mobilization of intraoperative circulating tumor cells (CTCs) and clusters. This exploratory study aimed to assess the potential association between the expression of substance P (SP) and neurokinin-1 receptor (NK-1R) in PDAC cells with CTC and cluster spread during pancreatoduodenectomy. Secondly, the potential impact on metastasis development and overall survival (OS) was also assessed. Methods: Twenty-one PDAC patients undergoing pancreatoduodenectomy were evaluated to analyze SP/NK-1R intra-tumor expression. Intraoperative portal vein samples were collected to quantify CTCs and clusters. Metastatic disease-free survival (MDFS) and OS were assessed during the 3-year follow-up. Results: High cytoplasmic expression of NK-1R in PDAC cells was associated with CTCs and cluster mobilization during surgery, between the beginning of the intervention and the resection of the pancreatic tumor ( P = 0.005 and P = 0.025, respectively). Cytoplasmic NK-1R expression in PDAC cells was also associated with lower MDFS 1 year after pancreatoduodenectomy ( P = 0.042). Similarly, the higher the cytoplasmic SP expression, the lower the OS ( P = 0.019). Conclusions: This exploratory study showed that higher NK-1R expression in PDAC cells’ cytoplasm was associated with higher intraoperative CTCs and cluster mobilization. A potential association between higher cytoplasmic expression of NK-1R and SP with lower MDFS and OS, respectively, was observed.