Guillaume Vares1, Vidhula Ahire2, Shigeaki Sunada3, Eun Ho Kim4, Sei Sai5, François Chevalier2, Paul-Henri Romeo6, Tadashi Yamamoto7, Tetsuo Nakajima8, Yannick Saintigny9. 1. Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan. Electronic address: guillaume.vares@oist.jp. 2. Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France. 3. Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan; Department of Molecular Genetics, Tokyo Medical and Dental University (TMDU), Japan. 4. Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea. 5. Department of Charged Particle Therapy Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan. 6. Research Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS), François Jacob Institute of Biology, CEA/DRF/IBFJ/IRCM, Fontenay-aux-Roses, France. 7. Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan. 8. Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan. 9. Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France. Electronic address: yannick.saintigny@cea.fr.
Abstract
BACKGROUND AND PURPOSE: High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. MATERIAL AND METHODS: Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. RESULTS: We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. CONCLUSION: Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.
BACKGROUND AND PURPOSE: High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. MATERIAL AND METHODS:Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. RESULTS: We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. CONCLUSION: Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.