Central role of spatial ROS distribution at the nanometric scale in the molecular response to carbon ion irradiation

Abstract : Background: Hadrontherapy is an alternative to radiotherapy in the treatment of Head-and-Neck cancers (HNSCC), because of accurate ballistic and high biological efficiency, even in hypoxic tumor areas. These cancers are of poor prognosis because of a high risk of recurrence related to the presence of cancer stem cells (CSCs) located in hypoxic niches. Aim of this work was to determine the molecular specificities of the response to carbon-ion irradiation versus photons in HNSCC cancer cell lines and their CSCs’ subpopulation, under hypoxic and normoxic conditions. Methods : SQ20B, FaDu cells, and their CSCs were irradiated with photons or carbon-ion (290MeV/n,NIRS) in normoxia or hypoxia (1%O2). Cell survival curves, expression of HIF-1a reactive oxygen species (ROS) and Migration/Invasion processes were quantified. Results/Conclusions: For CSCs and non-CSCs, an oxygen-enhancement-ratio (OER) upper than 1.2 was measured in response to photons, associated with stabilization of HIF-1α. This stabilization, depending on the ROS production, appears earlier in CSCs. Inhibition of HIF-1α expression results in decreased survival in HNSCC-CSCs after both type of radiation under hypoxia associated with a significant increase in residual DNA-DSBs. Furthermore, a relationship is demonstrated between HIF-1α expression and the DSBs’ detection and repair by the Homologous-Recombination. Finally, the dense and homogeneous ROS production induced by photons, essential for HIF-1α stabilization, leads to the activation of the 3 major epithelio-mesenchymal transition (EMT) signaling pathways (STAT3,MEK/p38/JNK,Akt/mTOR). At the opposite, the ROS concentrated into the carbon ion tracks are insufficient to activate HIF-1α and the upstream EMT pathways. All these results, supported by Monte-Carlo simulations, converge towards the central role of spatial ROS distribution at the nanometric scale to explain the specificities of the molecular response to carbon ions. Their therapeutic advantage may result both from unrepaired complex-DNA lesions and the non-activation of ROS-dependent-signaling pathways involved in tumor cell defense. Supported by Labex PRIMES-ANR-11-LABX-0063;ANR-11-IDEX-0007;ITMO-Cancer-AVIESAN
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Contributor : Béatrice Rayet <>
Submitted on : Friday, November 8, 2019 - 11:50:37 AM
Last modification on : Saturday, November 9, 2019 - 2:15:52 AM


  • HAL Id : hal-02355504, version 1



Anne -Sophie Wozny, Gersende Alphonse, Céline Malesys, Caterina Monini, Philippe Lalle, et al.. Central role of spatial ROS distribution at the nanometric scale in the molecular response to carbon ion irradiation. ICRR 2019, Aug 2019, Manchester, United Kingdom. ⟨hal-02355504⟩



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