Identification and characterisation of NANOG+/ OCT-4<sup>high</sup>/SOX2+ doxorubicin-resistant stem-like cells from transformed trophoblastic cell lines

Journal article


Balahmar, Reham M., Boocock, David J., Coveney, Clare, Ray, Sankalita, Vadakekolathu, Jayakumar, Regad, Tarik, Ali, Selman and Sivasubramaniam, Shiva 2018. Identification and characterisation of NANOG+/ OCT-4<sup>high</sup>/SOX2+ doxorubicin-resistant stem-like cells from transformed trophoblastic cell lines. Oncotarget. https://doi.org/10.18632/oncotarget.24151
AuthorsBalahmar, Reham M., Boocock, David J., Coveney, Clare, Ray, Sankalita, Vadakekolathu, Jayakumar, Regad, Tarik, Ali, Selman and Sivasubramaniam, Shiva
Abstract

Treatment of gestational trophoblastic diseases (GTD) involves surgery, radiotherapy and chemotherapy. Although, these therapeutic approaches are highly successful, drug resistance and toxicity remain a concern for high risk patients. This Chemoresistance has also been observed in the presence of cancer stem cells that are thought to be responsible for cases of cancer recurrence. In this study, we report the presence of previously unknown populations of trophoblastic stem-like cells (SLCs) that are resistant to the chemotherapeutic drug doxorubicin. We demonstrate that these populations express the stem cell markers NANOG and Sox2 and higher levels of OCT-4 (NANOG+/OCT-4high/SOX2+). Although chemoresistant, we show that the invasive capacity of these trophoblastic SLCs is significantly inhibited by doxorubicin treatment. To better characterise these populations, we also identified cellular pathways that are involved in SLCs-chemoresistance to doxorubicin. In summary, we provide evidence of the presence of NANOG+/OCT-4+/SOX2+ trophoblastic SLCs that are capable to contribute to the susceptibility to GTD and that may be involved in Chemoresistance associated with drug resistance and recurrence in high risk GTDs’ patients. We propose that targeting these populations could be therapeutically exploited for clinical benefit.

Treatment of gestational trophoblastic diseases (GTD) involves surgery, radiotherapy and chemotherapy. Although, these therapeutic approaches are highly successful, drug resistance and toxicity remain a concern for high risk patients. This Chemoresistance has also been observed in the presence of cancer stem cells that are thought to be responsible for cases of cancer recurrence. In this study, we report the presence of previously unknown populations of trophoblastic stem-like cells (SLCs) that are resistant to the chemotherapeutic drug doxorubicin. We demonstrate that these populations express the stem cell markers NANOG and Sox2 and higher levels
of OCT-4 (NANOG+/OCT-4high/SOX2+). Although chemoresistant, we show that the invasive capacity of these trophoblastic SLCs is significantly inhibited by doxorubicin treatment. To better characterise these populations, we also identified cellular pathways that are involved in SLCs-chemoresistance to doxorubicin. In summary, we provide evidence of the presence of NANOG+/OCT-4+/SOX2+ trophoblastic SLCs that are capable to contribute to the susceptibility to GTD and that may be involved in Chemoresistance associated with drug resistance and recurrence in high risk GTDs’ patients. We propose that targeting these populations could be therapeutically exploited for clinical benefit.

Keywordstrophoblast; stem-like cells (SLCs); doxorubicin; embryonic stem cells (ESCs); chemoresistance
Year2018
JournalOncotarget
PublisherImpact Journals
ISSN1949-2553
Digital Object Identifier (DOI)https://doi.org/10.18632/oncotarget.24151
Web address (URL)http://hdl.handle.net/10545/623288
hdl:10545/623288
Publication dates11 Jan 2018
Publication process dates
Deposited14 Jan 2019, 14:28
Accepted02 Jan 2018
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Archived with thanks to Oncotarget

ContributorsNottingham Trent University
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