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Shi B, Yang P, Qiao H, He J, Song B, Bai H, Jiang F, Zhang Y, Li Q, Yan T, Tu W, Yu D, Zhang S. EccDNA-Driven VPS41 Amplification Alleviates Genotoxic Stress via Lysosomal KAI1 Degradation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2501934. [PMID: 40271553 DOI: 10.1002/advs.202501934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/10/2025] [Indexed: 04/25/2025]
Abstract
Genotoxic therapies such as ionizing radiation eliminate cancer cells by inducing extensive DNA damage but often cause normal tissue toxicity, including cutaneous injury. Extrachromosomal circular DNA (eccDNA) refers to circular DNA fragments outside the chromosomal context, with their formation and persistence linked to DNA damage repair and genomic instability. Despite growing recognition of eccDNA in oncogenesis, its role under genotoxic stress in normal tissues remains poorly understood. Here, eccDNA is profiled in irradiated rat skin using Circle-seq, identifying alterations in eccDNA number and composition. Specifically, radiation induced circle17:44148731-48208624, in which vacuolar protein sorting 41 homolog (VPS41) is the sole radiation-induced amplification gene by semiquantitative PCR and gel electrophoresis. The findings show that eccDNA or VPS41 overexpression reduces radiation-induced skin injury (RISI) in vitro and in vivo. Proteomic and interaction analyses identified metastasis suppressor kangai-1 (KAI1) as a VPS41-interacting partner. Notably, VPS41 overexpression promotes KAI1 lysosomal degradation, protecting against radiation-induced apoptotic cell death. Peptide array analysis pinpoints the VPS41-KAI1 interaction through the K263 residue, consistent with AlphaFold prediction. The findings uncover a novel mechanism in which radiation-induced eccDNA, specifically VPS41, mitigates skin injury by modulating KAI1 degradation. This study highlights the role of eccDNA in cellular defense, providing strategies to enhance tissue resilience to genotoxic stress.
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Affiliation(s)
- Bin Shi
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563006, China
| | - Ping Yang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Huaijin Qiao
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jinchen He
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Bin Song
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Hao Bai
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Fengdi Jiang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Yining Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Qian Li
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Tao Yan
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Wenlin Tu
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Daojiang Yu
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
- Medical College of Tibet University, Tibet University Lhasa China, No. 1 South Lubulinka Road, Lhasa, 850001, China
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Tang W, Qiu X, Guo J, Xu G, Kong L, Liu W. Proton beam irradiation with anti-VEGF therapy for polypoidal choroidal vasculopathy: results of a 24-month, phase II randomized study. Graefes Arch Clin Exp Ophthalmol 2025; 263:659-668. [PMID: 39520549 DOI: 10.1007/s00417-024-06681-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/23/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
PURPOSE To determine the efficacy and safety of proton beam irradiation (PBI) and anti-vascular endothelial growth factor (anti-VEGF) therapy for polypoidal choroidal vasculopathy (PCV)/ aneurysmal type 1 macular neovascularization (AT1). METHODS The randomized clinical trial consisted of newly diagnosed active PCV/AT1 patients who were randomized 1:1 to treatment with three initial monthly intravitreal anti-VEGF agent (conbercept) injections with or without single 14 GyE radiation. Subsequent anti-VEGF therapy was given pro re nata. The primary outcome measures were number of anti-VEGF injections, best-corrected visual acuity (BCVA), and central retinal thickness (CRT) at 24 months. Secondary outcome measures included the polypoidal lesion regression rate, changes in the areas of polypoidal lesions and branching vascular network (BVN), and radiotherapy-related adverse events at 24 months. RESULTS A total of 45 eyes (86.5%) completed the 24-month follow-up. At 24 months, the combination therapy group required fewer anti-VEGF injections compared with the monotherapy group (5.9 ± 4.1 vs. 8.8 ± 5.3; P = 0.04). The mean gains in BCVA and the mean decrease in CRT were not significantly different between the two groups (P = 0.85 and P = 0.17, respectively). Combination therapy was superior to monotherapy for complete polypoidal lesion regression (80.0% vs. 48%, P = 0.03) and change in BVN area (- 1.03 ± 1.24 mm2 vs. 0.36 ± 0.77 mm2, P < 0.01). The radiation-related microvascular abnormalities were observed in 55.0% of eyes following combination therapy at 15.7 ± 2.5 months. CONCLUSION