Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance

Abstract

Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.

Keywords: neuropathic pain; pancreas; pancreatic ductal adenocarcinoma; perineural invasion; tumour microenvironment.

Figure 1

Perineural invasion from high-grade PDAC with desmoplastic and lymphocytic reaction into the surrounding stromal tissue (A). Hypertrophic nervous fibre bundle in the parenchyma away from PDAC cells (B).

Figure 2

Perineural invasion signalling pathways in pancreatic cancer. β2-adrinergic receptor (β2-AR), epithelial- mesenchymal transition (EMT), chemokine (C-X-C motif) ligand 4 (CXCL4), C-X-C motif chemokine 12 (CXCL12), neural chemokine fractalkine (CX3CL1), neural chemokine fractalkine receptor (CX3CR1), matrix metalloproteinases (MMP-2, MMP-9), myelin-associated glycoprotein (MAG), nerve growth factor (NGF), norepinephrine (NE), protein kinase A (PKA), signal transducer and activator of transcription 3 (Stat3), sympathetic nervous system (SNS) transforming growth factor beta (TFG-β),transmembrane mucins (MUC-1 MUC-4), tyrosine kinases receptor (TRK), tumour associated macrophages (TAMs).

Figure 3

Possible role of extracellular vesicles in pancreatic cancer’s perineural invasion. Extracellular vesicles (EVs); multivesicular body (MVB).

Figure 4

Schematic figure showing therapeutic agents and targets in pancreatic cancer’s perineural invasion. Anaplastic lymphoma kinase (ALK), FMS-like tyrosine kinase 3 (FLT-3), nerve growth factor (NGF), Janus kinase 2 (JAK2), proto-oncogene tyrosine–protein kinase-1 (ROS-1), Resininferatoxin (RTX), tyrosine kinases (TRK), transient receptor potential cation channel subfamily V member 1 (TRPV1).