Journal Article

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Rhim, Andrew D., Muha, Emily A., Li, Dongjun, Davis, Brian M., Saloman, Jami L., Albers, Kathryn M., Hartman, Douglas J., Crawford, Howard C.

2016

Overview

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

• Publisher: National Academy of Sciences
• Subject: Adenocarcinoma in Situ - pathology / Adenocarcinoma in Situ - physiopathology / Afferent Pathways / Animals / Animals, Newborn / Biological Sciences / Capsaicin - administration & dosage / Capsaicin - pharmacology / Capsaicin - therapeutic use / Carcinoma, Pancreatic Ductal - etiology / Carcinoma, Pancreatic Ductal - pathology / Carcinoma, Pancreatic Ductal - physiopathology / Carcinoma, Pancreatic Ductal - prevention & control / Carcinoma, Pancreatic Ductal - therapy / Cells / Central nervous system / Ceruletide - toxicity / Denervation / Disease Progression / Female / Ganglia, Sympathetic - physiopathology / Genes, ras / Humans / Male / Mice / Mice, Inbred C57BL / Mice, Transgenic / Myelitis - complications / Myelitis - genetics / Myelitis - physiopathology / Neoplasm Invasiveness / Nervous system / Neurons / Neuroscience / Pancreas / Pancreas - innervation / Pancreatic Neoplasms - etiology / Pancreatic Neoplasms - pathology / Pancreatic Neoplasms - physiopathology / Pancreatic Neoplasms - prevention & control / Pancreatic Neoplasms - therapy / Pancreatitis - chemically induced / Pancreatitis - complications / Pancreatitis - physiopathology / Precancerous Conditions - chemically induced / Precancerous Conditions - complications / Precancerous Conditions - physiopathology / Rodents / Sensory Receptor Cells - drug effects / Sensory Receptor Cells - physiology / Spinal Cord - physiopathology / Spinothalamic Tracts - physiopathology / Thoracic Vertebrae / Tumors