Perineural invasion in pancreatic ductal adenocarcinoma: Molecular mechanisms and clinical significance

Figure 2 Pain generation and sensitization associated with perineural invasion in pancreatic ductal adenocarcinoma. This figure summarizes two overlapping pathways involved in pain associated with perineural invasion in pancreatic ductal adenocarcinoma. On the left is the mechanical and anatomical pathway. After tumor cells infiltrate the perineural space, they may further encase or compress nerves, causing structural nerve damage and altering local neural signaling. These anatomical changes may constitute the structural basis for the characteristics of persistent cancer pain and neuropathic pain. The middle section depicts the chemical and neuroimmune pathway. Nerve growth factor receptor signaling may enhance the responsiveness of sensory neurons and promote sensitization of nociceptors; signals from nociceptors, along with modulation by immune and glial cells, may further increase local neural sensitivity. The right-hand section illustrates clinical pain outcomes that may arise from the integration of mechanical/anatomical injury and chemical/neuroimmune sensitization, including persistent cancer pain, neuropathic features, and interpatient heterogeneity. Solid lines show the mechanical/anatomical sequence from perineural infiltration to nerve sheath compression, structural nerve damage, and changes in nerve signaling. Dashed lines represent the convergence or regulation between altered nerve signals, nerve growth factor-related sensitization, nociceptor signaling, immune and glial modulation, and pain outcomes. The statement “PNI burden ≠ pain intensity” in the figure emphasizes that the anatomical burden of perineural invasion does not directly determine pain intensity. Pain in different patients may result from a combination of structural nerve damage and chemical/neuroimmune sensitization to varying degrees. PNI: Perineural invasion; NGF: Nerve growth factor.