How Schwann cells facilitate cancer progression in nerves

Abstract

Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression.

Keywords: Cancer; Invasion; Migration; Nerve; Perineural invasion; Schwann cell; Tumor microenvironment.

Fig. 1

Schematic representation of nerve structure and Schwann cells distribution. (a) Normal nerve structure showing a large caliber nerve trunk and single nerve fibers at contact with epithelial cells. Myelin, Remak and terminal Schwann cells are shown (b) Nerve with perineural invasion. Cancer cells are present around or in the nerve. At contact with cancer cells, Schwann cells can recruit cancer cells at nerve fibers, induce cancer cell protrusion formation and intercalate between cancer cells

Fig. 2

Molecules involved in the interactions between cancer cells and nerve cells. a Neurotrophic factors, neurotrophins (NGF, BDNF, NT3, and NT4) and their receptors (p75NTR, TrkA, TrkB, and Trkc). b Neurotrophic factors of the GDNF family (GDNF, ARTN, and NRTN) and their receptors (RET, GFRα1, GFRα2, and GFRα3). c Guidance molecules (CX3CL1 and CX3CR1, CCL2, and CCR2, NCAM1, L1CAM, Slit2, and Robo 1&2, PlexinB1, and Sema 4D&4F). d Other molecules [MMP2 and MMP9, MAG and MUC1, neurotransmitters norepinephrine (NE), and acetylcholine (Ach)]. N neuron, SC Schwann cell, CC cancer cell, CSC cancer stem cell, M macrophage. Full arrows show release of soluble factors by specific cell types. Dotted arrows point cell types that express corresponding receptors