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Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance

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dc.contributor.author Abou-Antoun, Tamara J.
dc.contributor.author Nazarian, Javad
dc.contributor.author Ghanem, Anthony
dc.contributor.author Vukmanovic, Stanislav
dc.contributor.author Sandler, Anthony D.
dc.date.accessioned 2019-11-07T12:39:20Z
dc.date.available 2019-11-07T12:39:20Z
dc.date.copyright 2018 en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://hdl.handle.net/10725/11503
dc.description.abstract Despite significant advances in cancer treatment and management, more than 60% of patients with neuroblastoma present with very poor prognosis in the form of metastatic and aggressive disease. Solid tumors including neuroblastoma are thought to be heterogeneous with a sub-population of stem-like cells that are treatment-evasive with highly malignant characteristics. We previously identified a phenomenon of reversible adaptive plasticity (RAP) between anchorage dependent (AD) cells and anchorage independent (AI) tumorspheres in neuroblastoma cell cultures. To expand our molecular characterization of the AI tumorspheres, we sought to define the comprehensive proteomic profile of murine AD and AI neuroblastoma cells. The proteomic profiles of the two phenotypic cell populations were compared to each other to determine the differential protein expression and molecular pathways of interest. We report exclusive or significant up-regulation of tumorigenic pathways expressed by the AI tumorspheres compared to the AD cancer cells. These pathways govern metastatic potential, enhanced malignancy and epithelial to mesenchymal transition. Furthermore, radio-therapy induced significant up-regulation of specific tumorigenic and proliferative proteins, namely survivin, CDC2 and the enzyme Poly [ADP-ribose] polymerase 1. Bio-functional characteristics of the AI tumorspheres were resistant to sutent inhibition of receptor tyrosine kinases (RTKs) as well as to 2.5 Gy radio-therapy as assessed by cell survival, proliferation, apoptosis and migration. Interestingly, PDGF-BB stimulation of the PDGFRβ led to transactivation of EGFR and VEGFR in AI tumorspheres more potently than in AD cells. Sutent inhibition of PDGFRβ abrogated this transactivation in both cell types. In addition, 48 h sutent treatment significantly down-regulated the protein expression of PDGFRβ, MYCN, SOX2 and Survivin in the AI tumorspheres and inhibited tumorsphere self-renewal. Radio-sensitivity in AI tumorspheres was enhanced when sutent treatment was combined with survivin knock-down. We conclude that AI tumorspheres have a differential protein expression compared to AD cancer cells that contribute to their malignant phenotype and radio-resistance. Specific targeting of both cellular phenotypes is needed to improve outcomes in neuroblastoma patients. en_US
dc.language.iso en en_US
dc.title Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance en_US
dc.type Article en_US
dc.description.version Published en_US
dc.title.subtitle a possible explanation for radio-therapy resistance en_US
dc.author.school SOP en_US
dc.author.idnumber 201005279 en_US
dc.author.department Pharmaceutical Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Plos one en_US
dc.journal.volume 13 en_US
dc.journal.issue 1 en_US
dc.article.pages e0189711 en_US
dc.identifier.doi https://doi.org/10.1371/journal.pone.0189711 en_US
dc.identifier.ctation Abou-Antoun, T. J., Nazarian, J., Ghanem, A., Vukmanovic, S., & Sandler, A. D. (2018). Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant properties: A possible explanation for radio-therapy resistance. PloS one, 13(1), e0189711. en_US
dc.author.email tamara.abouantoun@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189711 en_US
dc.author.affiliation Lebanese American University en_US


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