New treatment strategies to eradicate cancer stem cells and niches in glioblastoma

Abstract

Glioblastoma multiforme (GBM) harbors are not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity, self-renewal, and multi-lineage differentiation capabilities. Known as glioblastoma stem cells (GSCs), they are resistant to conventional chemo- and radiotherapy and may be a causative factor in recurrence. The treatment outcome in patients with GBM remains unsatisfactory and their mean survival time has not improved sufficiently. We studied clinical evidence and basic research findings to assess the possibility of new treatment strategies that target GSCs and their specific microenvironments (GBM niches) and raise the possibility of adding new treatments to eradicate GSCs and GBM niches.

Fig. 1

Recurrence of GBM. A–C: Contrast-enhanced MRI of a patient with GBM in the right frontal lobe obtained before surgery (A), after treatment with TMZ and radiotherapy (B), and at recurrence (C). D: Schematic drawing of GBM cell invasion into the deep brain. Although the GBM tumor mass is removed, invaded cells remain in the brain. Clusters of GSCs and non-GSCs form specific environments (GBM niches) with some extracellular matrix and secreting molecules. GBM recurs in the periphery of the removal cavity (marginal area) where some GSCs in GBM niches are resistant to chemo-radiotherapy and survive. GSCs without GBM niches in the invasive area die, stop growing, or grow below the detection level on MRI. GBM: glioblastoma multiforme, GSCs: glioblastoma stem cells, MRI: magnetic resonance imaging, TMZ: temozolomide.

Fig. 2

GBM niches. The stemness of GSCs is maintained by reciprocal signaling in the GBM niche. Perivascular and hypoxic (peri-necrotic) niches are important for GSCs. HIFs and VEGFs are key molecules for the establishment and maintenance of GBM niches. They harbor GSCs, non-GSCs, extracellular matrix, and secreting molecules. Representative genes and molecules are indicated in the box. A: Perivascular niche. Endothelial cells and pericytes in the perivascular area produce molecules for angiogenesis, and also interact with GSCs, non-GSCs, extracellular matrix, and secreting molecules that regulate the expression of genes involved in the maintenance of stemness. B: Hypoxic (peri-necrotic) niche. Hypoxia induces necrosis and regulates the expression of stemness genes. The population of GSCs increases and their proliferation slows. Some GSCs start to invade or enter into dormant state. FGF: fibroblast growth factor, GBM: glioblastoma multiforme, GSCs: glioblastoma stem cells, HIF: hypoxia-inducible factor, VEGF: vascular endothelial growth factor.

Fig. 3

Additional treatment to eradicate GSCs. Postoperative chemo- and radiotherapy decreases the number of viable GSCs and GBM niche cells, although nearly “naked” GSCs remain in these incomplete GBM niches where suitable microenvironment for supporting GSCs is damaged. Direct attack on the GSCs and/or disruption of GBM niches may result in the terminal differentiation, dormancy, and eradication of GSCs. GBM: glioblastoma multiforme, GSCs: glioblastoma stem cells.