Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche

Perineural invasion (PNI) can be found in a variety of malignant tumors. It is a sign of tumor metastasis and invasion and portends the poor prognosis of patients. The pathological description and clinical significance of PNI are clearly understood, but exploration of the underlying molecular mechanism is ongoing. It was previously thought that the low-resistance channel in the anatomic region led to the occurrence of PNI. However, with rapid development of precision medicine and molecular biology, we have gradually realized that the occurrence of PNI is not the result of a single factor. The latest study suggests that PNI of cancer is a continuous and multistep process. A specific peripheral microenvironment, also called the perineural niche, is formed by neural cells, supporting cells, recruited inflammatory cells, altered extracellular matrix, blood vessels, and immune components in the background of carcinoma. Various soluble signaling molecules and their receptors comprise a complex signal network, which achieves the interaction between nerve and tumor. Nerve cells and tumor cells can interact directly or through the opening and closing of the signal transduction pathways and/or the recognition and response of the ligands and receptors. The information is transferred to the targets accurately and effectively, leading to the specific interactions between the nerve cells and the malignant tumor cells. PNI occurs through changes in nerve cells and supporting cells in the background of cancer; change and migration of the perineural matrix; enhancement of the viability, mobility, and invasiveness of the tumor cells; injury and regeneration of nerve cells; interaction, chemotactic movement, contact, and adherence of the nerve cells and the tumor cells; escape from autophagy, apoptosis, and immunological surveillance of tumor cells; and so on. Certainly, exploring the mechanism of PNI clearly has great significance for blocking tumor progression and improving patient survival. The current review aims to elucidate the cellular and molecular mechanisms of PNI, which may help us find a strategy for improving the prognosis of malignant tumors.