PMID- 23455321 OWN - NLM STAT- MEDLINE DCOM- 20140423 LR - 20211021 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 33 IP - 8 DP - 2014 Feb 20 TI - Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest-derived cell line. PG - 977-85 LID - 10.1038/onc.2013.39 [doi] AB - Neuroblastoma arises from sympathoadrenal progenitors of the neural crest and expression of the neurotrophin receptor TrkB and its ligand, brain-derived neurotrophic factor (BDNF), is correlated with poor prognosis. Although activated TrkB signaling promotes a more aggressive phenotype in established neuroblastoma cell lines, whether TrkB signaling is sufficient to transform neural crest-derived cells has not been investigated. To address the role of TrkB signaling in malignant transformation, we removed two immunoglobulin-like domains from the extracellular domain of the full-length rat TrkB receptor to create a DeltaIgTrkB that is constitutively active. In the pheochromocytoma-derived cell line PC12, DeltaIgTrkB promotes differentiation by stimulating process outgrowth; however, in the rat neural crest-derived cell line NCM-1, DeltaIgTrkB signaling produces a markedly transformed phenotype characterized by increased proliferation, anchorage-independent cell growth, anoikis resistance and matrix invasion. Furthermore, expression of DeltaIgTrkB leads to the upregulation of many transcripts encoding cancer-associated genes including cyclind1, twist1 and hgf, as well as downregulation of tumor suppressors such as pten and rb1. In addition, DeltaIgTrkB NCM-1 cells show a 21-fold increase in mRNA for MYCN, the most common genetic marker for a poor prognosis in neuroblastoma. When injected into NOD SCID mice, control GFP NCM-1 cells fail to grow whereas DeltaIgTrkB NCM-1 cells form rapidly growing and invasive tumors necessitating euthanasia of all mice by 15 days post injection. In summary, these results indicate that activated TrkB signaling is sufficient to promote the formation of a highly malignant phenotype in neural crest-derived cells. FAU - Dewitt, J AU - Dewitt J AD - Department of Anatomy and Neurobiology and Neuroscience Graduate Program, University of Vermont, Burlington, VT, USA. FAU - Ochoa, V AU - Ochoa V AD - Department of Anatomy and Neurobiology and Neuroscience Graduate Program, University of Vermont, Burlington, VT, USA. FAU - Urschitz, J AU - Urschitz J AD - Department of Anatomy, Biochemistry, and Physiology, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA. FAU - Elston, M AU - Elston M AD - Department of Anatomy, Biochemistry, and Physiology, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA. FAU - Moisyadi, S AU - Moisyadi S AD - 1] Department of Anatomy, Biochemistry, and Physiology, John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA [2] Manoa BioSciences, Honolulu, HI, USA. FAU - Nishi, R AU - Nishi R AD - Department of Anatomy and Neurobiology and Neuroscience Graduate Program, University of Vermont, Burlington, VT, USA. LA - eng GR - R21 NS076969/NS/NINDS NIH HHS/United States GR - P30RR032135/RR/NCRR NIH HHS/United States GR - P30 GM103498/GM/NIGMS NIH HHS/United States GR - 5P20RR024206/RR/NCRR NIH HHS/United States GR - R21NS25788/NS/NINDS NIH HHS/United States GR - R01 GM083158/GM/NIGMS NIH HHS/United States GR - U54 MD007584/MD/NIMHD NIH HHS/United States GR - R01GM083158-01A1/GM/NIGMS NIH HHS/United States GR - P20 RR024206/RR/NCRR NIH HHS/United States GR - P20 GM103457/GM/NIGMS NIH HHS/United States GR - P30GM103498/GM/NIGMS NIH HHS/United States GR - P30 RR032135/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130304 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Immunoglobulins) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - *Cell Transformation, Neoplastic MH - Gene Expression MH - Immunoglobulins/metabolism MH - Neural Crest/cytology/*metabolism MH - PC12 Cells MH - Phenotype MH - Rats MH - Receptor, trkB/metabolism/*physiology MH - Signal Transduction PMC - PMC3930615 MID - NIHMS550072 COIS- Conflict of interest The authors declare no conflict of interest. EDAT- 2013/03/05 06:00 MHDA- 2014/04/24 06:00 PMCR- 2014/08/20 CRDT- 2013/03/05 06:00 PHST- 2012/06/27 00:00 [received] PHST- 2012/12/17 00:00 [revised] PHST- 2013/01/07 00:00 [accepted] PHST- 2013/03/05 06:00 [entrez] PHST- 2013/03/05 06:00 [pubmed] PHST- 2014/04/24 06:00 [medline] PHST- 2014/08/20 00:00 [pmc-release] AID - onc201339 [pii] AID - 10.1038/onc.2013.39 [doi] PST - ppublish SO - Oncogene. 2014 Feb 20;33(8):977-85. doi: 10.1038/onc.2013.39. Epub 2013 Mar 4.