Q. T. Ostrom, H. Gittleman, J. Fulop, M. Liu, R. Blanda et al., CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States, Neuro-Oncology, vol.17, pp.1-62, 2008.

R. Stupp, M. E. Hegi, W. P. Mason, . Van-den, M. J. Bent et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol, vol.10, p.15, 2009.

M. Weller, T. Cloughesy, J. R. Perry, and W. Wick, Standards of care for treatment of recurrent glioblastoma-Are we there yet? Neuro Oncol, vol.15, pp.4-27, 2013.

M. Gérard, A. Corroyer-dulmont, P. Lesueur, S. Collet, M. Chérel et al., Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma

D. Maucort-boulch, M. Baron, P. Pommier, D. C. Weber, J. Mizoe et al., Rationale for carbon ion therapy in high-grade glioma based on a review and a meta-analysis of neutron beam trials, Cancer Radiother, vol.14, pp.34-41, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00485111

S. E. Combs, Proton and Carbon Ion Therapy of Intracranial Gliomas, Prog. Neurol. Surg, vol.32, pp.57-65, 2018.

S. E. Combs, I. Burkholder, L. Edler, S. Rieken, D. Habermehl et al., Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial, BMC Cancer, vol.10, p.533, 2010.

S. Adeberg, S. B. Harrabi, V. Verma, D. Bernhardt, N. Grau et al., Treatment of meningioma and glioma with protons and carbon ions, Radiat. Oncol, vol.12, 0193.

L. Kong, J. Gao, J. Hu, R. Lu, J. Yang et al., Carbon ion radiotherapy boost in the treatment of glioblastoma: A randomized phase I/III clinical trial, Cancer Commun, vol.39, issue.5, 2019.

E. Fokas, G. Kraft, and H. An, Engenhart-Cabillic, R. Ion beam radiobiology and cancer: Time to update ourselves, Biochim. Biophys. Acta, vol.1796, pp.216-229, 2009.

K. Ando and Y. Kase, Biological characteristics of carbon-ion therapy, Int. J. Radiat. Biol, vol.85, pp.715-728, 2009.

N. Colwell, M. Larion, A. J. Giles, A. N. Seldomridge, S. Sizdahkhani et al., Hypoxia in the glioblastoma microenvironment: Shaping the phenotype of cancer stem-like cells, Neuro-Oncology, vol.19, pp.887-896, 2017.

L. H. Gray, A. D. Conger, M. Ebert, S. Hornsey, and O. C. Scott, The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy, Br. J. Radiol, vol.26, pp.638-648, 1953.

S. Rockwell, I. T. Dobrucki, E. Y. Kim, S. T. Marrison, and V. T. Vu, Hypoxia and radiation therapy: Past history, ongoing research, and future promise, Curr. Mol. Med, vol.9, pp.442-458, 2009.

H. Wang, H. Jiang, M. Van-de-gucht, and M. De-ridder, Hypoxic Radioresistance: Can ROS Be the Key to Overcome It? Cancers, vol.11, 2019.

Y. Furusawa, K. Fukutsu, M. Aoki, H. Itsukaichi, K. Eguchi-kasai et al., Inactivation of aerobic and hypoxic cells from three different cell lines by accelerated (3)He-, (12)Cand (20)Ne-ion beams, Radiat. Res, vol.154, pp.485-496, 2000.

L. Antonovic, A. Brahme, and Y. Furusawa, Toma-Dasu, I. Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions, J. Radiat. Res, vol.54, pp.18-26, 2013.

W. Tinganelli, M. Durante, R. Hirayama, M. Krämer, A. Maier et al., Kill-painting of hypoxic tumours in charged particle therapy, Sci. Rep, vol.5, 2015.

N. Albadari, S. Deng, and W. Li, The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy, Expert Opin. Drug Discov, vol.14, pp.667-682, 2019.

H. Harada, Hypoxia-inducible factor 1-mediated characteristic features of cancer cells for tumor radioresistance, J. Radiat. Res, vol.57, pp.99-105, 2016.

