Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor-neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.

Keywords: nerve remodeling; pain; pancreatic cancer; perineural invasion.

Figure 1

The complicated crosstalk between different types of cells in TME. Various signaling molecules participate in the interaction, thereby transforming the cell structure and function and facilitating the malignant development of PDAC. GDNF, glial cell line-derived neurotrophic factor; GFRα-RET, glial cell line-derived neurotrophic factor family receptor-α-rearranged during transfection; GM-CSF, granulocyte–macrophage colony-stimulating factor; GM-CSFR, granulocyte–macrophage colony-stimulating factor receptor; IL6R/gp130, interleukin-6 receptor/glycoprotein 130; L1CAM, L1 cell adhesion molecule; LIF, leukemia inhibitory factor; LIFR/gp130, leukemia inhibitory factor receptor/glycoprotein 130; MAG, myelin associated glycoprotein; MUC1, mucin 1; NCAM1, neural cell adhesion molecule; NT, neurotrophin; p75NTR, p75 neurotrophin receptor; PLXND1, plexin-D1; Robo, Roundabout; SEMA3D, semaphorin 3D; SP, substance P; TAM, tumor-associated macrophage; TrKA, tropomyosin receptor kinase A; TrKB, tropomyosin receptor kinase.

Figure 2

The alterations of pain conduction in PDAC patients. In the peripheral nervous system, local neurogenic inflammation in PDAC initiates the pain conduction. Schwann cells and macrophages regulate the process by the release of multiple pro-nociceptive factors. In the CNS, several pain-related brain regions undergo a series of reorganization and remodeling of synapses, contributing to the pain sensitization in PDAC patients. ACC, anterior cingulate cortex; PAG, periaqueductal gray; PFC, prefrontal cortex; SPM, specialized pro-resolving mediator.