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  • Review Article
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Neural plasticity in pancreatitis and pancreatic cancer

Key Points

  • Neural plasticity is an inherent feature of chronic pancreatitis and pancreatic cancer, and involves neuronal activation at the peripheral, spinal and supraspinal level

  • Neural plasticity, pancreatic neuritis, neural invasion and altered distribution of sympathetic and sensory nerve fibres constitute the pancreatic neuropathy in these diseases and correlate with the severity of neuropathic pain sensation

  • Pain and neural invasion are prognostic in pancreatic cancer and so understanding the underlying mechanisms holds major translational relevance

  • Patients with chronic pancreatitis exhibit central hyperalgesia and alterations in brain resting activity and brain microstructure

  • Current animal models of chronic pancreatitis and genetically engineered mouse models of pancreatic cancer largely fail to recapitulate the intrapancreatic neuropathy and plasticity of nerve trunks in the pancreas

  • Schwann cells of peripheral nerves are activated in the preneoplastic stage of cancer, possess strong affinity to cancer cells and initiate nerve-cancer cell interactions

Abstract

Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

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Figure 1: Anatomy of pancreatic innervation.
Figure 2: The cell bodies of the sensory fibres lie in the dorsal root ganglia.
Figure 3: Comparison of human and mouse pancreatic neuroplasticity in chronic pancreatitis and pancreatic cancer.
Figure 4: Neuropathic–neuroplastic alterations in human and experimental chronic pancreatitis.
Figure 5: Interactions between neurons, glial cells and cancer cells.

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Demir, I., Friess, H. & Ceyhan, G. Neural plasticity in pancreatitis and pancreatic cancer. Nat Rev Gastroenterol Hepatol 12, 649–659 (2015). https://doi.org/10.1038/nrgastro.2015.166

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