Y. Xia, L. Jiang, and T. Zhong, The role of HIF-1? in chemo-/radioresistant tumors, OncoTargets Ther, vol.11, pp.3003-3011, 2018.

J. Kessler, A. Hahnel, H. Wichmann, S. Rot, M. Kappler et al., HIF-1? inhibition by siRNA or chetomin in human malignant glioma cells: Effects on hypoxic radioresistance and monitoring via CA9 expression, BMC Cancer, vol.10, p.605, 2010.

C. Hsieh, C. Lee, J. Liang, C. Yu, and W. Shyu, Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity, Oncol. Rep, vol.24, pp.1629-1636, 2010.

E. A. Pérès, A. N. Gérault, S. Valable, S. Roussel, J. Toutain et al., Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe, Oncotarget, vol.6, pp.2101-2119, 2015.

P. Knizetova, J. Ehrmann, A. Hlobilkova, I. Vancova, O. Kalita et al., Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay, Cell Cycle, vol.7, pp.2553-2561, 2008.

J. Fang, S. Zhou, J. Fan, and S. Yan, Roles of glucose transporter-1 and the phosphatidylinositol 3-kinase/protein kinase B pathway in cancer radioresistance (review), Mol. Med. Rep, vol.11, pp.1573-1581, 2015.

W. Zhuang, B. Li, L. Long, L. Chen, Q. Huang et al., Knockdown of the DNA-dependent protein kinase catalytic subunit radiosensitizes glioma-initiating cells by inducing autophagy, Brain Res, pp.1371-1378, 2011.

F. S. Subtil, J. Wilhelm, V. Bill, N. Westholt, S. Rudolph et al., Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency, FASEB J, vol.28, pp.1412-1421, 2014.

A. Wozny, A. Lauret, P. Battiston-montagne, J. Guy, M. Beuve et al., Differential pattern of HIF-1? expression in HNSCC cancer stem cells after carbon ion or photon irradiation: One molecular explanation of the oxygen effect, Br. J. Cancer, vol.116, pp.1340-1349, 2017.
URL : https://hal.archives-ouvertes.fr/cea-01938093

K. Minami, M. Koizumi, Y. Hamada, S. Mori, N. Kawaguchi et al., The Effect of Carbon Ion Beam Irradiation for Hypoxia-Mediated Invasion of Glioblastoma, Nano Biomed, vol.6, p.11, 2014.

S. Chiblak, Z. Tang, D. Lemke, M. Knoll, I. Dokic et al., Carbon irradiation overcomes glioma radioresistance by eradicating stem cells and forming an antiangiogenic and immunopermissive niche, JCI Insight, 2019.

A. Brahme, Recent advances in light ion radiation therapy, Int. J. Radiat. Oncol. Biol. Phys, vol.58, pp.603-616, 2004.

B. Jones, A Simpler Energy Transfer Efficiency Model to Predict Relative Biological Effect for Protons and Heavier Ions. Front, Oncol, vol.5, 2015.

F. Marampon, G. L. Gravina, B. M. Zani, V. M. Popov, A. Fratticci et al., Hypoxia sustains glioblastoma radioresistance through ERKs/DNA-PKcs/HIF-1? functional interplay, Int. J. Oncol, vol.44, pp.2121-2131, 2014.

L. Huang, B. Li, S. Tang, H. Guo, W. Li et al., Mitochondrial KATP Channels Control Glioma Radioresistance by Regulating ROS-Induced ERK Activation, Mol. Neurobiol, vol.52, pp.626-637, 2015.

