| First Author | He S | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 19 | Pages | E2008-17 |
| PubMed ID | 24778213 | Mgi Jnum | J:211075 |
| Mgi Id | MGI:5573098 | Doi | 10.1073/pnas.1402944111 |
| Citation | He S, et al. (2014) GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A 111(19):E2008-17 |
| abstractText | The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)alpha1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRalpha1 released by nerves enhances PNI, even in the absence of cancer cell GFRalpha1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRalpha1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRalpha1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRalpha1(+/-) mice compared with GFRalpha1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRalpha1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRalpha1 expression, suggesting an alternate source of GFRalpha1 in PNI. These findings collectively demonstrate that GFRalpha1 released by nerves enhances PNI through GDNF-RET signaling and that GFRalpha1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior. |
