Targeting glioma stem cells: a novel framework for brain tumors

Abstract

The past decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells (GSC) and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. Herein, we present a novel framework for considering GSC targets based on direct and indirect strategies. Direct strategies target GSC molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect strategies target the microenvironment of the GSC, namely the perivascular, hypoxic and immune niches. Progress made on GSC targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting GSC provides an unprecedented opportunity for revolutionary approaches to treat high-grade gliomas that continue to have a poor patient prognosis.

Figure 1

Complex signaling pathways underlie glioma stem cell (GSC) resistance to standard therapy consisting of ionizing radiation (IR) and temozolomide (TMZ). Mechanisms include those based on more efficient DNA repair, as well as those independent of DNA repair. With respect to IR (blue shading), GSC have upregulated expression of checkpoint kinases Chk1/Chk2 and the L1 cell adhesion molecule (L1CAM)‐regulated NBS‐1 component of the complex activating early checkpoint responses, as well as Bmi1 and the histone deacetylase SirT1. With respect to TMZ (green shading), GSC have significantly higher expression of O⁶‐methylguanine‐DNA‐methyltransferase (MGMT) and upregulated expression of the ATP‐binding cassette sub‐family G member 2 (ABCG2) drug transporter protein responsible for drug efflux. The upregulation of the Notch and Hedgehog–Gli pathways (purple shading) has been implicated in GSC resistance to both IR and TMZ (albeit with minor downstream differences in Notch signaling). Both the Notch and Hedgehog–Gli pathways may be inhibited pharmacologically by γ‐secretase inhibitors (GSI) and cyclopamine, respectively, rendering them attractive from a translational viewpoint. LID, L1CAM intracellular domain; NBS‐1, nijmegen breakage syndrome‐1; NED, notch extracellular domain; NID, notch intracellular domain; NL, notch ligand; p, phosphorylated; PTC, patched; Shh, sonic hedgehog; SMO, smoothened; TF, transcription factor.

Figure 2

The Akt pathway is one of the effector mechanism of epidermal growth factor (EGF)/EGF receptor (EGFR), but warrants consideration as a stand‐alone target. Akt is a serine‐threonine kinase that is part of the phosphatidylinositol 3‐kinase (PI3‐K) signaling pathway. Glioma stem cells (GSC) are more dependent on Akt signaling than non‐GSC, rendering Akt a potential target preferentially affecting GSC. Upon EGFR activation, PI3‐K stimulates the production of phosphatidylinositol 3,4,5‐trisphosphate (PIP₃) from phosphatidylinositol 4,5‐bisphosphate (PIP₂), which, in turn, stimulates the phosphorylation of Akt. Akt is a critical regulator of multiple cellular functions, such as proliferation, survival and metabolism. Phosphatase and tensin homolog (PTEN) can directly counteract and reverse the effect of PI3‐K. Both EGFR and Akt may be inhibited by drugs used in the clinical setting. Erlotinib and gefitinib inhibit EGFR, whereas perifosine inhibits Akt. p, phosphorylated.

Figure 3

Glioma stem cells (GSC) actively contribute to mechanisms of immune privilege, creating an “immune niche”. Mechanisms of glioma immune resistance can be divided into three areas: (i) abnormal immune cell activation; (ii) deregulation of cellular immunity; and (iii) immunosuppressive factors. Glioma stem cells have been ascribed immunomodulatory properties in the three areas, leading to overall suppressed T cell proliferation, increased T cell apoptosis, and, most importantly, expansion of the regulatory T cell (T_reg) pool. Together, the results point to the immune niche as a potential indirect therapeutic target. CCL2, chemokine (C‐C motif) ligand 2; MHC, Major histocompatibility complex; PGE₂, prostaglandin E₂; STAT‐3, signal transducer and activator of transcription 3; TGF‐β, transforming growth factor‐β.