Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant.

Julie Konge,Jérôme Lebeau,Maud Goislard,Sandrine Morel-Altmeyer,Aurélie Vaurijoux,Gaetan Gruel,Denis Biard,François Leteurtre,Sylvie Chevillard

doi:10.18632/oncotarget.25240

Abstract

Failure of conventional antitumor therapy is commonly associated with cancer stem cells (CSCs), which are often defined as inherently resistant to radiation and chemotherapeutic agents. However, controversy about the mechanisms involved in the radiation response remains and the inherent intrinsic radioresistance of CSCs has also been questioned. These discrepancies observed in the literature are strongly associated with the cell models used. In order to clarify these contradictory observations, we studied the radiosensitivity of breast CSCs using purified CD24−/low/CD44+ CSCs and their corresponding CD24+/CD44low non-stem cells. These cells were generated after induction of the epithelial-mesenchymal transition (EMT) by transforming growth factor β (TGFβ) in immortalized human mammary epithelial cells (HMLE). Consequently, these 2 cellular subpopulations have an identical genetic background, their differences being related exclusively to TGFβ-induced cell reprogramming. We showed that mesenchymal CD24−/low/CD44+ CSCs are more resistant to radiation compared with CD24+/CD44low parental cells. Cell cycle distribution and free radical scavengers, but not DNA repair efficiency, appeared to be intrinsic determinants of cellular radiosensitivity. Finally, for the first time, we showed that reduced radiation-induced activation of the death receptor pathways (FasL, TRAIL and TNF-α) at the transcriptional level was a key causal event in the radioresistance of CD24−/low/CD44+ cells acquired during EMT.

Highlights

The epithelial-to-mesenchymal transition (EMT) program is critical for tumor progression and acquisition of invasive potential
The origin of these discrepancies could be related to the different cell models used, especially when properties of different cell lines were compared or when stem-like tumor cells were obtained after forced expression of transcription factors (TFs) involved in the epithelial-mesenchymal transition (EMT)/cancer stem cells (CSCs) phenotype
CD24−/low/CD44+ cells obtained upon a TGFβinduced EMT have acquired resistance to radiation-induced apoptosis

Summary

Introduction

The epithelial-to-mesenchymal transition (EMT) program is critical for tumor progression and acquisition of invasive potential. The inherent intrinsic radioresistance of CSCs has been challenged and some studies claim that CSCs are not more radioresistant, or even more sensitive to radiation than non-stem cells [11,12,13,14]. The origin of these discrepancies could be related to the different cell models used, especially when properties of different cell lines were compared or when stem-like tumor cells were obtained after forced expression of transcription factors (TFs) involved in the EMT/CSC phenotype. The main conclusions were an obvious lack of data and a need for more precisely defined endpoints to evaluate the radiation response of CSCs [15]

Methods

Results

Conclusion