Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies

Abstract

Malignant primary brain tumors are characterized by a short median survival and an almost 100% tumor-related mortality. Despite the addition of new chemotherapy regimes, the overall survival has improved marginally, and radiotherapy is only transiently effective, illustrating the profound impact of treatment resistance on prognosis. Recent studies suggest that a small subpopulation of cancer stem cells (CSCs) has the capacity to repopulate tumors and drive malignant progression and mediate radio- and chemoresistance. This implies that future therapies should turn from the elimination of the rapidly dividing, but differentiated tumor cells, to specifically targeting the minority of tumor cells that repopulate the tumor. Although there exists some support for the CSC hypothesis, there remain many uncertainties regarding theoretical, technical, and interpretational aspects of the data supporting it. If correct, the CSC hypothesis could have profound implications for the way tumors are classified and treated. In this review of the literature, we provide original data and hypotheses supporting alternative explanations and outline some of the therapeutic implications that can be derived.

Keywords: CD133; Neural stem cell; chemoresistance; glioblastoma; radioresistance.

Figure 1

Cellular origins of glioblastoma. The cancer stem cell is believed to arise from a transformed NSC or a transformed precursor in the CNS. Whether the transformation event happens before or after dedifferentiation is uncertain. This would give rise to tumor cells with various potentials for self-renewal, which express a variety of markers associated with both progenitor and mature cell types. Transformation of mature cells (astrocytes and oligodendocytes) by specific mutations may be equally permissive for tumorigenesis, resulting in clones with a self-renewing phenotype. Abbreviations: NSC, neural stem cell; GRP, glial-restricted progenitor; CSC, cancer stem cell; GalC, galactocerebrosidase; MBP, myelin basic protein; NG2, neuron-glia 2; O4, monoclonal antibody that recognizes the sulfatides; S100, calcium-binding protein specific for mature astrocytes; GFAP, glial fibrillary acidic protein; OPC, oligodendrocyte precursor cell.

Figure 2

CD133 in normal adult and fetal brain. (A) Adult human brain, subependymal zone (near hippocampus), showing a band of few CD133-positive cells. (B) Fetal human brain, subependymal zone. Note the perinuclear cytoplasmic staining in some cells in the brain parenchyma (▼) and the surface/membrane staining in ependymal cells (*).

Figure 3

Schematic diagram of CD133 structure and trypsin cleavage sites. (A) The five transmembrane structure of the CD133 molecule including the amino acid lengths of the intra- and extracellular loops and the number of predicted trypsin cleavage sites, http://www.expasy.ch/tools/peptidecutter/. Glycosylation sites are illustrated; the actual numbers and positions are as yet unknown. (B) Examples of commercially available CD133 antibodies and suppliers showing the variation in sizes of the detected protein on Western blot analysis.

Figure 4

CD133 expression is highly variable in patient GBM biopsies. (A) Real-time qPCR of tissue from normal human brain (NHB: n = 4) and patient GBM biopsies (n = 22). The expression level of CD133 in the NHB was used a reference (NHB = 1). Data show mean ± SEM from two independent experiments. (B and C) The hematoxylin and eosin-stained histological sections and cytoplasmic CD133 staining from two representative patient GBMs with high real-time qPCR values. (D) Positive control using colon adenocarcinoma tissue indicating high endoluminal CD133 positivity in the malignant tubular structures. (E) Positive control using gastrointestinal stromal tumor tissue indicating high surface and cytoplasmic CD133 location. Scale bar, 100 µm.