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

Abstract

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.sensory neuron | pancreatic ductal adenocarcinoma | tumorigenesis | inflammation | PanIN P ancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a median survival of ∼6 mo from diagnosis (National Cancer Institute). A number of unique features distinguish PDAC from other carcinomas, but the most striking is the exuberant desmoplastic infiltrate within tumors. This compartment exhibits an array of cell types, including activated myofibroblasts and myeloid-derived cells. Indeed, this inflammatory infiltrate is present at the inception of neoplasia and accumulates at a near exponential rate during progression to carcinoma and tumor formation. It provides a complex balance of pro-and antitumorigenic signals to neoplastic cells (and also to each other) that is a focus of intense investigation. The pancreas tumor microenvironment has been studied previously, but new tools [genetically engineered mouse models (GEMs) that faithfully recapitulate the salient features of human PDAC] now allow for a careful dissection of the stroma. Using these models, we showed that generalized inflammation is required for the development of precancerous pancreatic intraepithelial neoplasias (1) and that Hedgehog-dependent stromal elements, including activated myofibroblasts, serve to constrain tumor growth and spread (2). Other cellular components of the pancreatic inflammatory str...

How Schwann cells facilitate cancer progression in nerves

“…These data support a previous study showing that chemical denervation using benzalkonium chloride decreased tumorigenesis in a rat model of gastric cancer [35]. In a mouse model of pancreatic ductal adenocarcinoma, the ablation the sensory neurons of the autonomic nervous system reduces the initiation and progression of the cancer [4]. Treatment with capsaicin, a drug that suppresses sensory innervation induced a delay in precancerous PanIN formation.…”

“…Endoneurial macrophages have also been reported to play a role in PNI [24]. Neurons from autonomic and sensory innervation of organs, and specific neurotransmitters have also been strongly implicated in the regulation of cancer development and progression [1–4]. …”

“…Denervation leads to reduction of tumor growth in models of prostate, gastric, pancreatic, and skin cancer [1–4]. In a mouse model of prostate cancer, chemical or surgical ablation of hypogastric nerves results in diminished tumorigenesis [1].…”

“…Interestingly, nerves also stimulate cancer progression. The denervation of organs in several murine cancer models has been demonstrated to impair cancer formation [1–4]. It is known that non-malignant cells surrounding cancer cells, termed the tumor microenvironment, modulate cancer development.…”

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

“…A possible role of sensory nerves on PanIN tumorigenesis has been suggested by studies that show capsaicin, a TRPV1 antagonist at high doses, decreases tumor growth in PDAC mouse models (41,42). However, the mechanism for capsaicin's chemoprotective effects and the specific role of decreased intrapancreatic innervation is unknown.…”