Sa1716 The Murine Kpc- Pancreatic Cancer Model Accurately Resembles “Neural Remodeling” Seen in Human Chronic Pancreatitis and Pancreatic Cancer

Abstract

Backround: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (PDAC) in humans are characterized by neural alterations, including increased neural density (ND) and hypertrophy (NH), pancreatic neuritis (PN) and neural invasion (NI) by cancer cells. The aim of his study was to evaluate the widely used PDx1-Cre/KRASG12D/Trp53R172H (KPC) genetically engineered pancreatic cancer mouse model (GEMM) regarding those features seen in human PDAC to verify this model for future research in this particular field of PDAC. Methods: Pancreatic nerve fibers in WT(n=10), ELA-hIL1 β (CP, n=10) and KPC-mice (PDAC, n= 10) were analyzed by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and parasympathetic (choline acetyltransferase, ChaT) quality. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP). GAP-43 expression was used as an established marker for neuronal plasticity. The immune reactivity scores for these markers were compared to human samples of normal pancreas (NP, n=10), chronic pancreatitis (CP, n=10) and PDAC (n=10). Results: Pancreatic sympathetic was significantly reduced in murine CP and PDAC, whereas cholinergic innervation did not reveal major changes in nerves without neural invasion. Depending on the severity of neural invasion the cholinergic innervation was also decreased. Similar changes were in respective human samples. Expression pattern of GAP-43 showed an increase in enlarged nerve trunks in human as well as in murine samples. Perineural and endoneural invasion were prominent features of pancreatic cancer in both species. Conclusion: The routinely used KPC pancreatic cancer model resembles human PDAC accurately regarding neuropathic changes and neural remodeling seen in human patients. Therefore, this model is an excellent tool to further investigate the underlying interactions of cancer cells and neurons in PDAC.