133 Sensory Denervation Decreases PanIN Progression in a Mouse Model of Pancreatic Cancer

Abstract

BACKGROUND: Reciprocal molecular signaling between pancreatic ductal adenocarcinoma (PDAC) and nerves may promote perineural invasion (PNI) and tumor growth. The identity and function of sensory neuropeptides in the tumor microenvironment are unknown. We hypothesized that sensory neurons play an important role in tumor progression and that substance P (SP) is a candidate neuropeptide for mediating this effect. AIMS:1) to characterize SP receptor (NK1R) expression in PanIN epithelium 2) to determine NK1R expression in human PDAC cell lines 3) to study effects of sensory denervation on pancreatic intraepithelial neoplasia (PanIN) initiation and progression in the KPC ( Pdx1-Cre; LSL-Kras; LSLTrp53) mouse model. METHODS: KPC mice were injected with the sensory neurotoxin resiniferatoxin (RTX; Sigma) or control solution on postnatal day 7. Pancreata from 8and 12-week-old mice were fixed and subject to HE Santa Cruz). Images were taken with a Nikon Camera or Zeiss LSM 510 Meta microscope. PanINs were graded as early (grade 1) or advanced (grades 2 and 3). PanIN burden was calculated by the percentage of total surface area occupied in 5 random views per HE p = 0.02). All analyzed human PDAC cell lines expressed the NK1R. In vivo studies revealed axons in close proximity to PanIN epithelium (Fig.1). RTX-treated mice had a 50% decrease in pancreatic sensory axonal density when compared to control mice at 8 and 12 weeks (p < 0.05). RTX-treated mice had a significant reduction in advanced PanINs compared to control mice at both 8 weeks (0.05% versus 0.9%; p < 0.05) and 12 weeks (0.3% versus 8%; p < 0.05). CONCLUSIONS: The NK1R is expressed in distinct cells within the PanIN epithelium and the percentage of NK1R+ cells increases with PanIN grade. Human PDAC cell lines express the NK1R. Sensory denervation is associated with a significant reduction in progression from early to advanced PanIN in the KPC model. Sensory nerves are likely an important part of the PanIN microenvironment and may affect tumorigenesis via the NK1R. This study provides new insight into the pathogenesis and potential therapeutic targets in PDAC.