PBI (14 GyE) combined with anti-VEGF therapy could decrease the need for additional anti-VEGF injections for PCV/AT1. Longer follow-up is needed to fully evaluate the long-term safety of PBI. KEY MESSAGES What is known The current main methods for treating PCV/AT1 include anti-VEGF drugs as monotherapy or in combination with photodynamic therapy. However, some cases can be challenging with multiple repeated injections due to the relatively low regression rate of polyps and high recurrence rate. What is new Proton beam irradiation therapy with anti-VEGF drugs can synergistically promote the regression of polyps and the shrinkage of branching vascular network, and reduce the anti-VEGF treatment burden for patients with PCV/AT1. Radiation retinopathy was mild and did not appear to be visually significant at the 24-month follow-up. Proton beam irradiation can be a new strategy for the treatment of PCV/AT1.
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Affiliation(s)
- Wenyi Tang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
- NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xianxin Qiu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jingli Guo
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gezhi Xu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
- NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China
| | - Lin Kong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.
| | - Wei Liu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, China.
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
- NHC Key Laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
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Waldherr A, Fogtman A. Radiation symptoms resemble laminopathies and the physical underlying cause may sit at the lamin A C-terminus. Mol Med 2025; 31:69. [PMID: 39979866 PMCID: PMC11844092 DOI: 10.1186/s10020-025-01081-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/13/2025] [Indexed: 02/22/2025] Open
Abstract
Ionizing radiation causes three divergent effects in the human body: On one side, tissue death (= deterministic effects) sets on, on the other side, mutations and cancer growth (= stochastic effects) can occur. In recent years, the additional phenomenon of accelerated aging has come to light. In the following, we argue that these seemingly contradictory radiation responses namely: (i) increased cancer growth, (ii) ablation of cancer tissue or (iii) deterministic senescence, share an underlying cause from damage at the lamin A C-terminus. In other words, besides the typically described genomic radiation impact, we propose an additional destabilization pathway via oxidation at the nuclear envelope. We propose five concrete hypotheses that draw a direct mechanistic model from radiation damage and cellular oxidative stress, to micronuclei and clinical symptoms. In conjunction with lamin B compensation, we might be able to explain why deterministic or stochastic responses dominate. If our model holds true, a novel target for radiotherapeutics and radiooncology arises, and a rationale to closer connect laminopathy and radioprotection research.
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Affiliation(s)
- Alexandra Waldherr
- Max-Planck Institute for Biology, Max-Planck-Ring 5, 72076, Tübingen, Germany.
- European Space Agency, Space Medicine Team, EAC European Astronaut Center, EAC Linder Höhe, 51147, Troisdorf, Germany.
| | - Anna Fogtman
- European Space Agency, Space Medicine Team, EAC European Astronaut Center, EAC Linder Höhe, 51147, Troisdorf, Germany
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Zeng M, Lin A, Jiang A, Qiu Z, Zhang H, Chen S, Xu M, Liu Z, Cheng Q, Zhang J, Luo P. Decoding the mechanisms behind second primary cancers. J Transl Med 2025; 23:115. [PMID: 39856672 PMCID: PMC11762917 DOI: 10.1186/s12967-025-06151-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 01/19/2025] [Indexed: 01/27/2025] Open
Abstract
Second Primary Cancers (SPCs) are defined as cancers that develop either simultaneously or metachronously in the same individual who has been diagnosed with and survived one primary cancer. SPCs exhibit a high incidence rate and represent the primary cause of mortality among survivors of first primary cancers. There is growing concern about the dangers of SPCs. This review summarizes recent studies on the mechanisms of SPCs, including the roles of genomic changes after first primary cancer (FPC) treatments, stromal cell phenotypic and metabolic changes, hormone levels and receptor expression, immunosuppression, aberrant gene methylation, EGFR signaling, and cell-free DNA in SPC development. This comprehensive analysis contributes to elucidating current research trends in SPC mechanisms and enhances our understanding of the underlying pathophysiology. Furthermore, potential applications of intratumoral microbes, single-cell multi-omics, and metabolomics in investigating SPC mechanisms are also discussed, providing new ideas for follow-up studies.
