Targeting the main causes of recurrence in head and neck squamous cell carcinoma to overcome resistance to carbon ion radiation
Résumé
It is now well established that hadrontherapy can offer some potential benefit over conventional radiotherapy. However recent clinical trials have shown that the local treatment of head and neck squamous cell carcinoma (HNSCC) is much less efficient than in other head and neck cancers (Mizoe et al., 2004) and leads to locoregional recurrence. In order to obtain more insight into this recurrence, we studied the mechanisms of cell death in a radioresistant HNSCC cell line (SQ20B). These cells underwent a transient G2/M arrest after exposure to photons which is more prolonged after carbon irradiation. Although SQ20B cells showed typical signs of mitotic catastrophe, a subpopulation of cells escaped this process and re-entered the cell cycle. Two hypothesis were proposed in order to explain this cell regrowth. Firstly, we have investigated whether or not cancer stem cells (CSC) could be involved in this recurrence. After cell sorting, it is confirmed that the SQ20B-CSC were demonstrated to be highly resistant to irradiation and displaying High Reactive Oxygen Species scavenging systems. Scondly, the study of the genomic instability in SQ20B surviving cells showed that both types of irradiation induced chromosomal rearrangements and that the nature of DNA damage (DD) greatly impacted them. In order to radiosensitize these surviving cells, two pharmacological strategies were investigated. SQ20B-CSC cells were first treated with UCN-01, an inhibitor of the G2/M arrest which resulted in their radiosensitization through the triggering of apoptosis instead of mitotic catastrophe. Another strategy focused on the depletion of the endogenous glutathione content in SQ20B-CSC and non-CSC before irradiation which led to the activation of the intrinsic apoptotic pathway. Moreover, this treatment potentiated the effects of radiation with an increasing number of scattered DD after photon exposure without any consecutive chromosomal changes (CC). By contrast, this treatment increases the complexity of DD and minimizes CC after heavy ion radiation. Taken together, our results demonstrated that adjuvant therapies targeting CSC or enabling the minimization of transmissible CC could optimize the local control of tumors after hadrontherapy. This work was achieved within the scientific framework of ETOILE and the LabEx PRIMES. It was supported by Contrat-Plan-Etat-Region, the Ligue contre le Cancer (Ain).