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. 2021 Jul 15;41(8):642–660. doi: 10.1002/cac2.12188

FIGURE 2.

FIGURE 2

Chemokines and neurotransmitters in PNI and PDAC. Neural cells release C‐X‐C motif chemokine ligands (CX3CL and CXCL12), which can bind to receptors CX3CR1 and CXCR4, respectively, and activate the PI3K‐AKT pathway. In addition, neural cells secrete catecholamine and then induce tumor invasion to the nerves through the ADRB2‐PKA‐STAT3 signaling pathway. Similarly, HGF secreted by DRG binds to MET receptors on PDAC cells in a paracrine manner. The activation of MET leads to the upregulation of NGF and MMP9, which may enhance PNI. Abbreviations: ADRB2, adrenoceptor beta 2; CREB, CREB/ATF BZIP transcription factor; CX3CL1, C‐X3‐C motif chemokine ligand 1; CX3CR1, C‐X3‐C motif chemokine receptor 1; CXCL12, C‐X‐C motif chemokine ligand 12; CXCR4, C‐X‐C motif chemokine receptor 4; DRG, dorsal root ganglia; ECM, extracellular matrix; HGF, hepatocyte growth factor; MET, met proto‐oncogene, receptor tyrosine kinase; MMP9, matrix metallopeptidase 9; NGF, nerve growth factor; NGFR, nerve growth factor receptor; PDAC, pancreatic ductal adenocarcinoma; PKA, protein kinase CAMP‐activated catalytic; PNI, perineural invasion; STAT3, signal transducer and activator of transcription 3