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Affiliation(s)
- Meiyuan Zeng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhengang Qiu
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Hongman Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Shifu Chen
- HaploX Biotechnology, Shenzhen, China
- Faculty of Data Science, City University of Macau, Macau, China
| | | | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
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Saini S, Gurung P. A comprehensive review of sensors of radiation-induced damage, radiation-induced proximal events, and cell death. Immunol Rev 2025; 329:e13409. [PMID: 39425547 PMCID: PMC11742653 DOI: 10.1111/imr.13409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
Radiation, a universal component of Earth's environment, is categorized into non-ionizing and ionizing forms. While non-ionizing radiation is relatively harmless, ionizing radiation possesses sufficient energy to ionize atoms and disrupt DNA, leading to cell damage, mutation, cancer, and cell death. The extensive use of radionuclides and ionizing radiation in nuclear technology and medical applications has sparked global concern for their capacity to cause acute and chronic illnesses. Ionizing radiation induces DNA damage either directly through strand breaks and base change or indirectly by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radiolysis of water. This damage triggers a complex cellular response involving recognition of DNA damage, cell cycle arrest, DNA repair mechanisms, release of pro-inflammatory cytokines, and cell death. This review focuses on the mechanisms of radiation-induced cellular damage, recognition of DNA damage and subsequent activation of repair processes, and the critical role of the innate immune response in resolution of the injury. Emphasis is placed on pattern recognition receptors (PRRs) and related receptors that detect damage-associated molecular patterns (DAMPs) and initiate downstream signaling pathways. Radiation-induced cell death pathways are discussed in detail. Understanding these processes is crucial for developing strategies to mitigate the harmful effects of radiation and improve therapeutic outcomes.
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Affiliation(s)
- Saurabh Saini
- Inflammation ProgramUniversity of IowaIowa CityIowaUSA
- Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
- Iowa City Veterans Affairs (VA) Medical CenterIowa CityIowaUSA
| | - Prajwal Gurung
- Inflammation ProgramUniversity of IowaIowa CityIowaUSA
- Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
- Iowa City Veterans Affairs (VA) Medical CenterIowa CityIowaUSA
- Interdisciplinary Graduate Program in Human ToxicologyUniversity of IowaIowa CityIowaUSA
- Immunology Graduate ProgramUniversity of IowaIowa CityIowaUSA
- Center for Immunology and Immune Based DiseaseUniversity of IowaIowa CityIowaUSA
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6
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Grosu-Bularda A, Lita FF, Hodea FV, Bordeanu-Diaconescu EM, Cretu A, Dumitru CS, Cacior S, Marinescu BM, Lascar I, Hariga CS. Navigating the Complexities of Radiation Injuries: Therapeutic Principles and Reconstructive Strategies. J Pers Med 2024; 14:1100. [PMID: 39590592 PMCID: PMC11595796 DOI: 10.3390/jpm14111100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/21/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Radiation injuries, particularly those resulting from therapeutic or accidental exposure, present complex challenges for medical management. These injuries can manifest localized skin damage or extend to deeper tissues, presenting as various clinical entities that require treatment strategies, ranging from conservative management to complex surgical interventions. Radiation treatment constitutes a fundamental component of neoplastic management, with nearly two out of three oncological instances undergoing it as an element of their therapeutic strategy. The therapeutic approach to radiation injury consists of expanding prophylactic measures while maintaining the efficacy of treatment, such as conservative treatment or local debridement followed by reconstruction. The armamentarium of reconstructive methods available for plastic surgeons, from secondary healing to free tissue transfer, can be successfully applied to radiation injuries. However, the unique pathophysiological changes induced by radiation necessitate a careful and specialized approach for their application, considering the altered tissue characteristics and healing dynamics. The therapeutic strategy is guided by both the severity and progression of the injury, with the primary aim of restoring functionality and aesthetic aspects while simultaneously minimizing the risk of complications. This paper explores the various conditions encompassed by the term "radiation injury," reviews both non-surgical and surgical therapeutic strategies for managing these injuries, and highlights the unique challenges associated with treating irradiated tissues within specific oncological contexts.
