Carbon irradiation overcomes glioma radioresistance by eradicating stem cells and forming an antiangiogenic and immunopermissive niche

Chiblak, Sara; Tang, Zheng; Lemke, Dieter; Knoll, Maximilian; Đokić, Ivana; Warta, Rolf; Moustafa, Mahmoud; Mier, Walter; Brons, Stephan; Rapp, Carmen; Muschal, Stefan; Seidel, Philipp; Bendszus, Martin; Adeberg, Sebastian; Wiestler, Otmar D.; Haberkorn, Uwe; Debus, Jürgen; Herold‐Mende, Christel; Wick, Wolfgang; Abdollahi, Amir

doi:10.1172/jci.insight.123837

Cited by 63 publications

(71 citation statements)

References 30 publications

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“…RT can be used to modulate the accumulation and distribution of nanoparticles to enhance drug delivery and antitumor efficacy [127]. Apart from X-rays, other types of radiation, such as carbon irradiation and proton irradiation, have also evolved, with the aim of increasing the target dose in cancer tissue while minimizing collateral damage to normal tissue [128,129].…”

Section: Mdscs and Rt Resistancementioning

confidence: 99%

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Khan

Mittal

McGee

et al. 2020

IJMS

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Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

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Section: Mdscs and Rt Resistancementioning

confidence: 99%

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Khan

Mittal

McGee

et al. 2020

IJMS

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“…96-well plates were irradiated with 4Gy photon, proton and carbon beams separately. Proton or carbon ions were administered at the Heidelberg Ion-Beam Therapy Center (HIT) as described [16,37]. For organoids which were irradiated with proton and carbon particles a 15 mm spread-out bragg peak (SOBP) with a middle depth of 120 mm was chosen.…”

Section: Irradiation Of Human Intestinal Organoids With Photon Protomentioning

confidence: 99%

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

Nowrouzi

Sertorio

Akbarpour

et al. 2020

Cancers

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Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficiency as a paradigm for enhanced radiosensitivity. For the two Fanconi anemia (FA) patients (HIO-104 and 106, previously published as FA-A#1 IND-iPS1 and FA-A#2 IND-iPS3), FANCA expression was reconstituted as a prerequisite for generation of HIO via lentiviral expression of a doxycycline inducible construct. For radiosensitivity analysis, FANCA deficient and FANCA rescued as well as wtHIO were sham treated or irradiated with 4Gy photon, proton or carbon ions at HIT, respectively. Immunofluorescence staining of HIO for 53BP1-foci was performed 1 h post IR and gene expression analyses was performed 12 and 48 h post IR. 53BP1-foci numbers and size correlated with the higher RBE of carbon ions. A FANCA dependent differential gene expression in response to radiation was found (p < 0.01, ANOVA; n = 1071 12 h; n = 1100 48 h). Pathways associated with FA and DNA-damage repair i.e., transcriptional coupled nucleotide excision repair, homology-directed repair and translational synthesis were found to be differentially regulated in FANCA deficient HIO. Next, differential regulated genes were investigated as a function of radiation quality (RQ, p < 0.05, ANOVA; n = 742 12 h; n = 553 48 h). Interestingly, a gradual increase or decrease of gene expression was found to correlate with the three main qualities, from photon to proton and carbon irradiation. Clustering separated high-linear energy transfer irradiation with carbons from proton and photon irradiation. Genes associated with dual incision steps of TC-NER were differentially regulated in photon vs. proton and carbon irradiation. Consequently, SUMO3, ALC1, POLE4, PCBP4, MUTYH expression correlated with the higher RBE of carbon ions. An interaction between the two studied parameters FA and RQ was identified (p < 0.01, 2-way ANOVA n = 476). A comparison of genes regulated as a function of FA, RQ and RBE suggest a role for p53 interacting genes BRD7, EWSR1, FBXO11, FBXW8, HMGB1, MAGED2, PCBP4, and RPS27 as modulators of FA in response to radiation. This proof of concept study demonstrates that patient tailored evaluation of GI response to radiation is feasible via generation of HIO and comparative transcriptome profiling. This methodology can now be further explored for a personalized assessment of GI radiosensitivity and RBE estimation.

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“…Similarly, the levels of proinflammatory cytokines rise after carbon therapy compared with x-ray irradiation in RAW264.7 macrophages [72]. Reduced macrophage M2 polarization and increased CD8+ inflammation have been observed in vivo in a syngeneic orthotopic glioblastoma mouse model after carbon irradiation [73].…”

Section: Hadrontherapy To Reverse Tumor Microenvironment-induced Immumentioning

confidence: 92%

Hadrontherapy Interactions in Molecular and Cellular Biology

Thariat

Valable

Laurent

et al. 2019

IJMS

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The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

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Carbon irradiation overcomes glioma radioresistance by eradicating stem cells and forming an antiangiogenic and immunopermissive niche

Cited by 63 publications

References 30 publications

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

Hadrontherapy Interactions in Molecular and Cellular Biology

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