Abstract
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.
Highlights
Tumor heterogeneity at both primary and distant metastatic sites has been observed in most cancers at the time of clinical diagnosis [1, 2], where evidence of genetic clonal diversity has been linked to tumor progression [3]
Many of our prior and current findings of clonal heterogeneity www.impactjournals.com/oncotarget were triggered by switching primary parental cells from serum adherent (SA) conditions to those promoting the growth of non-adherent neurospheres (NS) as summarized (Figure 1A)
We found marked copy number variation in specific subpopulations of gliomas derived from single cells that were dependent on culture conditions
Summary
Tumor heterogeneity at both primary and distant metastatic sites has been observed in most cancers at the time of clinical diagnosis [1, 2], where evidence of genetic clonal diversity has been linked to tumor progression [3]. The complex interplay between tumor subpopulations defines the evolution of many cancers [4], and drives the selective pressure for tumor growth and survival against the challenges of radio- and chemotherapy. Significant evidence has reinforced the importance of tumor heterogeneity, where specific subpopulations of cells exhibit distinct phenotypes that compliment one another for achieving enhanced tumorigenicity and treatment resistance [5,6,7]. Multiple complex interactions regulate the transition between different subpopulations within a given cancer, which under certain circumstances can be achieved through epigenetic and/or transcriptional alterations in breast cancer [8], or via chromosome mis-segregation [6] or re-gain of chromosome double minute in malignant glioma [7]. A more detailed understanding of the differential responses to irradiation www.impactjournals.com/oncotarget by distinct subpopulations of glioma cells should provide information useful for improving the curability of gliomas and other deadly cancers
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