Table 1.

Summary of factor function and its mechanism.

Factor Family	Factors	Receptor	Mechanisms	Functions
Neurotrophic factors	NGF	TrkA	Activation of Trk receptors results in either neuronal differentiation or mitogenic stimuli. Transmit the signals related to the survival and apoptosis of nerve cells to the inside of cells, thus regulating the development and apoptosis of cells.	Stimulate nerve growth
	BDNF, NT-4/5	TrkB		Affects myelination during nerve regeneration; Promote migration and invasion
	NT3	TrkC		Inhibit the formation of myeloid cells in the peripheral nervous system to promote the proliferation of SCs
	NRTN/Artemin	GFRα	Activate RET tyrosine kinase (TK) by binding their homologous GDNF family receptor -α (GFRα) receptors	Promote cancer cell invasion and neuronal plasticity; Promote the proliferation of nerve fibers around the tumor; Regulate the interaction between SCs and tumor cells.
	GDNF	GFRα1	Active RAS/ERK, MAPK, JNK, and PI3-K-Akt.	Prompt pro-MMP-9 expression and activation of MMP-9 to affect nerve adhesion and invasion; Initiate cancer cell migration, and PNI effect, and induced migration along the nerve; Prompt invasion and metastasis formation; Enhance the expression of integrin.
Neuregulins	NRG1	ErbB	Active MAPK, PI-3K.	Increase the gap connection communication between SCs; Adjust the physiological characteristics of SCs, and promote the movement and migration of SCS
Neuropeptides	SP	NK-1R, EGFR, HER2	Active MAPK (including ERK1/2 and P38mapk); Active NK-1R/Akt/NF-κB signal pathway; Transactive EGFR and HER2.	Increase MMP-2, MMP-9, VEGF, and VEGFR; Stimulate cell proliferation; Lead to growth; Avoid apoptosis.
	GAL	GALR2	Active MAPK signal pathways and inactive TTP.	Promote Prostaglandin E2 generation to promote the secretion of pro-inflammatory mediators and neuropeptides by tumor cells; Promotes cytokine secretion (including IL-6, VEGF, IL-8); Induce angiogenesis and neurogenesis.
Chemokines	CXCL10, CCL21	CXCR3, CCR7	Active AKT, MEK, and RAC signal pathways in tumor cells	Promote cancer cells’ invasiveness, migration, proliferation, epithelial–mesenchymal transition; and sensitize sensory nerves; Recruit bone marrow-derived cells (BMDC) and M2 macrophages; GDNF secreted by the recruited macrophages activates RET-GDNF receptor α1 (GFRα1) in cancer cells and promotes the invasion of PNI and cancer cells; Enhance the adhesion between cancer cells and nerves.
	CCL2	CCR2	Active MAPK, AKT signal pathways.
	CXCL12	CXCR4/CXCR7	Active AKT, ERK, and sonic hedgehog-dependent pathways;
	CCL2	CCR2	Active RET-GDNF receptor α1 (GFRα1) in cancer cells.
	CX3CL1	CX3CR1	CX3CL1 direct contact CX3CR1 to adhere to nerve cells.