Schwann cells induce cancer cell dispersion and invasion
Sylvie Deborde, … , Alan Hall, Richard J. Wong
Sylvie Deborde, … , Alan Hall, Richard J. Wong
Published April 1, 2016; First published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1538-1554. https://doi.org/10.1172/JCI82658.
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Research Article Cell biology Oncology

Schwann cells induce cancer cell dispersion and invasion

Abstract

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

Authors

Sylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, Richard J. Wong

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Figure 1

Increase of GFAP+ SCs in human and in murine perineural invasion specimens.

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Increase of GFAP+ SCs in human and in murine perineural invasion specime...
(A) Representative images of nerve sections with GFAP (green) and S100 (red) staining in patients with adenocarcinoma pancreatic cancer and corresponding H&E sections. Control images are from a different tissue section from the same patient, taken in an area of the pancreas without cancer. Scale bar: 100 μm. PNI, perineural invasion specimens. (B) Quantification of nerves that scored negatively (0), moderately (+), or highly (++) for GFAP in 8 patients (numbered 1–8) in control and matched tumor sections. (C) Quantification of GFAP+ nerves (+ and ++) expressed by percentage per slide (n = 8). (D) A murine sciatic nerve injected with PBS or MiaPaCa-2 cells, showing increased levels of GFAP+ SCs in cancer cell–injected nerves. Immunofluorescence staining for GFAP (green) and nuclei (blue). Scale bar: 200 μm. (E and F) Quantification of GFAP+ SCs in PBS- (n = 23 images from 5 nerves), MiaPaCa-2 cell– (n = 13 images from 3 nerves), and Panc1 cell–injected sciatic nerves (n = 16 images from 3 nerves), as measured by (E) the area covered by GFAP signal and (F) the integrated fluorescent intensity. (G) Myelin protein zero (MPZ) staining in murine sciatic nerves injected with PBS or MiaPaCa-2 cells. Immunofluorescence staining for myelin protein zero (green) and nuclei (blue). Scale bar: 200 μm. (H and I) Quantification of myelin protein zero staining in PBS- (n = 15 images from 5 nerves), MiaPaCa-2 cell– (n = 15 images from 3 nerves), and Panc1 cell–injected sciatic nerves (n = 9 images from 3 nerves), as measured by area covered by (H) the myelin protein zero signal and (I) the integrated fluorescent intensity. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, t test (C) or 1-way ANOVA with Holm-Sidak’s multiple comparisons test (E, F, H, and I).