TY - JOUR
T1 - C-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
AU - von Bueren, André O.
AU - Oehler, Christoph
AU - Shalaby, Tarek
AU - von Hoff, Katja
AU - Pruschy, Martin
AU - Seifert, Burkhardt
AU - Gerber, Nicolas U.
AU - Warmuth-Metz, Monika
AU - Stearns, Duncan
AU - Eberhart, Charles G.
AU - Kortmann, Rolf D.
AU - Rutkowski, Stefan
AU - Grotzer, Michael A.
N1 - Funding Information:
This study was supported by the Swiss National Science Foundation, the Swiss Research Foundation Child and Cancer, and German Children’s Cancer Foundation (Deutsche Kinderkrebsstiftung). Special thanks to Wiebke Treulieb and Christine Lindow (HIT data center) for their excellent data management. We are greatly indebted to the participating pediatric centers in Austria, Germany and Switzerland and to the contributing pathologists for submitting tumor samples. We would like to thank Professor Dr. Josef Jiricny for his advice. The authors thank Florian Marty for his technical assistance in the clonogenic survival assay.
PY - 2011/2/16
Y1 - 2011/2/16
N2 - Background: To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB).Methods: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging.Results: In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively).Conclusions: c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.
AB - Background: To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB).Methods: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging.Results: In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively).Conclusions: c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.
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U2 - 10.1186/1471-2407-11-74
DO - 10.1186/1471-2407-11-74
M3 - Article
C2 - 21324178
AN - SCOPUS:79951556119
SN - 1471-2407
VL - 11
JO - BMC cancer
JF - BMC cancer
M1 - 74
ER -