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Affiliation(s)
- Andreea Grosu-Bularda
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Flavia-Francesca Lita
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
- Clinical Department Plastic Surgery and Reconstructive Microsurgery, Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania
| | - Florin-Vlad Hodea
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Eliza-Maria Bordeanu-Diaconescu
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Andrei Cretu
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Catalina-Stefania Dumitru
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Stefan Cacior
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Bogdan-Mihai Marinescu
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinical Department Plastic Surgery and Reconstructive Microsurgery, Central Military Emergency University Hospital “Dr. Carol Davila”, 010825 Bucharest, Romania
| | - Ioan Lascar
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Cristian-Sorin Hariga
- Department 11, Discipline Plastic and Reconstructive Surgery, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (I.L.); (C.-S.H.)
- Clinic of Plastic Surgery and Reconstructive Microsurgery, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
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Sarma PAP, Abbadie C, Cleri F. Cooperative dynamics of PARP-1 zinc-finger domains in the detection of DNA single-strand breaks. Sci Rep 2024; 14:23257. [PMID: 39370429 PMCID: PMC11456590 DOI: 10.1038/s41598-024-73707-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 09/19/2024] [Indexed: 10/08/2024] Open
Abstract
The DNA single-strand break (SSB) repair pathway is initiated by the multifunctional enzyme PARP-1, which recognizes the broken DNA ends by its two zinc-finger domains, Zn1 and Zn2. Despite a number of experiments performed with different DNA configurations and reduced fragments of PARP-1, many details of this interaction that is crucial to the correct initiation of the repair chain are still unclear. We performed Molecular Dynamics (MD) computer simulations of the interaction between the Zn1/Zn2 domains of PARP-1 and a DNA hairpin including a missing nucleotide to simulate the presence of an SSB, a construct used in recent experiments. The role of Zn1 and Zn2 interacting with the SSB ends is studied in detail, both independently and cooperatively. We also explored, PARP-1 operating as a dimer, with the two Zn-fingers coming from two separate copies of the enzyme. By an extensive set of all-atom molecular simulations employing state-of-the art force fields, assisted by empirical docking and free-energy calculations, we conclude that the particular conformation of the DNA hairpin can indeed spontaneously open up by thermal fluctuations, up to extremely kinked deformations. However, such extreme localized deformations are rarely observed in free, long DNA fragments. Protein side-loops make contact with the DNA hairpin grooves, and help Zn2 to penetrate deep in the SSB gap. In this way, Zn2 can interact with the nucleotides opposite to the missing base. Overall, Zn1 plays a secondary role: the crucial factor for the interaction is rather the relative arrangement of the Zn1/Zn2 couple, and their mutual orientation with respect to the 3 ' and 5 ' SSB end terminals. This helps to obtain an early interacting configuration, which ultimately leads to molecular PARP-1-DNA structures similar to those observed experimentally. Such findings represent an important step toward defining the detailed function of PARP-1 in the early stages of SSB recognition.
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Affiliation(s)
- Parvathy A P Sarma
- Institut d'Electronique Microelectronique et Nanotechnologie (IEMN CNRS UMR8520) and Département de Physique, Université de Lille, 59652, Villeneuve d'Ascq, France
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France
| | - Corinne Abbadie
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France
| | - Fabrizio Cleri
- Institut d'Electronique Microelectronique et Nanotechnologie (IEMN CNRS UMR8520) and Département de Physique, Université de Lille, 59652, Villeneuve d'Ascq, France.
