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Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line

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...

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Autores principales: DeWitt, John, Ochoa, Vanessa, Urschitz, Johann, Elston, Marlee, Moisyadi, Stefan, Nishi, Rae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930615/
https://www.ncbi.nlm.nih.gov/pubmed/23455321
http://dx.doi.org/10.1038/onc.2013.39
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author DeWitt, John
Ochoa, Vanessa
Urschitz, Johann
Elston, Marlee
Moisyadi, Stefan
Nishi, Rae
author_facet DeWitt, John
Ochoa, Vanessa
Urschitz, Johann
Elston, Marlee
Moisyadi, Stefan
Nishi, Rae
author_sort DeWitt, John
collection PubMed
description 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 ΔIgTrkB that is constitutively active. In the pheochromocytoma-derived cell line PC12, ΔIgTrkB promotes differentiation by stimulating process outgrowth; however, in the rat neural crest derived cell line NCM-1, ΔIgTrkB signaling produces a markedly transformed phenotype characterized by increased proliferation, anchorage-independent cell growth, anoikis resistance, and matrix invasion. Furthermore, expression of ΔIgTrkB leads to up-regulation of many transcripts encoding cancer-associated genes including cyclind1, twist1, and hgf, as well as down-regulation of tumor suppressors such as pten, and rb1. In addition, ΔIgTrkB 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 while ΔIgTrkB 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.
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spelling pubmed-39306152014-08-20 Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line DeWitt, John Ochoa, Vanessa Urschitz, Johann Elston, Marlee Moisyadi, Stefan Nishi, Rae Oncogene Article 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 ΔIgTrkB that is constitutively active. In the pheochromocytoma-derived cell line PC12, ΔIgTrkB promotes differentiation by stimulating process outgrowth; however, in the rat neural crest derived cell line NCM-1, ΔIgTrkB signaling produces a markedly transformed phenotype characterized by increased proliferation, anchorage-independent cell growth, anoikis resistance, and matrix invasion. Furthermore, expression of ΔIgTrkB leads to up-regulation of many transcripts encoding cancer-associated genes including cyclind1, twist1, and hgf, as well as down-regulation of tumor suppressors such as pten, and rb1. In addition, ΔIgTrkB 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 while ΔIgTrkB 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. 2013-03-04 2014-02-20 /pmc/articles/PMC3930615/ /pubmed/23455321 http://dx.doi.org/10.1038/onc.2013.39 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
DeWitt, John
Ochoa, Vanessa
Urschitz, Johann
Elston, Marlee
Moisyadi, Stefan
Nishi, Rae
Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title_full Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title_fullStr Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title_full_unstemmed Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title_short Constitutively active TrkB confers an aggressive transformed phenotype to a neural crest derived cell line
title_sort constitutively active trkb confers an aggressive transformed phenotype to a neural crest derived cell line
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930615/
https://www.ncbi.nlm.nih.gov/pubmed/23455321
http://dx.doi.org/10.1038/onc.2013.39
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