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Review
. 2016 Apr;77(2):96-106.
doi: 10.1055/s-0036-1571835. Epub 2016 Mar 10.

Mechanisms of Perineural Invasion

Richard L Bakst  1 , Richard J Wong  2
Affiliations
Review

Mechanisms of Perineural Invasion

Richard L Bakst et al. J Neurol Surg B Skull Base. 2016 Apr.

Abstract

Perineural invasion (PNI) is the neoplastic invasion of nerves. PNI is widely recognized as an important adverse pathological feature of many malignancies, including pancreatic, prostate, and head and neck cancers and is associated with a poor prognosis. Despite widespread acknowledgment of the clinical significance of PNI, the mechanisms underlying its pathogenesis remain largely unknown. Recent theories of PNI pathogenesis have placed a significant emphasis on the active role of the nerve microenvironment, with PNI resulting from well-orchestrated reciprocal interactions between cancer and host. Elucidating the mechanisms involved in PNI may translate into targeted therapies for this ominous process.

Keywords: chemokine; head and neck cancer; neurotrophic factors; perineural invasion.

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Figures

Fig. 1
Fig. 1
Peripheral nerve structure. A nerve sheath is composed of three tissue layers consisting of the epineurium, perineurium, and endoneurium.
Fig. 2
Fig. 2
In vitro dorsal root ganglion (DRG) model of perineural invasion. (A) Murine DRG are suspended in a Matrigel matrix (Corning Lifesciences, Tewksbury, Massachusetts, United States) following explant. (B) Over the next few days, neurites sprout from the central ganglion. (C) Cancer is cocultured adjacent to the DRG and over time invades the neurites (dotted black line), which can be quantified.
Fig. 3
Fig. 3
In vivo sciatic nerve model of perineural invasion (PNI). (A) Cancer is injected into the distal sciatic nerve. (B) With time, the sciatic nerve becomes infiltrated and thickened as cancer invades unidirectionally toward the spinal cord as seen grossly, (C) on magnetic resonance imaging (dotted white line), and (D) histologically. (E) PNI can be functionally followed by monitoring hind limb function.
Fig. 4
Fig. 4
Molecular mechanisms of perineural invasion (PNI). PNI results from multidirectional signaling between the cancer and the nerve microenvironment involving various signaling and cellular adhesion molecules. BDNF, brain-derived neurotrophic factor; COX2, cyclooxygenase-2; CSF1, colony stimulating factor 1; CSF1R, colony stimulating factor 1 receptor; ECM, extracellular matrix; GAL; galanin; GDNF, glial cell line-derived neurotrophic factor; GFRα, GDNF receptor-α; L1CAM, L1 cell adhesion molecule; MAG, myelin-associated glycoprotein; MMP, matrix metalloproteinase; NCAM, neural cell adhesion molecule; NGF, nerve growth factor; NT3, neurotrophin-3; PGE2, prostaglandin E2.
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