Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

Abstract

Cancer stem cells (CSCs) or cancer initiating cells (CICs) maintain self-renewal and multilineage differentiation properties of various tumors, as well as the cellular heterogeneity consisting of several subpopulations within tumors. CSCs display the malignant phenotype, self-renewal ability, altered genomic stability, specific epigenetic signature, and most of the time can be phenotyped by cell surface markers (e.g., CD133, CD24, and CD44). Numerous studies support the concept that non-stem cancer cells (non-CSCs) are sensitive to cancer therapy while CSCs are relatively resistant to treatment. In glioblastoma stem cells (GSCs), there is clonal heterogeneity at the genetic level with distinct tumorigenic potential, and defined GSC marker expression resulting from clonal evolution which is likely to influence disease progression and response to treatment. Another level of complexity in glioblastoma multiforme (GBM) tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs, and the potential for non-GSCs to revert (dedifferentiate) to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population. Moreover, exposure of the differentiated GBM cells to therapeutic doses of temozolomide (TMZ) or ionizing radiation (IR) increases the GSC pool both in vitro and in vivo. This review describes various subtypes of GBM, discusses the evolution of CSC models and epigenetic plasticity, as well as interconversion between GSCs and differentiated non-GSCs, and offers strategies to potentially eliminate GSCs.

Keywords: Cancer stem cells; Dedifferentiation; Epigenetic; GBM plasticity; GBM stem cells; Glioblastoma; Stemness.

Figure 1

Genetic alterations and aberrant signaling pathways in primary and secondary GBM. A. The continued growth and recurrence of primary GBM is due to the presence of GSCs which express various protein markers and display self-renewal and tumorigenic potential. Modified from Masui et al.B. Epigenetic changes in GBM. Numerous molecular alterations shown in this figure and described in the text occur in primary GBM. Mutations in p53 tumor suppressor protein (p53) and ATRX typically occur in low-grade gliomas and secondary GBM. Mutation of the IDH1 gene is commonly found in low-grade gliomas and secondary GBM, but is rare in primary GBM. Mutation of IDH1 leads to aberrant DNA methylation and mutations in the important chromatin modifier ATRX, affecting chromatin structure. Figure was modified from Kondo et al.

Figure 2

Relationship between neuronal stem cells, differentiation, GSCs, cancer initiation, and dedifferentiation. NSCs are able to differentiate into neural progenitors. Neural progenitors differentiate into neurons and glial progenitors differentiate to oligodendrocytes, ependymal cells, and astrocytes. GBM is initiated from the transformation of NSCs into GSCs. Similarly, glial progenitors are able to trigger tumor development following malignant transformation of normal progenitor cells. Astrocytes, neurons, oligodendrocytes, and ependymal cells also have the potential to initiate tumorigenesis.

Figure 3

Multiple signaling networks in GSCs. A complex and integrated signaling network governs self-renewal, stemness, and maintaince of CSCs including GSCs. As shown in this figure, this network of proteins belong to many pivotal cellular pathways and include several plasma membrane receptors, cytoplasmic signaling proteins, specific transcription factors, growth factors, and ligands.

Figure 4

MicroRNAs identified in GSCs. A summary of deregulated microRNAs regulating various cellular processes is listed. This is summary of the previously reported publications cited in the reference list., , , ,