Perineural invasion and associated pain in pancreatic cancer

Key Points

  • Perineural invasion (PNI) is the process through which cancer cells invade the perineural spaces of surrounding nerves and is not simply the movement of cancer cells along a path of low resistance, as was previously thought. PNI is a directed process that involves many signalling molecules from various signalling pathways; these signalling molecules are produced by both the cancer cells and the nerves. Once the cancer cells have invaded the nerves, they are able to thrive within the neuronal spaces. This constitutes a means for the cancer cells to spread to distant locations.

  • The incidence of PNI is particularly high in pancreatic cancer. Although the exact cause for this increased affinity is as yet unclear, the strong neurotropic effects of pancreatic cancer cells are thought to contribute to this phenomenon. Additionally, reciprocal signalling between the pancreatic cancer cells and the surrounding nerves leads to neurogenesis, as well as the increased growth of pancreatic cancer cells.

  • PNI also contributes to the generation of the pain that is experienced by pancreatic cancer patients, and many of the signalling molecules that are involved in PNI are also known to be involved in pain signalling. Thus, we hypothesize that agents targeting these signalling pathways may have the potential to prevent PNI and may help to alleviate pain in patients with pancreatic cancer.

Abstract

Perineural invasion (PNI) is a prominent characteristic of pancreatic cancer. PNI is a process whereby cancer cells invade the surrounding nerves, thus providing an alternative route for metastatic spread and pain generation. PNI is thought to be an indicator of aggressive tumour behaviour and has been shown to correlate with poor prognosis of patients with pancreatic cancer. Recent studies demonstrated that some signalling molecules and pathways that are involved in PNI are also involved in pain generation. Targeting these signalling pathways has shown some promise in alleviating pain and reducing PNI, which could potentially improve treatment outcomes for patients with pancreatic cancer.

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Figure 1: Perineural invasion in pancreatic cancer.
Figure 2: Signalling molecules involved in the process of perineural invasion in pancreatic cancer.
Figure 3: Signalling molecules involved in pain generation in pancreatic cancer.

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Acknowledgements

This work is dedicated to S. Greene and S. Salmon, who taught us just how tough perineural invasion by pancreatic cancer can be. We would also like to thank C. Nulsen for her invaluable and critical insights during the preparation of this manuscript. Research in the authors' laboratories was supported by grants from the US National Institutes of Health National Cancer Institute (grants CA140924 and CA109552), the American Association for Cancer Research Stand Up to Cancer programme and the US National Foundation for Cancer Research.

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Correspondence to Haiyong Han.

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Glossary

Perineurium

The connective tissue sheath that surrounds bundles of nerves known as fascicles.

Dorsal root ganglia

A mass of sensory afferent nerve cell bodies that is located on the dorsal root of the spinal cord, one on each side for each spinal nerve.

Neurolytic blocks

A process in which a neurolytic or analgesic agent is injected into or near nerves that are involved in pain signalling. Neurolytic blocks are used to combat chronic pain states or pain that is caused by cancer.

Coeliac plexus blocks

A process in which the nerves of the coeliac plexus are subjected to neurolysis using neurolytic agents, such as a 50–100% solution of alcohol or a 10% solution of phenol, that are injected into the coeliac plexus guided by ultrasound and computed tomography (CT) imaging.

Thermal hyperalgesia

Increased pain responses following an increase in temperature.

Tactile allodynia

Pain sensations caused by mechanical stimuli such as touch that usually do not invoke pain responses.

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Bapat, A., Hostetter, G., Von Hoff, D. et al. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 11, 695–707 (2011). https://doi.org/10.1038/nrc3131

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