Gaps and Doubts in Search to Recognize Glioblastoma Cellular Origin and Tumor Initiating Cells

Aneta Wlodarczyk,Dagmara Grot,Piotr Rieske,Ewelina Stoczynska-Fidelus

doi:10.1155/2020/6783627

Abstract

Cellular origin of glioblastoma (GB) is constantly discussed and remains a controversial subject. Unfortunately, neurobiologists are not consistent in defining neural stem cells (NSC) complicating this issue even further. Nevertheless, some suggestions referring to GB origin can be proposed based on comparing GB to central nervous system (CNS) cells. Firstly, GB cells show in vitro differentiation pattern similar to GFAP positive neural cells, rather than classical (GFAP negative) NSC. GB cells in primary cultures become senescent in vitro, similar to GFAP positive neural progenitors, whereas classical NSC proliferate in vitro infinitely. Classical NSC apoptosis triggered by introduction of IDH1R132H undermines hypothesis stating that IDH-mutant (secondary) GB origins from these NSC. Analysis of biological role of typical IDH-wildtype (primary) GB oncogene such as EGFRvIII also favors GFAP positive cells rather than classical NSC as source of GB. Single-cell NGS and single-cell transcriptomics also suggest that GFAP positive cells are GB origin. Considering the above-mentioned and other discussed in articles data, we suggest that GFAP positive cells (astrocytes, radial glia, or GFAP positive neural progenitors) are more likely to be source of GB than classical GFAP negative NSC, and further in vitro assays should be focused on these cells. It is highly possible that several populations of tumor initiating cells (TIC) exist within GB, adjusting their phenotype and even genotype to various environmental conditions including applied therapy and periodically going through different TIC states as well as non-TIC state. This adjustment is driven by changes in number and types of amplicons. The existence of various populations of TIC would enable creating neoplastic foci in different environments and increase tumor aggressiveness.

Highlights

Cellular origin of glioblastoma (GB) is constantly discussed and remains a controversial subject
Considering the above-mentioned and other discussed in articles data, we suggest that GFAP positive cells are more likely to be source of GB than classical GFAP negative neural stem cells (NSC), and further in vitro assays should be focused on these cells
The loss of division capacity shown by radial glial cells in vitro has something to do with radial glia transition to astrocytes observed during final stages of central nervous system (CNS) development [40]

Summary

Review Article

Gaps and Doubts in Search to Recognize Glioblastoma Cellular Origin and Tumor Initiating Cells. Bhaduri et al firstly proposed that “developmental programs are reactivated in the tumors” [3] They suggested, “While radial glia are not believed to be present in the normal adult human brain it is possible that there is a latent or quiescent population that can give rise to GSCs and glioblastoma or that a neuronal or glial cell de-differentiates into a oRG-like cell to initiate tumors” [3]. Is shows that results of different studies indicating that GB is derived from astrocytes and radial glia can be coherent not contradictory Another recently published article by Lee et al with very elegant single-cell NGS study proves that primary GB (IDHwildtype) arises from subventricular zone (SVZ) astrocyte like NSC [25]. Verhaak et al, who performed an integrated genomic analysis of GB specimens and characterized four different GB subtypes (proneural, neural, classical, and mesenchymal) suggested one of the possibilities is that tumors in specific subtypes develop as the result of different cells of origin [55]. is general idea was further supported by Alcantara et al, with two phenotypically and molecularly distinct main GB subtypes [56]

Glial progenitor

Malign Senescence

Differentiation arrest

Reprograming EGFRvIII

Findings

Non TIC