Abstract
EGFR amplification in cells having double minute chromosomes (DM) is commonly found in glioblastoma multiforme (GBM); however, how much it contributes to the current failure to treat GBM successfully is unknown. We studied two syngeneic primary cultures derived from a GBM with and without cells carrying DM, for their differential molecular and metabolic profiles, in vivo growth patterns, and responses to irradiation (IR). Each cell line has a distinct molecular profile consistent with an invasive “go” (with DM) or angiogenic “grow” phenotype (without DM) demonstrated in vitro and in intracranial xenograft models. Cells with DM were relatively radio-resistant and used higher glycolytic respiration and lower oxidative phosphorylation in comparison to cells without them. The DM-containing cell was able to restore tumor heterogeneity by mis-segregation of the DM-chromosomes, giving rise to cell subpopulations without them. As a response to IR, DM-containing cells switched their respiration from glycolic metabolism to oxidative phosphorylation and shifted molecular profiles towards that of cells without DM. Irradiated cells with DM showed the capacity to alter their extracellular microenvironment to not only promote invasiveness of the surrounding cells, regardless of DM status, but also to create a pro-angiogenic tumor microenvironment. IR of cells without DM was found primarily to increase extracellular MMP2 activity. Overall, our data suggest that the DM-containing cells of GBM are responsible for tumor recurrence due to their high invasiveness and radio-resistance and the mis-segregation of their DM chromosomes, to give rise to fast-growing cells lacking DM chromosomes.
Highlights
Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer and characteristically recurs despite treatment with post-operative radiation and chemotherapy
The primary human cultures established under neural sphere (NS) or serum adherent (SA) culture conditions, as depicted in Figure 1A, were derived from a recurrent glioblastoma multiforme (GBM) patient (G43) 14 months after initial resection followed by Temozolomide and radiotherapy, and Avastin and Velcade
In contrast to similar variations of Chr7 (Figure 1D and 1F), EGFR copy score showed a high level of EGFR gene amplification in 51A and its clonal line 51AS7, but not in 51B or the other two clonal lines of 51A (51AS3 and 51AS5), which originated from soft-agar colonies (Figure 1A)
Summary
Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer and characteristically recurs despite treatment with post-operative radiation and chemotherapy. Overall survival of patients has been shown to depend on the specific molecular GBM subtype, with proneural and neural subtypes showing poorest response to conventional therapeutic intervention, while classical and mesenchymal subtypes exhibit statistically significant, www.impactjournals.com/oncotarget albeit quantitatively marginal, improvements in survival through extensive tumor resection and chemo/radiation therapies [1]. Intra-tumoral heterogeneity is a hallmark of GBM where the “M” stands for “multiforme”, and where subpopulations of cells can be distinguished based on their phenotypic resemblance to neuronal-glial stem cells. Subpopulations that exhibit properties similar to neuronal-glial stem cells and tumor-initiating capabilities, referred to as stem-like tumor initiating cells (STIC), differ from the majority of cells forming the tumor mass, referred to as tumor mass-forming cells (TMC). In GBM, STIC were shown to participate directly in tumor vascularization [2, 3]
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