Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer

Simple Summary Perineural invasion is a complicated process involving a series of cells and extracellular matrix components in the tumor microenvironment, particularly the crosstalk between cancer cells and neurons. Perineural invasion occurs in many malignant tumors, including gastric carcinoma, biliary tract tumor and pancreatic cancer. It is identified in approximately 80-100% of pancreatic cancer patients and is correlated with poor survival and decreased quality of life. Extensive studies have revealed the subtle molecule regulatory mechanisms during perineural invasion, as well as the potential causal link with pancreatic cancer-associated pain. Here, we introduce the underlying mechanism of perineural invasion and its possible relationship with the intractable pain in pancreatic cancer patients. 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.