Discovery of Power-Law Growth in the Self- Renewal of Heterogeneous Glioma Stem Cell Populations
Date
2015-08-18
Journal Title
Journal ISSN
Volume Title
Publisher
PLOS (Public Library of Science)
Abstract
BACKGROUND
Accumulating evidence indicates that cancer stem cells (CSCs) drive tumorigenesis. This
suggests that CSCs should make ideal therapeutic targets. However, because CSC populations
in tumors appear heterogeneous, it remains unclear how CSCs might be effectively
targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity
during self-renewal, we established a glioma sphere (GS) forming model, to generate a population
in which glioma stem cells (GSCs) become enriched. We hypothesized, based on
the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines
of GSs are generated that progressively show increased proliferative ability.
METHODOLOGY/PRINCIPAL FINDINGS
To test this hypothesis, we determined whether, with each passage, glioma neurosphere
culture generated from four different glioma cell lines become progressively proliferative
(i.e., enriched in large spheres). Rather than monitoring self-renewal, we measured heterogeneity
based on neurosphere clone sizes (#cells/clone). Log-log plots of distributions of
clone sizes yielded a good fit (r>0.90) to a straight line (log(% total clones) = k*log(#cells/
clone)) indicating that the system follows a power-law (y = xk) with a specific degree exponent
(k = −1.42). Repeated passaging of the total GS population showed that the same
power-law was maintained over six passages (CV = −1.01 to −1.17). Surprisingly, passage
of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide,
which is well known as a standard therapy for glioblastoma multiforme (GBM), suppressed
the self-renewal of clones, but it never disrupted the power-law behavior of a GS
population.
CONCLUSIONS/SIGNIFICANCE
Although the data above did not support the stated hypothesis, they did strongly suggest a
novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth
governs the self-renewal of heterogeneous glioma stem cell populations. That the data
always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and
scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors
govern the generation of neurospheres. That the power-law behavior and the original
GS heterogeneity are maintained over multiple passages indicates that these rules are
invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during
tumor growth. Discovery of this power-law behavior provides a mechanism that could be
targeted in the development of new, more effective, anti-cancer agents.
Introduction
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Citation
Sugimori M, Hayakawa Y, Boman BM, Fields JZ, Awaji M, Kozano H, et al. (2015) Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations. PLoS ONE 10(8): e0135760. doi:10.1371/journal. pone.0135760