A. Tomiyama, K. Tachibana, K. Suzuki, S. Seino, J. Sunayama et al., MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

A. Calipel, A. Lux, S. Guérin, J. Lefaix, C. Laurent et al., Differential Radiosensitivity of Uveal Melanoma Cell Lines After X-rays or Carbon Ions Radiation, Investig. Ophthalmol. Vis. Sci, vol.56, pp.3085-3094, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01585033

S. E. Combs, J. Bohl, T. Elsasser, K. Weber, D. Schulz-ertner et al., Radiobiological evaluation and correlation with the local effect model (LEM) of carbon ion radiation therapy and temozolomide in glioblastoma cell lines, Int. J. Radiat. Biol, vol.85, pp.126-137, 2009.

S. Ferrandon, N. Magné, P. Battiston-montagne, N. Hau-desbat, O. Diaz et al., Cellular and molecular portrait of eleven human glioblastoma cell lines under photon and carbon ion irradiation, Cancer Lett, vol.360, pp.10-16, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01118990

M. T. Chew, D. A. Bradley, M. Suzuki, N. Matsufuji, T. Murakami et al., The radiobiological effects of He, C and Ne ions as a function of LET on various glioblastoma cell lines, J. Radiat. Res, vol.60, pp.178-188, 2019.

K. Tsuboi, T. Moritake, Y. Tsuchida, K. Tokuuye, A. Matsumura et al., Cell cycle checkpoint and apoptosis induction in glioblastoma cells and fibroblasts irradiated with carbon beam, J. Radiat. Res, vol.48, pp.317-325, 2007.

M. T. Chew, A. Nisbet, M. Suzuki, N. Matsufuji, T. Murakami et al., Potential lethal damage repair in glioblastoma cells irradiated with ion beams of various types and levels of linear energy transfer, J. Radiat. Res, vol.60, pp.59-68, 2019.

C. Stahler, J. Roth, N. Cordes, G. Taucher-scholz, and W. Mueller-klieser, Impact of carbon ion irradiation on epidermal growth factor receptor signaling and glioma cell migration in comparison to conventional photon irradiation, Int. J. Radiat. Biol, vol.89, pp.454-461, 2013.

A. Wozny, G. Vares, G. Alphonse, A. Lauret, C. Monini et al., 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, Cancers, vol.11, p.468, 2019.
URL : https://hal.archives-ouvertes.fr/hal-02124279

C. Klein, I. Dokic, A. Mairani, S. Mein, S. Brons et al., Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation, Radiat. Oncol, vol.12, pp.1-8, 2017.

E. A. Pérès, S. Valable, J. Guillamo, L. Marteau, J. Bernaudin et al., Targeting the erythropoietin receptor on glioma cells reduces tumour growth, Exp. Cell Res, vol.317, pp.2321-2332, 2011.

A. Torsvik, D. Stieber, P. Ø. Enger, A. Golebiewska, A. Molven et al., U-251 revisited: Genetic drift and phenotypic consequences of long-term cultures of glioblastoma cells, Cancer Med, vol.3, pp.812-824, 2014.

V. Bocchini, R. Casalone, P. Collini, G. Rebel, and F. Lo-curto, Changes in glial fibrillary acidic protein and karyotype during culturing of two cell lines established from human glioblastoma multiforme, Cell Tissue Res, vol.265, pp.73-81, 1991.

F. Durantel, E. Balanzat, A. Cassimi, F. Chevalier, Y. Ngono-ravache et al., Dosimetry for radiobiology experiments at GANIL, Nucl. Instrum. Methods Phys. Res. Sect. A Accel. Spectrometers Detect. Assoc. Equip, vol.816, pp.70-77, 2016.
URL : https://hal.archives-ouvertes.fr/cea-01938057

L. Bodgi, A. Canet, L. Pujo-menjouet, A. Lesne, J. Victor et al., Mathematical models of radiation action on living cells: From the target theory to the modern approaches. A historical and critical review, J. Theor. Biol, vol.394, pp.93-101, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01382777

C. A. Schneider, W. S. Rasband, K. W. Eliceiri, and . Nih, Image to ImageJ: 25 years of image analysis, Nat. Methods, vol.9, pp.671-675, 2012.

, This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, © 2020 by the authors. Licensee MDPI