Abstract
Glioma cells with stem cell traits are thought to be responsible for tumor maintenance and therapeutic failure. Such cells can be enriched based on their inherent drug efflux capability mediated by the ABC transporter ABCG2 using the side population assay, and their characteristics include increased self-renewal, high stem cell marker expression and high tumorigenic capacity in vivo. Here, we show that ABCG2 can actively drive expression of stem cell markers and self-renewal in glioma cells. Stem cell markers and self-renewal was enriched in cells with high ABCG2 activity, and could be specifically inhibited by pharmacological and genetic ABCG2 inhibition. Importantly, despite regulating these key characteristics of stem-like tumor cells, ABCG2 activity did not affect radiation resistance or tumorigenicity in vivo. ABCG2 effects were Notch-independent and mediated by diverse mechanisms including the transcription factor Mef. Our data demonstrate that characteristics of tumor stem cells are separable, and highlight ABCG2 as a potential driver of glioma stemness.
Highlights
Cancer stem cells have been functionally enriched based on drug efflux capability using the side population (SP) assay[7]
For 5 of the 7 genes with higher expression in the SP compared to the main population (MP), Fumitremorgin C (FTC) treatment reduced expression of these markers in the SP but not in the MP (Fig. 1b), suggesting that ABCG2 may drive at least part of the stem cell phenotype of SP cells
To sorted PDGF-induced glioma primary cultures (PIGPCs), higher stem cell marker expression in U87-ABCG2 cells was diminished by pharmacological inhibition of ABCG2 activity via FTC, whereas FTC treatment did not affect stem cell marker expression in U87-Empty cells (Fig. 1d)
Summary
Cancer stem cells have been functionally enriched based on drug efflux capability using the side population (SP) assay[7]. The SP phenotype - defined as the ability of cells to efflux Hoechst 33342 dye as measured by fluorescence activated cell sorting (FACS) - is dependent on the activity of the ATP-binding cassette transporter ABCG28, which itself may regulate stem cell phenotypes[9,10]. SP cells from proneural/PDGFB-driven GBM express higher levels of stem cell markers, display increased self-renewal, increased chemo-resistance, and are more tumorigenic when compared to the sorted main population (MP) cells[7], but with the exception of chemo-resistance, the contribution of ABCG2 to this phenotype is unclear. We found that ABCG2 function correlates with high stem cell marker expression and self-renewal capacity (Bleau et al.7), but can actively drive these characteristics of stem-like cells in some GBM cultures. In addition to demonstrating a novel and active role for the stem cell marker ABCG2 in driving parts of the glioma stem cell phenotype, our findings emphasize the need to separate the various stem cell characteristics that are usually considered as a collective unit
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