Table 2.

Major PNI-Related Chemokine Proteins and Mechanisms of PNI

Chemokines	Receptor	Mechanisms in PNI	Refs
CCL2 (MCP-1)	CCR2	Inflammatory mononuclear cells of CCR2(+) are recruited to the area of the PNI by CCL2 released by Schwann cells. They are differentiated from macrophages and promote the occurrence of PNI through the process of Akt induction.	[78,79]
		The CCL2-CCR2 pathway activates P42/MAPK through G-protein-coupled receptors to regulate the adhesion and movement of macrophages.
		In the in vitro experiment of mouse dorsal root ganglion (DRG) in prostatic cancer, nerves injured by tumor invasion promote the release of CCL2, generate an inflammatory reaction of nerve restoration, and induce CCR2 cancer cells to migrate to these nerves. By activating the MAPK and Akt pathways in pc3 cells, they promote the occurrence of PNI.
CCL5	CCR5	In salivary adenoid cystic carcinoma (SACC), the CCL5-CCR5 axis stimulates SACC cells after being activated and causes the Ca2+ concentration of the sarcoplasmic reticulum to rise, resulting in high-level actin polymerization and recombination of the cytoskeleton, forming a pseudopod to enhance the invasion capability of tumor cells, which plays a key role in PNI.	[80]
CCL21	CCR7	CCL21-CCR7 promotes the proliferation and migration of CD133+ pancreatic cancer cells by regulating EMT and ERK/NF-κB.	[81]
CXCL5	CXCR2	The CXCL5-CXCR2 pathway can activate and promote the migration of hepatocellular carcinoma EMT and tumor through PI3K/Akt/GSK-3β/Snail signal transduction.	[82]
CXCL12 (SDF-1)	CXCR4	Overexpressed CXCR4 in bile duct carcinoma and pancreatic cancer is closely related to PNI, lymphatic metastasis, TNM staging, and vessel invasion.	[83-86]
		CXCR4 promotes VEGF expression, the mitosis and proliferation of vascular endothelial cells, and tumor to generate new vessels. It also promotes the specific growth tendency of axons and increases nerve-tumor contact.
		The CXCL12-CXCR4 axis can upregulate MAPK, Rho family protein CDC42, PAK, and Akt through arrestin; promote the synthesis of intracellular golgiosome microtubules and microfilament; increase their contractility and contraction frequency to promote EMT; enhance the transformation and moving ability of tumor cells; and increase the migration ability and invasion of tumor cells.
		Enhance the anti-apoptosis of tumor cells through the Akt/Bcl-2/NF-κB pathway and by reducing the expression level of caspase, downregulate the MHC-I level to induce tumor cells to escape from the immune surveillance of mechanism.
		As chemotherapeutics, the retardant AMD3100 (Mozobil, plerixafor) of the CXCL12/CXCR4 axis and CTCE-9908 have achieved antitumor effects in solid tumors, but they need to be further researched.
CXCL12 (SDF-1)	CXCR7	Studies of Dona E demonstrate that besides CXCR4, CXCR7 can be used as the second receptor of CXCL12. By chelating with CXCL12, the CXCR7 ligand can regulate and change the overall availability, distribution, and concentration gradient of CXCL12 in the tumor microenvironment and the synergism of CXCR4 to cause PNI.	[87]
CX3CL1 (Fractalkine)	CX3CR1	CX3CR1 and CX3CL1 constitute a high-affinity signal pathway and can be highly expressed in early pancreatic cancer and prostatic cancer. CX3CR1 activates and induces the adhesion molecule through G-protein dependency and β1 integrin, to take part in the adhesion of nerve cells and induction of the tendency for nerve growth of tumor cells.	[88]