Table 3.

Other molecules related to PNI

Molecules	Mechanism of PNI	Other clinical features	Refs
SP (Substance P)	Activate MAPK and ERK1/2 to promote the differentiation of cells and induce the migration of cells after being bound with the receptor NK-1R and its subtypes. Accelerate the secretion of MMP-2 and the formation of new vessels and then promote the occurrence of PNI.	Substance P and its receptor NK-1R are highly expressed in several tumors and are related to the pains caused by cancer.	[90]
	NK1 receptor antagonist can block the mitogenic function of substance P and produce apoptosis-promoting function in vitro and in vivo.
Galanin	Activate NFAT (nuclear factor of activated T cells) after being bound with GAL-R2 and promote the transcription of cyclooxygenase-2 (COX-2) and GAL in tumor cells under the induction of calcineurin dephosphorylation. COX-2 promotes the generation of prostaglandin E2 (PGE2) and promotes the invasion of tumor.	To be released after nerve cells are injured or have inflammation, having three receptors of GAL-R1, GAL-R2, and GAL-R3.	[91,92]
	The newly transcribed GAL can induce neurogenesis and promote PNI. When this indicates PNI, there is not only invasion of tumor to nerves but also neurogenesis in tumor tissues.
Slug	Upregulate MMP-inducing factors and downregulate E-cadherin to promote the EMT process of tumor cells.	Slug belongs to important members of the zinc finger transcription factor family, and its expression level in tumor tissues with PNI is obviously higher than that in normal tissues.	[93,94]
	Promote PNI and distant metastasis of tumor cells through the MAPK signal pathway, and such processes can be blocked by the targeted inhibitor MicroRNA-181a of the MAPK pathway.
NPY (Neuropeptide Y)	Synthesized and released in tumor cells and sympathetic nervous system nerves. NPY has a function of promoting growth and can be changed due to receptors of tumor-specific expression.	NPY and its receptors are expressed in cells and vessels of various tumors and play a complex role.	[95]
	As an angiogenesis factor, NPY can powerfully induce the proliferation, differentiation, and migration of endothelial cells; promote the generation of vessels; and then promote the growth of tumor in the PNI process.
Survivin	Survivin is a type of anti-apoptosis factor that has recently been gradually recognized. It can directly block the apoptosis of cells by blocking the apoptosis of receptors and inhibiting the activity of mitochondria, and studies show that it takes part in the anti-apoptosis function in PNI.	When pancreatic cancer is accompanied by PNI, there is always high expression of survivin.	[33]