title: Neurotrophin signaling via TrkB and TrkC receptors promotes the growth of brain tumor-initiating cells.
abstract: Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.
authors.affiliation: From the Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta T2N 4N2, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Lawn
authors.affiliation: the Departments of Neuro-Oncology.
authors.forename: Niveditha
authors.initials: N
authors.lastname: Krishna
authors.affiliation: the Departments of Neuro-Oncology.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pisklakova
authors.affiliation: Biomedical Informatics, and.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Qu
authors.affiliation: Biomedical Informatics, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Fenstermacher
authors.affiliation: Tissue Core, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fournier
authors.affiliation: the Departments of Neuro-Oncology, the Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, Florida 33612.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Vrionis
authors.affiliation: the Departments of Neuro-Oncology, the Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, Florida 33612.
authors.forename: Nam
authors.initials: N
authors.lastname: Tran
authors.affiliation: From the Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta T2N 4N2, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.affiliation: the Departments of Neuro-Oncology, the Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, Florida 33612 Rajappa.Kenchappa@Moffitt.org.
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.affiliation: From the Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta T2N 4N2, Canada, the Departments of Neuro-Oncology, the Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, Florida 33612 Peter.Forsyth@Moffitt.org.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*
chemical_list: D009414:Nerve Growth Factors; D020813:Receptor, trkB; D020812:Receptor, trkC
keywords: Brain-derived Neurotrophic Factor (BDNF); Cancer Stem Cells; Extracellular Signal-regulated Kinase (ERK); Glioblastoma; Neurotrophic Factor; Neurotrophin 3; Neurotrophin Receptor; Trk Receptor