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Rafiepour P, Sina S, Amoli ZA, Shekarforoush SS, Farajzadeh E, Mortazavi SMJ. A mechanistic simulation of induced DNA damage in a bacterial cell by X- and gamma rays: a parameter study. Phys Eng Sci Med 2024; 47:1015-1035. [PMID: 38652348 DOI: 10.1007/s13246-024-01424-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 04/07/2024] [Indexed: 04/25/2024]
Abstract
Mechanistic Monte Carlo simulations calculating DNA damage caused by ionizing radiation are highly dependent on the simulation parameters. In the present study, using the Geant4-DNA toolkit, the impact of different parameters on DNA damage induced in a bacterial cell by X- and gamma-ray irradiation was investigated. Three geometry configurations, including the simple (without DNA details), the random (a random multiplication of identical DNA segments), and the fractal (a regular replication of DNA segments using fractal Hilbert curves), were simulated. Also, three physics constructors implemented in Geant4-DNA, i.e., G4EmDNAPhysics_option2, G4EmDNAPhysics_option4, and G4EmDNAPhysics_option6, with two energy thresholds of 17.5 eV and 5-37.5 eV were compared for direct DNA damage calculations. Finally, a previously developed mathematical model of cell repair called MEDRAS (Mechanistic DNA Repair and Survival) was employed to compare the impact of physics constructors on the cell survival curve. The simple geometry leads to undesirable results compared to the random and fractal ones, highlighting the importance of simulating complex DNA structures in mechanistic simulation studies. Under the same conditions, the DNA damage calculated in the fractal geometry was more consistent with the experimental data. All physics constructors can be used alternatively with the fractal geometry, provided that an energy threshold of 17.5 eV is considered for recording direct DNA damage. All physics constructors represent a similar behavior in generating cell survival curves, although the slopes of the curves are different. Since the inverse of the slope of a bacterial cell survival curve (i.e., the D10-value) is highly sensitive to the simulation parameters, it is not logical to determine an optimal set of parameters for calculating the D10-value by Monte Carlo simulation.
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Affiliation(s)
- Payman Rafiepour
- Department of Nuclear Engineering, School of Mechanical Engineering, Shiraz University, Shiraz, Iran
| | - Sedigheh Sina
- Department of Nuclear Engineering, School of Mechanical Engineering, Shiraz University, Shiraz, Iran.
- Radiation research center, School of Mechanical Engineering, Shiraz University, Shiraz, Iran.
| | - Zahra Alizadeh Amoli
- Department of Food Hygiene and Public Health, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Seyed Shahram Shekarforoush
- Department of Food Hygiene and Public Health, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Ebrahim Farajzadeh
- Secondary Standard Dosimetry Laboratory (SSDL), Pars Isotope Co, Karaj, Iran
| | - Seyed Mohammad Javad Mortazavi
- Ionizing and Non-ionizing Radiation Protection Research Center (INIRPRC), Shiraz University of Medical Sciences, Shiraz, Iran
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Carpenter AD, Fatanmi OO, Wise SY, Tyburski JB, Cheema AK, Singh VK. Proteomic analysis of plasma at the preterminal stage of rhesus nonhuman primates exposed to a lethal total-body dose of gamma-radiation. Sci Rep 2024; 14:13571. [PMID: 38866887 PMCID: PMC11169553 DOI: 10.1038/s41598-024-64316-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 06/07/2024] [Indexed: 06/14/2024] Open
Abstract
The identification and validation of radiation biomarkers is critical for assessing the radiation dose received in exposed individuals and for developing radiation medical countermeasures that can be used to treat acute radiation syndrome (ARS). Additionally, a fundamental understanding of the effects of radiation injury could further aid in the identification and development of therapeutic targets for mitigating radiation damage. In this study, blood samples were collected from fourteen male nonhuman primates (NHPs) that were exposed to 7.2 Gy ionizing radiation at various time points (seven days prior to irradiation; 1, 13, and 25 days post-irradiation; and immediately prior to the euthanasia of moribund (preterminal) animals). Plasma was isolated from these samples and was analyzed using a liquid chromatography tandem mass spectrometry approach in an effort to determine the effects of radiation on plasma proteomic profiles. The primary objective was to determine if the radiation-induced expression of specific proteins could serve as an early predictor for health decline leading to a preterminal phenotype. Our results suggest that radiation induced a complex temporal response in which some features exhibit upregulation while others trend downward. These statistically significantly altered features varied from pre-irradiation levels by as much as tenfold. Specifically, we found the expression of integrin alpha and thrombospondin correlated in peripheral blood with the preterminal stage. The differential expression of these proteins implicates dysregulation of biological processes such as hemostasis, inflammation, and immune response that could be leveraged for mitigating radiation-induced adverse effects.
