FIGURE 1.

Neurotrophins in PNI and PDAC. Neurotrophins are associated with PNI in pancreatic tumorigenesis. A series of interactions between multiple neurotrophin ligands and receptors, such as SEMA3D‐PLXND1, ARTN‐GFRA3, and PTN‐SDC3, promote the movement of cancer cells toward neural cells. The binding of GDNF to RET receptors activates downstream KRAS signaling and upregulates the expression of MMPs. It also accelerates the formation of stress fibers, thus resulting in cellular polarization and metastasis during PNI. Abbreviations: ANXA2, annexin A2; CDC42, cell division cycle 42; ECM, extracellular matrix; GDNF, glial cell‐derived neurotrophic factor; MAPK, mitogen‐activated protein kinase; MAP2K, mitogen‐activated protein kinase kinase; MMP, matrix metallopeptidase; NTRK1, neurotrophic receptor tyrosine kinase 1; NTRK2, neurotrophic receptor tyrosine kinase 2; PDAC, pancreatic ductal adenocarcinoma; PLXND1, plexin D1; PNI, perineural invasion; PTN, pleiotrophin; RAF, Raf‐1 proto‐oncogene, serine/threonine kinase; RET, ret proto‐oncogene; RHOA, Ras homolog family member A; ROBO1, roundabout guidance receptor 1; SDC3, syndecan 3; SEMA3D, semaphorin 3D; SLIT2, slit guidance ligand 2