Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(-/low) Stem Cell Phenotype - PubMed (original) (raw)

Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(-/low) Stem Cell Phenotype

Xuefeng Gao et al. Front Oncol. 2016.

Abstract

The enrichment of putative CD44(+)/CD24(-/low) breast stem cell populations following exposure to ionizing radiation (IR) has been ascribed to their inherent radioresistance and an elevated frequency of symmetric division during repopulation. However, recent studies demonstrating radiation-induced phenotypic reprogramming (the transition of non-CD44(+)/CD24(-/low) cells into the CD44(+)/CD24(-/low) phenotype) as a potential mechanism of CD44(+)/CD24(-/low) cell enrichment have raised the question of whether a higher survival and increased self-renewal of existing CD44(+)/CD24(-/low) cells or induced reprogramming is an additional mode of enrichment. To investigate this question, we combined a cellular automata model with in vitro experimental data using both MCF-10A non-tumorigenic human mammary epithelial cells and MCF-7 breast cancer cells, with the goal of identifying the mechanistic basis of CD44(+)/CD24(-/low) stem cell enrichment in the context of radiation-induced cellular senescence. Quantitative modeling revealed that incomplete phenotypic reprogramming of pre-senescent non-stem cells (reprogramming whereby the CD44(+)/CD24(-/low) phenotype is conveyed, along with the short-term proliferation capacity of the original cell) could be an additional mode of enriching the CD44(+)/CD24(-/low) subpopulation. Furthermore, stem cell enrichment in MCF-7 cells occurs both at lower doses and earlier time points, and has longer persistence, than that observed in MCF-10A cells, suggesting that phenotypic plasticity appears to be less regulated in breast cancer cells. Taken together, these results suggest that reprogramming of pre-senescent non-stem cells may play a significant role in both cancer and non-tumorigenic mammary epithelial populations following exposure to IR, a finding with important implications for both radiation therapy and radiation carcinogenesis.

Keywords: breast cancer cells; cancer stem cells; cellular automata; radiation; reprogramming; senescence.

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Figures

Figure 2

Figure 2

The comparisons between model simulation results (mean ± SD; n = 10 simulations) of applying hypothesis (i), (ii), or (iii) (alone or in combinations) and in vitro data (mean ± SD; n = 3) on the (A)% of CD44+/CD24−/low cells in MCF-10A cells and (B) MCF-7 cells; and the (C)% of SA-β-gal positive cells in MCF-10A cells and (D) MCF-7 cells. The comparisons between simulation results of applying hypothesis (iv) or (v) and in vitro data on the (E)% of CD44+/CD24−/low cells in MCF-10A cells and (F) MCF-7 cells; and the (G)% of SA-β-gal positive cells in MCF-10A cells and (H) MCF-7 cells. Hyp stands for hypothesis in the figure legends. Best fitting for MCF-10A cells under Hyp (iv) [corresponding to **(E,G)**]: reprogramming rate (_p_r) increases to 0.09 per CC (intact or pre-senescent) per day for 38 h during days 3–5 after irradiation. Best fitting for MCF-7 cells under Hyp (iv) [corresponding to **(F,H)**]: reprogramming rate (_p_r) increases to 0.08 per CC (intact or pre-senescent) per day during first 4 days after irradiation, then decreases to 0.0198 for the following time points.

Figure 1

Figure 1

Radiation-induced enrichment of CD44+/CD24−/low putative stem cells in (A) MCF-10A cells and (B) MCF-7 cells in vitro is in a dose dependent manner (mean ± SD; n = 3).

Figure 3

Figure 3

Following the hypothesis of IR-induced incomplete phenotypic reprogramming, the model simulation predicted the proportions of intact (solid colors) vs. pre-senescent (striped colors) CD44+/CD24−/low sub-populations for (A) MCF-10A cells (corresponding to Hyp (iv) curve in Figure 2E) and (B) MCF-7 cells [corresponding to Hyp (iv) curve in Figure 2F]. Data points are plotted on a log scale.

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