Oncotarget

Research Papers:

Dormant glioblastoma cells acquire stem cell characteristics and are differentially affected by Temozolomide and AT101 treatment

Vivian Adamski, Annika Hempelmann, Charlotte Flüh, Ralph Lucius, Michael Synowitz, Kirsten Hattermann and Janka Held-Feindt _

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Oncotarget. 2017; 8:108064-108078. https://doi.org/10.18632/oncotarget.22514

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Abstract

Vivian Adamski1, Annika Hempelmann1, Charlotte Flüh1, Ralph Lucius2, Michael Synowitz1, Kirsten Hattermann2,*, Janka Held-Feindt1,*

1Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany

2Department of Anatomy, University of Kiel, 24118 Kiel, Germany

*These authors shared senior authorship

Correspondence to:

Janka Held-Feindt, email: Janka.Held-Feindt@uksh.de

Keywords: cellular dormancy; stemness; cellular plasticity; chemoresistance; R-(-)-gossypol

Received: July 19, 2017    Accepted: October 28, 2017    Published: November 18, 2017

ABSTRACT

Cellular dormancy is defined as a state in which cells enter quiescence driven by intrinsic or extrinsic factors, and striking parallels exist between the concept of cellular dormancy in malignancies and the cancer stem cell theory. We showed now that the proven dormancy markers insulin-like growth factor-binding protein 5, ephrin receptor A5 and histone cluster 1 H2B family member K were expressed in human glioblastomas in situ, were located in single tumor cells, and could be co-stained with each other and with the stem cell markers krüppel-like factor 4, octamer binding transcription factor 4 and sex determining region Y-box 2. Human non-stem glioblastoma cell lines and primary cultures were characterized by expression of individual, cell-type specific dormancy- and stemness-associated markers, which were (up)regulated and could be co-stained in a cell-type specific manner upon Temozolomide-induced dormancy in vitro. The induction patterns of dormancy- and stemness-associated markers were reflected by cell-type specific responses to Temozolomide-induced and combined Temozolomide/AT101-mediated cytotoxicity in different glioblastoma cell lines and primary cultures in vitro, and accompanied by higher self-renewal capacity and lower TMZ-sensitivity of Temozolomide-pretreated cells. We postulate that a better understanding of the dormant state of tumor cells is essential to further improve efficiency of treatment.


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