Schwann cell contact induces cancer cell dispersion and perineural invasion.

  • Major finding: Schwann cell contact induces cancer cell dispersion and perineural invasion.

  • Mechanism: Schwann cells promote cancer cell protrusions away from neighboring cells in an NCAM1-dependent manner.

  • Impact: Cancer cells exploit normal Schwann cell nerve repair programs to promote perineural invasion.

In a variety of malignancies, cancer cells can invade along nerves in an aggressive perineural invasion, which is associated with pain and paralysis as well as reduced survival. A better understanding of the regulation of perineural invasion may aid in the development of improved therapeutic strategies. Schwann cells are a type of glial cell that supports neuronal guidance during nerve repair, similar to cells from the tumor microenvironment contributing to cancer cell invasion. Deborde and colleagues hypothesized that the ability of Schwann cells to guide cells, remodel the matrix, and secrete paracrine signals during neuronal repair might facilitate cancer cell invasion. Analysis of histologic sections from 8 patients with pancreatic adenocarcinoma revealed increased perineural invasion, with more Schwann cells expressing GFAP, a marker for a Schwann cell subtype that facilitates repair during neuronal guidance, than matched control sections. Similar results were observed in thyroid cancer, salivary duct carcinoma, and cutaneous squamous cell carcinoma. Further, in a xenograft model of perineural invasion, cancer cells increased the number of GFAP+ Schwann cells. The presence of GFAP+ Schwann cells in 3-D cancer cell sphere cultures disrupted the spheres and enhanced invasion by promoting dissociation of individual cells, formation of linear cell chains, and disruption of cancer cell contacts by intercalating between cells. At Schwann cell contact sites, cancer cells formed protrusions and migrated toward Schwann cells, which depended on the presence of NCAM1, which has been correlated with the presence of perineural invasion. Invasion of pancreatic cancer cells injected into the sciatic nerves of NCAM1 knockout mice was decreased compared to WT mice. Taken together, these findings indicate that NCAM1 is a critical mediator of Schwann cell–induced cancer cell invasion, and suggest that disruption of Schwann cell–cancer cell contacts may reduce tumor invasion.

Deborde S, Omelchenko T, Lyubchik A, Zhou Y, He S, McNamara WF, et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest 2016;126:1538–54.

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