Table 1.

Molecules involved in the Schwann cell (SC)-tumor interactions.

Molecules		Mechanisms	Refs
Neurotrophins	NGF	(i) The highly specific and strong affinity chemical attraction between NGF and p75NTR mediated the migration of SCs to pancreatic cancer cells and colon cancer cells instead of normal cells. After using small-molecule inhibitors of TrkA and p75 NTR to block the p75NTR signaling pathway, this chemoattraction process was inhibited.	[36]
	BDNF	(i) SC-released BDNF activated the BDNF/TrkB signaling pathway to promote EMT in salivary adenoid cystic carcinoma, which was represented by the downregulation of E-cadherin and the upregulation of N-cadherin and vimentin, mesenchymal-like morphology changes, and enhanced invasion and migration capabilities.	[72–74]
		(ii) In head and neck squamous cell carcinoma, SCs and tumor cells both highly expressed BDNF and TrkB. The BDNF/TrkB signaling axis is crucial to increase SC migration and tumor metastasis.
	NT-3	(i) In salivary adenoid cystic carcinoma, tumors secreting NT-3 are bound to TrkC on SCs. Activation of the NT-3/TrkC signaling axis promotes the directional migration and inhibits the cell apoptosis of both SCs and tumor cells. SCs can move to tumor cells before the tumors invade nerves and stimulate tumors to release more NT-3. This phenomenon forms a positive feedback axis to regulate the development of PNI and leads to poor prognosis.	[75]
Cytokines	CCL2	(i) In the TME of cervical cancer, SC upregulates the CCL2 secretion, and tumor cells upregulate the CCR2 receptor. Enhanced CLL2/CCR2 signal transduction promotes the proliferation, migration, invasion, and EMT of cervical cancer and invasion along the sciatic nerve. In turn, tumor cells promote SCs to secrete more MMP-2, MMP-9, and MMP-12, which enhances the degradation of ECM to eliminate tissue obstacles for the movement and migration of SCs and tumor metastasis.	[76]
	CXCL5	(i) In lung cancer, SC-derived CXCL5 is upregulated, and CXCL5 binds to CXCR2 to activate the PI3K/AKT/GSK-3β/Snail/Twist signaling pathway in tumor cells, which enhances the invasion and metastasis of lung cancer via EMT.	[77]
	CXCL12	(i) Tumor or hypoxia induces the high expression of CXCR4/CXCR7 in SCs, which is recruited by CXCL12 from pancreatic cancer cells; thus, it initiates the cancer-nerve contact in the early stage of tumors. This CXCL12-dependent mechanism can also suppress intrinsic molecular pain pathways and spinal astrocytes and microglia in SCs in vivo to decrease the pain sensation.	[78]
	GM-CSF	(i) In pancreatic cancer, the expression of HIF-1α is upregulated and induced the secretion of GM-CSF by tumor cells. GM-CSF can promote the migration of SCs, which promotes the tumor-nerve interactions and occurrence of PNI.	[79]
	IL-6	(i) In the interactions between pancreatic cancer and SCs, IL-1β secreted by tumor cells combines with IL-1R1 on SCs to activate the nuclear factor (NF)-κB pathway, which increases the production of cytokines, including IL-6, in SCs. In turn, IL-6 activates the STAT3 signaling pathway in cancer cells by binding to the IL-6R-GP130 complex to promote EMT, migration, and invasion of cancer cells.	[80, 81]
		(ii) Hypoxia and IL-6 secreted from tumor cells induce the reactive gliosis of SCs that suppress spinal astroglia and microglia; thus, they inhibit the painful conduction in the early stages of tumors.
	TNF-α	(i) TNF-α is overexpressed in oral cancer and can activate and recruit SCs. The activated SCs increase the proliferation and migration and release more TNFα and NGF to promote cancer proliferation, progression, and nociception.	[82]
	TGF-β	(i) A large amount of TGF-β secreted by SCs activated the TGF-β/SMAD signaling pathway in pancreatic cancer cells to induce EMT to promote the migration, invasion process, and PNI.	[70]
Others	Adenosine	(i) The interactions between SCs and oral squamous carcinoma cells increase adenosine production, which stimulates the cell proliferation and migration of two cell types through binding to ADORA2B and further stimulates the secretion of IL-6 in SCs.	[83]
	L1CAM	(i) In pancreatic cancer, SCs secrete soluble L1CAM combined with integrin on tumor cells and activate the STAT3 kinase signaling pathway to increase the secretion of MMP-2 and MMP-9 and promote PNI.	[84]

Abbreviation: A6BA, laminin-binding integrin A6B1; ADORA2B, adenosine receptor A2B; BDNF, brain-derived neurotrophic factor; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CXCL, C-X-C motif chemokine ligand; CXCR, C-X-C motif chemokine receptor; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIF-1α, hypoxia-inducible factor-1α; IL-1β, interleukin-1β; IL-1R1, interleukin-1 receptor type 1; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; LACAM, L1 cell adhesion molecule; MMP, matrix metalloprotein; NF-κB, nuclear factor-κB; NGF, nerve growth factor; NT-3, neurotrophin-3; p75NTR, p75 neurotrophin receptor; PNI, perineural invasion; SCs, Schwann cells; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor-β; TME, tumor microenvironment; TNF-α, tumor necrosis factor-α; TrkA/B/C, tropomyosin-related receptor tyrosine kinases A/B/C.