Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic strategy in GBMs.
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We thank Dr. Lee Lucas for her guidance with the statistical methods and Drs. Tom Gridley, Wendy Craig and Christine Lu-Emerson for their critical review of the manuscript. We also thank Jesse Hammer at the Jackson Laboratory’s Multimedia Department for his expert assistance in preparing the figures. We would like to acknowledge the Maine Medical Center BioBank, for their assistance in procuring biospecimens in accordance with IRB guidelines, and the Maine Medical Center Histology Core Facility (Grants P30GM103392 (R. Friesel, P.I.) and P30GM106391 (D. Wojchowski, P.I.), by the National Institute of General Medical Sciences) for their assistance with the immunohistochemistry staining.
This work was funded by unrestricted research grants from the Maine Medical Center Neuroscience Institute, the Northern New England Clinical Oncology Society, and the Schering-Plough Corporation (Grant ID XX-3903) to IFE and CB. This work was also supported by the Oliver S. and Jennie R. Donaldson Charitable Trust grant to KY. These sponsors had no involvement in study design, data collection, analysis or interpretation, manuscript writing, or the decision to submit the article for publication.
Conflict of interest
The authors report no conflicts of interest beyond the direct research support detailed above.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Maine Medical Center Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Ivette F. Emery and Archana Gopalan have contributed equally to this work.
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Emery, I.F., Gopalan, A., Wood, S. et al. Expression and function of ABCG2 and XIAP in glioblastomas. J Neurooncol 133, 47–57 (2017). https://doi.org/10.1007/s11060-017-2422-z
- Glioma stem cells