TABLE 1.
Molecular factors involved in perineural invasion (PNI).
| Category | Molecule | Effects in PNI | References |
| Neurotransmitters and their receptors | NE/ADR | Promote cancer cells proliferation, migration, and PNI | Guo et al., 2013; Ma et al., 2019 |
| ACh/AChR | Provoke proliferation and migration of cancer cells | March et al., 2020 | |
| Neurotrophins and their receptors | NGF/TRKA/p75NTR | Mediate a mutual tropism between the nerves and cancer cells | Ceyhan et al., 2008; Ma et al., 2008 |
| NT-3/TRKC | Unclear | — | |
| NT-4/5 | Unclear | — | |
| BDNF/TRKB | Promote cancer cell proliferation | Sclabas et al., 2005 | |
| GDNF/RET/GFRα | Facilitate migration and PNI | Veit et al., 2004; Gil et al., 2010 | |
| Chemokines and their receptors | CX3CR1/CX3CL1 | Contribute to migration and PNI | Marchesi et al., 2010a |
| CCR2/CCL2 | He et al., 2015 | ||
| CXCR4/CXCL12 | Zhang et al., 2008 | ||
| MMPs | MMP-2 | Degrade the matrix around the tumor and the nerve tissue | Klein et al., 2004 |
| MMP-9 | |||
| Other cell-surface molecules and receptors | L1-CAM | A membrane receptor of the immunoglobulin supergene family; contribute to PNI and neuropathic pain | Yamanaka et al., 2007; Ben et al., 2010; Na’ara et al., 2019 |
| NCAM | A membrane receptor of the immunoglobulin supergene family that regulates neuronal adhesion and migration | Kameda et al., 1999; Shang et al., 2007 | |
| Semaphorin 3A/plexins A1-A4 and neuropilin-1 | Regulate the interactions between nerves and cancer cells in the tumor microenvironment | Müller et al., 2007 | |
| Semaphorin 4F | Ding et al., 2013 |
ACh, acetylcholine; ADR, adrenergic receptors; AChR, acetylcholine receptor; BDNF, brain-derived neurotrophic factor; CX3CL1, C-X3-C motif chemokine ligand 1; CX3CR1, C-X3-C motif chemokine receptor 1; CCL2, C-C chemokine ligand 2; CCR2, C-C chemokine receptor 2; CXCR4, C-X-C chemokine receptor type 4; CXCL12, C-X-C motif chemokine 12; GDNF, glial cell line-derived neurotrophic factor; GFRα, GDNF family receptor-alpha; L1-CAM, L1 cell adhesion molecule; MMPs, matrix metalloproteinases; NCAM, neural cell adhesion molecule; NE, norepinephrine; NGF, nerve growth factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; PNI, perineural invasion; p75NTR, p75 neurotrophin receptor; RET, rearranged during transfection; TRKA, tropomyosin receptor kinase A; TRKB, Tropomyosin receptor kinase B; TRKC, tropomyosin receptor kinase C.