title: Invasive oral cancer stem cells display resistance to ionising radiation.
abstract: There is a significant amount of evidence to suggest that human tumors are driven and maintained by a sub-population of cells, known as cancer stem cells (CSC). In the case of head and neck cancer, such cells have been characterised by high expression levels of CD44 cell surface glycoprotein, while we have previously shown the presence of two diverse oral CSC populations in vitro, with different capacities for cell migration and proliferation. Here, we examined the response of oral CSC populations to ionising radiation (IR), a front-line measure for the treatment of head and neck tumors. We show that oral CSC initially display resistance to IR-induced growth arrest as well as relative apoptotic resistance. We propose that this is a result of preferential activation of the DNA damagerepair pathway in oral CSC with increased activation of ATM and BRCA1, elevated levels of DNA repair proteins RAD52, XLF, and a significantly faster rate of DNA double-strand-breaks clearance 24 hours following IR. By visually identifying CSC sub-populations undergoing EMT, we show that EMT-CSC represent the majority of invasive cells, and are more radio-resistant than any other population in re-constructed 3D tissues. We provide evidence that IR is not sufficient to eliminate CSC in vitro, and that sensitization of CD44hi/ESAlow cells to IR, followed by secondary EMT blockade, could be critical in order to reduce primary tumor recurrence, but more importantly to be able to eradicate cells capable of invasion and distant metastasis.
authors.affiliation: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Emilios
authors.initials: E
authors.lastname: Gemenetzidis
authors.affiliation: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gammon
authors.affiliation: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Biddle
authors.affiliation: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Emich
authors.affiliation: Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Mackenzie
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis; D019313:BRCA1 Protein / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002469:Cell Separation; D004260:DNA Repair; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009062:Mouth Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000502:physiology*; D011839:Radiation, Ionizing; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; D034741:RNA, Small Interfering; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: EMT; apoptosis; cancer stem cells; invasion; irradiation