ROS Production and Distribution: A New Paradigm to Explain the Differential Effects of X-ray and Carbon Ion Irradiation on Cancer Stem Cell Migration and Invasion.

Anne-Sophie Wozny,Caterina Monini,Charlotte Cuerq,Tetsuo Nakajima,Gersende Alphonse,Nicolas Magné,Claire Rodriguez-Lafrasse,Alexandra Lauret,Guillaume Vares,Michael Beuve,Jean-Claude Monboisse,Akira Fujimori

doi:10.3390/cancers11040468

Abstract

Although conventional radiotherapy promotes the migration/invasion of cancer stem cells (CSCs) under normoxia, carbon ion (C-ion) irradiation actually decreases these processes. Unraveling the mechanisms of this discrepancy, particularly under the hypoxic conditions that pertain in niches where CSCs are preferentially localized, would provide a better understanding of the origins of metastases. Invasion/migration, proteins involved in epithelial-to-mesenchymal transition (EMT), and expression of MMP-2 and HIF-1α were quantified in the CSC subpopulations of two head-and-neck squamous cell carcinoma (HNSCC) cell lines irradiated with X-rays or C-ions. X-rays triggered HNSCC-CSC migration/invasion under normoxia, however this effect was significantly attenuated under hypoxia. C-ions induced fewer of these processes in both oxygenation conditions. The differential response to C-ions was associated with a lack of HIF-1α stabilization, MMP-2 expression, or activation of kinases of the main EMT signaling pathways. Furthermore, we demonstrated a major role of reactive oxygen species (ROS) in the triggering of invasion/migration in response to X-rays. Monte-Carlo simulations demonstrated that HO● radicals are quantitatively higher after C-ions than after X-rays, however they are very differently distributed within cells. We postulate that the uniform distribution of ROS after X-rays induces the mechanisms leading to invasion/migration, which ROS concentrated in C-ion tracks are unable to trigger.

Highlights

Cancer stem cells (CSCs), a subpopulation within the bulk tumor, are intimately involved in radio- and chemo-resistance, self-renewal and clonal growth via the generation of a non-stem-cell populations [1]
We found that in head-and-neck squamous cell carcinoma (HNSCC)-cancer stem cells (CSCs) under normoxia, the three main signaling pathways (MEK/p38/JNK, Akt/mTOR and STAT3) involved in epithelial-to-mesenchymal transition (EMT) were activated in response to X-rays
We previously presented evidence that the telomeric status of glioblastoma is important in the response to X-rays, but not to carbon ion (C-ion), a result supported by the differences in the spatial distribution of reactive oxygen species (ROS) [31]

Summary

Introduction

Cancer stem cells (CSCs), a subpopulation within the bulk tumor, are intimately involved in radio- and chemo-resistance, self-renewal and clonal growth via the generation of a non-stem-cell populations [1]. In contrast to X-ray irradiation where ionization is spread uniformly inside cells, C-ions produce a very high ionization density within individual tracks. This high dose induces complex and unrepairable DNA damage leading to cell death [7]. Several studies have reported that C-ions kill CSCs better than conventional radiotherapy [8,9,10]. Most of the time, X-rays promote migration and invasiveness under normoxia [11], C-ions produce a significant benefit by decreasing the migration and invasiveness of cancer cells in vitro [11,12] and in vivo [13,14]. A few studies report anti-invasive capacities in response to X-rays, whereas C-ions can be pro-invasive [15]

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