Linking differential radiation responses to glioma heterogeneity
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Chao Ke1,2, Katherine Tran3, Yumay Chen4, Anne T. Di Donato1, Liping Yu3, Yuanjie Hu1, Mark E. Linskey1, Ping H. Wang4, Charles L. Limoli3, Yi-Hong Zhou1,2
1 Neurological Surgery, University of California, Irvine, CA, USA
2 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
3 Radiation Oncology, University of California, Irvine, CA, USA
4 Medicine, University of California, Irvine, CA, USA
Yi-Hong Zhou, email:
Charles Limoli, email:
Keywords: glioma, cellular heterogeneity, tumorigenicity, redox homeostasis, metabolic state, radiosensitivity.
Received: December 3, 2013 Accepted: March 11, 2014 Published: March 12, 2014
The phenotypic and genetic diversity that define tumor subpopulations within high-grade glioma can lead to therapeutic resistance and tumor recurrence. Given that cranial irradiation is a frontline treatment for malignant glioma, understanding how irradiation selectively effects different cellular subpopulations within these heterogeneous cancers should help identify interventions targeted to better combat this deadly disease. To analyze the radiation response of distinct glioma subpopulations, 2 glioma cells lines (U251, A172) were cultured under conditions that promoted either adherence or non-adherent spheroids. Past work has demonstrated that subpopulations derived from defined culture conditions exhibit differences in karyotype, proliferation, gene expression and tumorigenicity. Spheroid cultures from each of the glioma cell lines were found to be more radiosensitive, which was consistent with higher levels of oxidative stress and lower levels of both oxidative phosphorylation and glycolytic metabolism 1 week following irradiation. In contrast, radioresistant non-spheroid parental cultures showed increased glycolytic activity in response to irradiation, while oxidative phosphorylation was affected to a lesser extent. Overall these data suggest that prolonged radiation-induced oxidative stress can compromise the metabolic state of certain glioma subpopulations thereby altering their sensitivity to an important therapeutic intervention used routinely for the control of glioma.
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