Targeting the Cancer-Neuronal Crosstalk in the Pancreatic Cancer Microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the pancreatic cancer field. A histological hallmark of PDAC is perineural invasion (PNI), whereby cancer cells invade surrounding nerves, providing an alternative route for metastatic spread. The extent of PNI has been positively correlated with early tumor recurrence and reduced overall survival. Multiple studies have shown that mechanisms involved in PNI are also involved in tumor spread and pain generation. Targeting these pathways has shown promising results in alleviating pain and reducing PNI in preclinical models. In this review, we will describe the mechanisms and future treatment strategies to target this mutually trophic interaction between cancer cells to open novel avenues for the treatment of patients diagnosed with PDAC.

Keywords: crosstalk; microenvironment; neuron; pancreatic ductal adenocarcinoma.

Figure 3

(A). Schematic illustration showing the routes of sensory, sympathetic and parasympathetic nerve fibers. (B). Mechanisms of cancer–neuronal crosstalk are shown separately for sensory, sympathetic, and parasympathetic neurons. Solid, black lines with an arrow symbolize activation, whereas red lines with a bar symbolize inhibition. Some signaling mechanisms are described in non-PDAC cancers. These are labeled with a dotted line. Their role in PDAC has to be confirmed in the future. The effect of interaction (↑ increase; ↓ decrease) is listed below for each mediator. Data collected from [12,16,40,42,44,53]. Abbreviations: β-adrenergic receptor 2 (ADBR2), nerve growth factor (NGF).

Figure 4

Mediators involved in the cancer–neuronal crosstalk. (A–F). Several mediators are involved in the close cancer–neuronal crosstalk, including NGF, chemokines (e.g., CX3CL1, CXCL10, CCL21), GDNF, SLIT2, Semaphorin 3D and Serine. Solid, black lines with an arrow symbolize activation, whereas red lines with a bar symbolize inhibition. Some signaling mechanisms are only described in non-PDAC cancers. These are labeled with a dotted line. Their role in PDAC has to be confirmed in the future. The effects of interaction (↑ increase; ↓ decrease) are listed below for each mediator. Data collected from [8,15,78,82,83,84,85,86,87,88,89]. Abbreviations: C-X3-C motif ligand 1 (CX3CL1); CX3C motif chemokine receptor 1 (CX3CR1); C-X-C motif chemokine 10 (CXCL10); C-X-C Motif Chemokine Receptor 3 (CXCR3); C-C Motif) Ligand 21 (CCL21); C-C chemokine receptor type 7 (CCR7); glial-cell-derived neurotrophic factor family of ligands (GDNF); nerve growth factor (NGF); nerve growth factor receptor (NGFR); Pancreatic ductal adenocarcinoma (PDAC); rearranged during transfection (RET); roundabout receptors (Robo); Slit glycoproteins (Slit). Red symbol crossing out Serine means Serine deprivation.

Figure 1

PRISMA flow diagram on article selection. We performed a literature search in PubMed using these terms: “(pancreatic cancer [title]) AND neuron”, “(pancreatic ductal adenocarcinoma [title]) AND neuron”, “(pancreatic cancer [title/abstract]) AND neuron [title/abstract]”, “(pancreatic cancer [title/abstract]) AND sympathetic [title/abstract]”, “(pancreatic cancer [title/abstract]) AND parasympathetic [title/abstract]”, “(pancreatic cancer [title/abstract]) AND ablation [title/abstract]”, “(pancreatic cancer [title/abstract]) AND neuronal [title/abstract]”, “(pancreatic cancer [title/abstract]) AND neural [title/abstract]”.

Figure 2

Neural invasion. (A). PDAC cells (arrow) infiltrate a nerve (asterisk). More than 33% of the circumference of the nerve is affected (perineural invasion). Stained with Hematoxylin and Eosin. Image at 20× magnification. (B). Healthy pancreas with a nerve bundle (asterisk). Stained with Hematoxylin and Eosin. The entire tissue shown represents the exocrine part of the pancreas. Endocrine parts are not shown. Image at 20× magnification.