Glioblastoma, cancer stem cells and hypoxia

Abstract

Glioblastoma (GBM) prognosis remains dismal, with most patients succumbing to disease within 1 or 2 years of diagnosis. Recent studies have suggested that many solid tumors, including GBM, are maintained by a subset of cells termed cancer stem cells (CSCs). It has been shown that these cells are inherently radio- and chemotherapy resistant, and may be maintained in vivo in a niche characterized by reduced oxygen tension (hypoxia). This review examines the recently described effects of hypoxia on CSC in GBM, and the potential promise in targeting the hypoxic pathway therapeutically.

Figure 1

Potential cancer stem cell niches. GHliblastoma cancer stem cells (GBM CSCs) are suggested to localize to either the vascular (A) or hypoxic (B–C) niches. These microenvironments are distinct not only by the presence of oxygen (vascular) or lack thereof (hypoxic), but also their cellular composition. A. GBM CSC associated with the vasculature. Interaction between endothelial cells and GBM CSC maintains CSC in an undifferentiated state. Physical as well as diffusible factors may be involved in this process (in the bottom panel, arrow points to a well perfused vessel as indicated by the presence of numerous erythrocytes). B. Hypoxic niche, which is often found adjacent to necrosis, appears as glomeruloid tufts. CSC may contact proliferating endothelial cells directly and reciprocal signaling may promote endothelial cell proliferation as well as maintenance of the CSC identity (on the bottom panel, arrows point at single erythrocytes, indicating poor perfusion). C. Thrombosis as a potential mechanism for hypoxic niche formation (top). Pseudopalisades forming around a central vessel containing a thrombus. Note the early stage of necrosis and how the pseudopalisades take on the contour of the occluded vessel (marked with an arrow, bottom) (p. vessel—perfused vessel).

Figure 2

HIF‐1α plays a pivotal role in many physiological and pathological processes (shown on the left side). Agents that inhibit hypoxia inducible factor 1α (HIF‐1α) activity have been reported to control various downstream processes (shown on the right side). The majority of these agents inhibit HIF‐1α translation 1, 2, 3, 4, 5, 6, 7, 8. However, agents that increase HIF‐1α degradation 9, 10, 11 or reduce its ability to bind DNA 12, 13, 14 have also been reported. Fewer agents were identified as inhibitors of HIF‐1α transactivation (17) or binding to other proteins such as the transcription activator p300 (15) and to its heterodimeric partner, HIF‐1β(16). HDAC = Histone deacetylase.