A proposed quantitative index for assessing the potential contribution of reprogramming to cancer stem cell kinetics - PubMed (original) (raw)

A proposed quantitative index for assessing the potential contribution of reprogramming to cancer stem cell kinetics

Xuefeng Gao et al. Stem Cells Int. 2014.

Abstract

Enrichment of cancer stem cells (CSCs) is thought to be responsible for glioblastoma multiforme (GBM) recurrence after radiation therapy. Simulation results from our agent-based cellular automata model reveal that the enrichment of CSCs may result either from an increased symmetric self-renewal division rate of CSCs or a reprogramming of non-stem cancer cells (CCs) to a stem cell state. Based on plateau-to-peak ratio of the CSC fraction in the tumor following radiation, a downward trend from peak to subsequent plateau (i.e., a plateau-to-peak ratio exceeding 1.0) was found to be inconsistent with increased symmetric division alone and favors instead a strong reprogramming component. The two contributions together are seen to be the product of a dynamic equilibrium between CSCs and CCs that is highly regulated by the kinetics of single cells, including the potential for CCs to reacquire a stem cell state and confer phenotypic plasticity to the population as a whole. We conclude that tumor malignancy can be gauged by a degree of cancer cell plasticity.

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Figures

Figure 1

Figure 1

The bottom and top transparent regions in (a) and (b) represent the percentages of CD133+ subpopulation in the U87-MG cell line before and after fractionated irradiation (3 × 2 Gy), respectively [8]. (a) CSC fraction in silico after fractionated irradiation (3 × 2 Gy) under different mechanisms (means ± SD, n = 5). (b) The CD133+ fraction observed in the U87-MG population before and after fractionated irradiation can also be reproduced in silico by applying an induced reprogramming rate. In silico tumor regrowth dynamics for different rates of symmetric divisions and reprogramming: (c) total tumor cell number and (d) percentage of CSCs. Tumors initiated by a single surviving CSC maintain a steady proportion of CSCs under either (e) a constant symmetric division rate or (f) a constant cell reprogramming rate.

Figure 2

Figure 2

(a) Potential mechanisms by which (fractionated) IR increases the proportion of CSCs. Radiation induces the activation and stabilization of stemness-associated signaling (i) promotes symmetric self-renewal divisions, while repressing differentiation commitment, and/or (ii) evokes reprogramming of progenitor cells into a stem-like state. (b) The tumorigenicity is regulated by the degree of cell plasticity. 0 and 1 stand for minimum and maximum, respectively, in the according axis.

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