Abstract
Background Ependymoma management remains challenging because of the inherent chemoresistance of this tumor. To determine whether ependymoma stem cells (SCs) might contribute to therapy resistance, we investigated the sensitivity of ependymoma SCs to temozolomide and etoposide. Methods The efficacies of the two DNA damaging agents were explored in two ependymoma SC lines in vitro and in vivo models. Results Ependymoma SC lines were highly sensitive to temozolomide and etoposide in vitro, but only temozolomide impaired tumor-initiation properties. Consistently, temozolomide but not etoposide showed significant antitumoral activity on ependymoma SC-driven subcutaneous and orthotopic xenografts by reducing the mitotic fraction. In vitro temozolomide at the EC50 (10 μM) induced accumulation of cells in the G 2/M phase that was unexpectedly accompanied by downregulation of p27 and p21 without modulation of full-length p53 (FLp53). Differentiation-committed ependymoma SCs acquired resistance to temozolomide. Inhibition of proliferation was partly due to apoptosis, that occurred earlier in differentiated cells as compared to neurospheres. The activation of apoptosis correlated with an increase in p53β/γ isoforms without modulation of FLp53 under both serum-free and differentiation-promoting media. Incubation of cells in both conditions with temozolomide resulted in increased glioneuronal differentiation exhibiting elevated glial fibrillary acidic protein, galactosylceramidase, and βIII-tubulin expression compared to untreated controls. O 6-methylguanine DNA methyltransferase (MGMT) transcript levels were very low in SCs, and were increased by treatment and, epigenetically, by differentiation through MGMT promoter unmethylation. Conclusion Ependymoma growth might be impaired by temozolomide through preferential depletion of a less differentiated, more tumorigenic, MGMT-negative cell population with stem-like properties.
| Original language | English |
|---|---|
| Pages (from-to) | 1067-1077 |
| Number of pages | 11 |
| Journal | Neuro-Oncology |
| Volume | 16 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- Differentiation
- Ependymoma stem cells
- MGMT
- Orthotopic models
- Temozolomide
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Clinical Neurology
- Medicine(all)
Cite this
Ependymoma stem cells are highly sensitive to temozolomide in vitro and in orthotopic models. / Meco, Daniela; Servidei, Tiziana; Lamorte, Giuseppe; Binda, Elena; Arena, Vincenzo; Riccardi, Riccardo.
In: Neuro-Oncology, Vol. 16, No. 8, 2014, p. 1067-1077.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ependymoma stem cells are highly sensitive to temozolomide in vitro and in orthotopic models
AU - Meco, Daniela
AU - Servidei, Tiziana
AU - Lamorte, Giuseppe
AU - Binda, Elena
AU - Arena, Vincenzo
AU - Riccardi, Riccardo
PY - 2014
Y1 - 2014
N2 - Background Ependymoma management remains challenging because of the inherent chemoresistance of this tumor. To determine whether ependymoma stem cells (SCs) might contribute to therapy resistance, we investigated the sensitivity of ependymoma SCs to temozolomide and etoposide. Methods The efficacies of the two DNA damaging agents were explored in two ependymoma SC lines in vitro and in vivo models. Results Ependymoma SC lines were highly sensitive to temozolomide and etoposide in vitro, but only temozolomide impaired tumor-initiation properties. Consistently, temozolomide but not etoposide showed significant antitumoral activity on ependymoma SC-driven subcutaneous and orthotopic xenografts by reducing the mitotic fraction. In vitro temozolomide at the EC50 (10 μM) induced accumulation of cells in the G 2/M phase that was unexpectedly accompanied by downregulation of p27 and p21 without modulation of full-length p53 (FLp53). Differentiation-committed ependymoma SCs acquired resistance to temozolomide. Inhibition of proliferation was partly due to apoptosis, that occurred earlier in differentiated cells as compared to neurospheres. The activation of apoptosis correlated with an increase in p53β/γ isoforms without modulation of FLp53 under both serum-free and differentiation-promoting media. Incubation of cells in both conditions with temozolomide resulted in increased glioneuronal differentiation exhibiting elevated glial fibrillary acidic protein, galactosylceramidase, and βIII-tubulin expression compared to untreated controls. O 6-methylguanine DNA methyltransferase (MGMT) transcript levels were very low in SCs, and were increased by treatment and, epigenetically, by differentiation through MGMT promoter unmethylation. Conclusion Ependymoma growth might be impaired by temozolomide through preferential depletion of a less differentiated, more tumorigenic, MGMT-negative cell population with stem-like properties.
AB - Background Ependymoma management remains challenging because of the inherent chemoresistance of this tumor. To determine whether ependymoma stem cells (SCs) might contribute to therapy resistance, we investigated the sensitivity of ependymoma SCs to temozolomide and etoposide. Methods The efficacies of the two DNA damaging agents were explored in two ependymoma SC lines in vitro and in vivo models. Results Ependymoma SC lines were highly sensitive to temozolomide and etoposide in vitro, but only temozolomide impaired tumor-initiation properties. Consistently, temozolomide but not etoposide showed significant antitumoral activity on ependymoma SC-driven subcutaneous and orthotopic xenografts by reducing the mitotic fraction. In vitro temozolomide at the EC50 (10 μM) induced accumulation of cells in the G 2/M phase that was unexpectedly accompanied by downregulation of p27 and p21 without modulation of full-length p53 (FLp53). Differentiation-committed ependymoma SCs acquired resistance to temozolomide. Inhibition of proliferation was partly due to apoptosis, that occurred earlier in differentiated cells as compared to neurospheres. The activation of apoptosis correlated with an increase in p53β/γ isoforms without modulation of FLp53 under both serum-free and differentiation-promoting media. Incubation of cells in both conditions with temozolomide resulted in increased glioneuronal differentiation exhibiting elevated glial fibrillary acidic protein, galactosylceramidase, and βIII-tubulin expression compared to untreated controls. O 6-methylguanine DNA methyltransferase (MGMT) transcript levels were very low in SCs, and were increased by treatment and, epigenetically, by differentiation through MGMT promoter unmethylation. Conclusion Ependymoma growth might be impaired by temozolomide through preferential depletion of a less differentiated, more tumorigenic, MGMT-negative cell population with stem-like properties.
KW - Differentiation
KW - Ependymoma stem cells
KW - MGMT
KW - Orthotopic models
KW - Temozolomide
UR - http://www.scopus.com/inward/record.url?scp=84904346409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904346409&partnerID=8YFLogxK
U2 - 10.1093/neuonc/nou008
DO - 10.1093/neuonc/nou008
M3 - Article
C2 - 24526307
AN - SCOPUS:84904346409
VL - 16
SP - 1067
EP - 1077
JO - Neuro-Oncology
JF - Neuro-Oncology
SN - 1522-8517
IS - 8
ER -