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

Shivadas Sivasubramaniam; Reham M  Balahmar; David  Boocock; Clare Coveney; Sankalitha Ray; Jayakumar  Vadakekolathu; Tarik  Regard; Selman  Ali

doi:10.18632/oncotarget.24151

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

Shivadas Sivasubramaniam, Reham M Balahmar, David Boocock , Clare Coveney , Sankalitha Ray, Jayakumar Vadakekolathu, Tarik Regard, Selman Ali

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	7054-7065
Number of pages	11
Journal	Oncotarget
Volume	9
Issue number	6
DOIs	https://doi.org/10.18632/oncotarget.24151
Publication status	Published - 11 Jan 2018

Keywords

chemoresistance; doxorubicin; embryonic stem cells (ESCs); stem-like cells (SLCs); trophoblast.

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10.18632/oncotarget.24151

Cite this

@article{c3dfca58a99c416898a8a2b65376d10d,

title = "Identification and characterisation of NANOG+/ OCT-4high/SOX2+ doxorubicin-resistant stem-like cells from transformed trophoblastic cell lines.",

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.",

keywords = "chemoresistance; doxorubicin; embryonic stem cells (ESCs); stem-like cells (SLCs); trophoblast.",

author = "Shivadas Sivasubramaniam and Balahmar, {Reham M} and David Boocock and Clare Coveney and Sankalitha Ray and Jayakumar Vadakekolathu and Tarik Regard and Selman Ali",

year = "2018",

month = jan,

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doi = "10.18632/oncotarget.24151",

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TY - JOUR

T1 - Identification and characterisation of NANOG+/ OCT-4high/SOX2+ doxorubicin-resistant stem-like cells from transformed trophoblastic cell lines.

AU - Sivasubramaniam, Shivadas

AU - Balahmar, Reham M

AU - Boocock , David

AU - Coveney , Clare

AU - Ray, Sankalitha

AU - Vadakekolathu, Jayakumar

AU - Regard, Tarik

AU - Ali, Selman

PY - 2018/1/11

Y1 - 2018/1/11

N2 - 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.

AB - 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.

KW - chemoresistance; doxorubicin; embryonic stem cells (ESCs); stem-like cells (SLCs); trophoblast.

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DO - 10.18632/oncotarget.24151

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