Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance
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 cel...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , |
| التنسيق: | article |
| منشور في: |
2018
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/11503 https://doi.org/10.1371/journal.pone.0189711 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189711 |
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| _version_ | 1864513488814080000 |
|---|---|
| author | Abou-Antoun, Tamara J. |
| author2 | Nazarian, Javad Ghanem, Anthony Vukmanovic, Stanislav Sandler, Anthony D. |
| author2_role | author author author author |
| author_facet | Abou-Antoun, Tamara J. Nazarian, Javad Ghanem, Anthony Vukmanovic, Stanislav Sandler, Anthony D. |
| author_role | author |
| dc.creator.none.fl_str_mv | Abou-Antoun, Tamara J. Nazarian, Javad Ghanem, Anthony Vukmanovic, Stanislav Sandler, Anthony D. |
| dc.date.none.fl_str_mv | 2018 2019-11-07T12:39:20Z 2019-11-07T12:39:20Z 2019-11-07 |
| dc.identifier.none.fl_str_mv | 1932-6203 http://hdl.handle.net/10725/11503 https://doi.org/10.1371/journal.pone.0189711 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. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189711 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Plos one |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance a possible explanation for radio-therapy resistance |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_216252ef21c284fe3ea740d3f9ea0849 |
| identifier_str_mv | 1932-6203 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. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/11503 |
| publishDate | 2018 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistancea possible explanation for radio-therapy resistanceAbou-Antoun, Tamara J.Nazarian, JavadGhanem, AnthonyVukmanovic, StanislavSandler, Anthony D.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.PublishedN/A2019-11-07T12:39:20Z2019-11-07T12:39:20Z20182019-11-07Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1932-6203http://hdl.handle.net/10725/11503https://doi.org/10.1371/journal.pone.0189711Abou-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.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189711enPlos oneinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/115032021-03-19T10:47:38Z |
| spellingShingle | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance Abou-Antoun, Tamara J. |
| status_str | publishedVersion |
| title | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| title_full | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| title_fullStr | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| title_full_unstemmed | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| title_short | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| title_sort | Molecular and functional analysis of anchorage independent, treatment-evasive neuroblastoma tumorspheres with enhanced malignant propertiesor radio-therapy resistance |
| url | http://hdl.handle.net/10725/11503 https://doi.org/10.1371/journal.pone.0189711 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189711 |