The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

Abstract

Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

Keywords:

• chemoresistance
• glioma stem cells
• malignant glioma
• mechanisms
• plasticity
• recurrence

Financial &competing interests disclosure

This work was supported by the NCI (R01CA122930, R01CA138587), the NIH (R01NS077388), the National Institute of Neurological Disorders and Stroke (U01NS069997), and the American Cancer Society (RSG-07-276-01-MGO). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Glioma stem cells (GSCs) develop upon mutation of neural progenitor cells or neural stem cells. GSCs then mediate tumorigenesis, resistance to therapy and recurrence.

• GSCs are inherently resistant to standard of care therapy. The mechanisms of resistance include MGMT promoter methylation status, enhanced repair of DNA damage, impaired induction of apoptosis, aberrant DNA checkpoint analysis, ABC-type transporter expression and multidrug resistance, phenotypic plasticity and specialized cyto-protective niches.

• Current pharmacologic strategies to target GSCs include the induction of differentiation, disruption of GSC niches, immunotherapy, and restoration of sensitivity to current therapy.

• Targeting GSCs while limiting toxicity to normal tissue is of critical current and future significance. GSC-specific microenvironments, cell markers, gene expression profiles and signaling pathways currently serve as the best targets for a directed approach.

• Similar to the combination of temozolomide and radiation, future therapy for glioblastoma multiforme (GBM) is likely to require a combinatorial approach to eliminate two very different cell populations: GSCs and differentiated cells.

• Progress in GBM and GSC-directed therapy will require a combination of traditional and progressive approaches, including genetic analysis of individual tumors and detailed single-cell study. Such tailored investigation and therapy will attempt to match the heterogeneity found in GBM.