412 Neuroplastic Changes in a Mouse Model of Pancreatic Ductal Adenocarcinoma (PDAC)

Abstract

Perineural tumor invasion of intrapancreatic nerves and extrapancreatic nerve plexuses is a key feature of pancreatic malignancies and is thought to play an important role in pancreatic cancer-related pain and cancer spread. Here we provide a preliminary description of changes in pancreatic innervation in a mouse model of PDAC that will allow us to examine the mechanisms underlying cancer-induced pathophysiology of the peripheral nervous system. Several neurotrophic factors, including nerve growth factor (NGF) and members of the glial cell line-derived neurotrophic factor (GDNF) family of growth factors, and their receptors can be found in the pancreas and are increased in human pancreatic tumors. These growth factors are capable of inducing neuronal outgrowth and may contribute to sprouting and hypertrophy of pancreatic nerves, which is one of the hallmarks of human PDAC. We hypothesized that artemin, a member of the GDNF family of growth factors, and NGF play a central role in this cross-talk between cancer cells and pancreatic nerves. Experiments were performed with transgenic mice with pancreas-specific expression of the mutated Kras oncogene and heterozygous deletion of the p53 tumor suppressor (Kras). Animals were sacrificed at time points ranging from 13.9-17.4weeks and tissuewas retrieved for histological analysis and assessment of growth factor expression using real time PCR. All Kras mice had developed multifocal pancreatic cancer (by week 13) as evidenced by large masses, obstruction of the biliary tree (by week 17) and a strong desmoplastic reaction. Normal pancreatic innervation was altered with hypertrophied nerves running along blood vessels and extending into the pancreatic parenchyma and tumor nodules, but not into the fibrous tissue. Immunohistochemical experiments showed prominent expression of tyrosine hydroxylase and the artemin receptor GFRα3 on nerve fibers. Compared to wildtype mice, the expression of NGF and its receptor trkA was increased 3.22-fold and 8.85-fold, respectively, in cancer animals. While not statistically significant, a 1.99-fold increase in artemin expression was measured in the Kras animals. Finally, a 2.27-fold decrease in the expression of GFRα3 in cancer animals was observed. These data indicate significant neuroplastic changes occur in the Kras model of pancreatic cancer and these changes correlate with altered expression of growth factors, mimicking data obtained in human resection specimens. Thus, this animal model will enable us to systemically study the impact of changes in trophic factor signaling on cancer growth and animal behavior.