title: Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor.
abstract: 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 GFRα1 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/GFRα1 receptors expressed by the cancer cells.
authors.affiliation: The Laboratory for Applied Cancer Research, The Clinical Research Center at Rambam, Haifa, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Shabtay-Orbach
authors.affiliation: The Laboratory for Applied Cancer Research, The Clinical Research Center at Rambam, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Rapaport School of Medicine, The Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Amit
authors.affiliation: The Laboratory for Applied Cancer Research, The Clinical Research Center at Rambam, Haifa, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Binenbaum
authors.affiliation: The Laboratory for Applied Cancer Research, The Clinical Research Center at Rambam, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Rapaport School of Medicine, The Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: Shorook
authors.initials: S
authors.lastname: Na'ara
authors.affiliation: The Laboratory for Applied Cancer Research, The Clinical Research Center at Rambam, Haifa, Israel.|Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Rapaport School of Medicine, The Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gil
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D019899:Paracrine Communication; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051096:Proto-Oncogene Proteins c-ret
keywords: MAPK; RET; astrocytes; glial-derived neurotrophic factor; glioma; invasion