Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor

It was suggested that the brain microenvironment plays a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion. In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial-derived neurotrophic factor (GDNF) on tumor invasion. Astrocytes-conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET-Fc chimera or anti-GDNF Ab and by small interfering RNA directed against GDNF expression by astrocytes. Glioma cells incubated with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream activation of AKT. Tumor migration and GDNF-RET-AKT activation was inhibited by the RET small-molecule inhibitor pyrazolopyrimidine-1 (PP1) and by the AKT inhibitor LY294002. Finally, blocking of RET by PP1 or knockout of the RET coreceptor GFR1 in glioma cells reduced the size of brain tumors in immunocompetent mice. We suggest a mechanism by which astrocytes attracted to the glioma tumors facilitate brain invasion by secretion of GDNF and activation of RET/GFR1 receptors expressed by the cancer cells. What's new? Glioblastomas arise in astrocytes, the cells that support the brain, but reproduce quickly and spread to the brain itself. How do astrocytes promote this invasiveness? These authors tested the role of the signaling molecule GDNF in spurring cancer growth. They found that in an astrocyte-rich environment, cultured glioma cells migrated more than usual - but this mobility boost vanished when they prevented GDNF from binding to its receptor, RET. In mice with gliomas, blocking RET slowed the growth of the tumors considerably. This demonstrates for the first time that astrocytes promote tumor invasion via GDNF and RET, and could suggest new treatment avenues.