CS-14NEUROTROPHIN RECEPTORS TrkB AND TrkC ARE REQUIRED FOR SURVIVAL OF BRAIN TUMOR INITIATING CELLS

Neurotrophins (NGF, BDNF and NT3) and their receptors (TrkA, TrkB, TrkC and p75NTR) are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75NTR is required for glioma invasion and proliferation. However, the role of other Trk receptors has not been examined. In this study, we investigated the importance of neurotrophin receptors TrkB and TrkC in survival of brain tumor initiating cells (BTICs). We used human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas and examined the expression of neurotrophin receptors and studied their role in survival/growth these cells in vitro, we have also examined the mechanism underlie. Here, we show that human malignant glioma tissues and tumor-initiating cells express the neurotrophin receptors TrkB and TrkC, not TrkA and they also express neurotrophins NGF, BDNF and NT3. Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 stimulates Trk phosphorylation, activates Erk and Akt and enhances tumor-initiating cell viability and growth. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition using inhibitors of Trk, Erk and Akt, decreases neurotrophin-dependent Trk phosphorylation, Erk and Akt activation and BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling and further neurotrophin signaling is required for maintains long-term BTIC growth in the absence of EGF and FGF, and this effect is attenuated with Trk, Erk and Akt inhibitors. In vivo experiments are under progress. Our results highlight a novel role for neurotrophin signaling in malignant glioma and suggest that Trks could be a target for combinatorial treatment.