Editors' ChoiceCancer

Nerves Have the Nerve to Ask for It

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Science Signaling  20 May 2014:
Vol. 7, Issue 326, pp. ec132
DOI: 10.1126/scisignal.2005495

Perineural invasion (PNI), the growth of tumor along nerves, is associated with neurological symptoms and decreased survival in patients with diverse types of cancer. The neurotrophic factor GDNF is secreted by nerves and can attract cancer cells. GDNF binds to the membrane-tethered GDNF receptor (GFR) α1, and the GDNF-GFRα1 complex binds to oncogenic receptor tyrosine kinase RET to activate downstream signaling, including phosphorylation of AKT and extracellular signal-regulated kinases (ERKs). In the presence of soluble GDNF, GFRα1 can act in cis or in trans to stimulate RET activity. He et al. showed that both GDNF and GFRα1 were released by nerves to promote RET activation and PNI. In Boyden chamber assays, adding soluble GFRα1 to media containing GDNF enhanced the directional migration of pancreatic cancer cells (which have endogenous RET and GFRα1), pancreatic cells with GFRα1 knockdown, or murine fibroblasts (which lack endogenous RET and GFRα1) overexpressing RET toward GDNF and increased autophosphorylation of RET and activation of AKT and ERK. Fibroblasts overexpressing RET, but not nontransfected fibroblasts, migrated toward explants of dorsal root ganglia (DRG), a mixture of peripheral neurons, glia, and support cells that secretes GDNF. Cultured media from DRG explants contained soluble GFRα1 and stimulated RET activation and directional migration of fibroblasts overexpressing RET. Adding an antibody against GFRα1 to DRG-cultured media blocked RET activation in RET-overexpressing fibroblasts and reduced the invasion of pancreatic cancer cells into DRG explants in a coculture assay. Similar to control pancreatic cancer cells, cells with stable knockdown of RET or GFRα1 formed tumors when injected into the connective tissue of the sciatic nerve of mice. However, whereas control cells and cells with GFR1α1 knockdown induced paralysis and PNI, those with RET knockdown did not, suggesting that GFRα1 is not required in the tumor cells for PNI to occur in vivo. Thus, the release of GFRα1 and GDNF by peripheral nerves may attract cancer cells and promote PNI.

S. He, C.-H. Chen, N. Chernichenko, S. He, R. L. Bakst, F. Barajas, S. Deborde, P. J. Allen, E. Vakiani, Z. Yu, R. J. Wong, GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc. Natl. Acad. Sci. U.S.A. 111, E2008–E2017 (2014). [Abstract] [Full Text]

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