Glioblastoma Cancer Stem Cells Are a Cellular State, Not Clonal Entities

Amsterdam, Netherlands—Results from a recent study pinpoint intrinsic plasticity as the reason behind stem cellassociated, phenotypic heterogeneity in glioblastoma, and significantly affect the development of strategies for targeting cancer stem-like states.

These findings, which were presented at the 25th Biennial Congress of the European Association for Cancer Research, were the product of an investigation by Anna Golebiewska, PhD, Scientist, Department of Oncology, Luxembourg Institute of Health, and colleagues.

“To date there is no curative treatment available for patients with glioblastoma…The cancer stem cell (CSC) hypothesis posits that GBMs rely on a small subpopulation of cells with stemness properties responsible for tumour progression and recurrence. Recent experimental data from GBM and other cancers however suggest that CSCs may not be a stable entity,” Dr Golebiewska and colleagues said.

Thus, issue remains as to whether such cells are a distinct subpopulation of tumor cells, or if they represent a shifting entity that any cancer cell can adopt based on environmental factors.

Classifying and Analyzing Tumor Cell Subpopulations

A total of 16 tumor cell subpopulations, which were classified based on their expression the cell membrane markers CD133, CD15, A2B5 and CD44, were FACS isolated and analyzed to determine whether they are capable of self-renewal and restructuring the original heterogeneous population in different environments.

Using mathematic Markov modelling, Dr Golebiewska and colleagues calculated state transitions between cell states. They also further assessed intra-tumoral heterogeneity at the single-cell transcriptomic level.

A Clonal Entity or a Cellular State?

Dr Golebiewska and colleagues observed markers that were heterogeneously expressed in patient-derived GBM xenografts and stem-like cell cultures, and likened this finding to patient biopsies. Stem-cell properties with the capacity to adapt their marker expression profiles and reform the original subpopulations were found in all tumor cell subpopulations.

A different tendency to reform the original heterogeneity over time was revealed through mathematic modelling; this propensity was free of the proliferation index but associated with tumorigenic potential. All tumor cell subpopulations reached a steady state microenvironment-specific equilibrium, despite their varying potential to adapt to new environments.

“Our results suggest that GBM CSCs do not represent a clonal entity defined by distinct functional properties and transcriptomic signatures, but rather a cellular state that is determined by environmental conditions. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions of existing populations, striving towards an equilibrium instructed by the microenvironment,” Dr Golebiewska and colleagues said.

“Our data provides evidence that stem cell-associated phenotypic heterogeneity in GBM is a result of intrinsic plasticity, which has important implications for the design of treatment strategies targeting cancer stem-like states,” they concluded.Hina Khaliq

Source: Golebiewska A, Dirkse A, Buder T, et al. SPOT-006 Stem cell-associated heterogeneity in glioblastoma is a result of intrinsic tumour plasticity shaped by the microenvironment. ESMO Open. 2018;3:doi: 10.1136/esmoopen-2018-EACR25.39

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