Table 1.

Mediators in the perineural niche and tumor microenvironment in PNI.

Factors	Interrelated factors	Role in PNI	References
Perineurial cells	Tight junctions	The tight connections in the perineurial cells are the main players of the neural barrier function	(26, 27)
Other PNI-related cells	Schwann cells	Interact with preneoplastic cells	(31)
	TAMs	Positive correlation with PNI	(32, 33)
	Stellate cells	Induce the proliferation of cancer cell and associated with the generation of neuronal plasticity	(34, 35)
Nerve fibers	NGF secretion	Associated with NGF production and lymph node invasion in cancer	(36)
NGF family and receptors	NGF-TRKA	Positive correlations with PNI and poor prognosis in cancer	(37)
	BDNF-TRKB	Significantly correlated with advanced clinical stage, poor prognosis, PNI, vascular invasion, and distant metastasisin SACC; Have a role in the EMT process in SACC	(38, 39)
GDNF family and receptors	GDNF-GFRα1-RET	Induce tumor cell migration	(40)
Chemokines and receptors	CXCL12/CXCR4	Significantly correlated with PNI and increased secretion of MMPs	(41)
	CX3CL1/CX3CR1	Significant positive correlation with PNI and promote tumor migration and invasion	(42)
MMPs	MMP-2 and MMP-9	Degradation of ECM and basement membrane and involved in NGF–TRKA signaling and GDNF–RET pathway	(43)