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Affiliation(s)
- Alana D Carpenter
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine "America's Medical School", Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Oluseyi O Fatanmi
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine "America's Medical School", Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Stephen Y Wise
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine "America's Medical School", Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | | | - Amrita K Cheema
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA
| | - Vijay K Singh
- Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine "America's Medical School", Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA.
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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10
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Zhou Z, Huang S, Fan F, Xu Y, Moore C, Li S, Han C. The multiple faces of cGAS-STING in antitumor immunity: prospects and challenges. MEDICAL REVIEW (2021) 2024; 4:173-191. [PMID: 38919400 PMCID: PMC11195429 DOI: 10.1515/mr-2023-0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 03/28/2024] [Indexed: 06/27/2024]
Abstract
As a key sensor of double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) detects cytosolic dsDNA and initiates the synthesis of 2'3' cyclic GMP-AMP (cGAMP) that activates the stimulator of interferon genes (STING). This finally promotes the production of type I interferons (IFN-I) that is crucial for bridging innate and adaptive immunity. Recent evidence show that several antitumor therapies, including radiotherapy (RT), chemotherapy, targeted therapies and immunotherapies, activate the cGAS-STING pathway to provoke the antitumor immunity. In the last decade, the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry. However, up to now, none of STING agonists have been approved for clinical use. Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node (dLN), research on the optimal way to activate STING in tumor microenvironment (TME) appears to be a promising direction. Moreover, besides enhancing IFN-I signaling, the cGAS-STING pathway also plays roles in senescence, autophagy, apoptosis, mitotic arrest, and DNA repair, contributing to tumor development and metastasis. In this review, we summarize the recent advances on cGAS-STING pathway's response to antitumor therapies and the strategies involving this pathway for tumor treatment.
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Affiliation(s)
- Zheqi Zhou
- Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, Health Science Center, Peking University, Beijing, China
| | - Sanling Huang
- Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, Health Science Center, Peking University, Beijing, China
| | - Fangying Fan
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Yan Xu
- Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, Health Science Center, Peking University, Beijing, China
| | - Casey Moore
- Departments of Immunology, Pathology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sirui Li
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Chuanhui Han
- Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, Health Science Center, Peking University, Beijing, China
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11
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Shireman JM, White Q, Ni Z, Mohanty C, Cai Y, Zhao L, Agrawal N, Gonugunta N, Wang X, Mccarthy L, Kasulabada V, Pattnaik A, Ahmed AU, Miller J, Kulwin C, Cohen-Gadol A, Payner T, Lin CT, Savage JJ, Lane B, Shiue K, Kamer A, Shah M, Iyer G, Watson G, Kendziorski C, Dey M. Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure. iScience 2024; 27:109601. [PMID: 38623341 PMCID: PMC11016778 DOI: 10.1016/j.isci.2024.109601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/12/2024] [Accepted: 03/25/2024] [Indexed: 04/17/2024] Open
Abstract
Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.
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Affiliation(s)
- Jack M. Shireman
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Quinn White
- Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Zijian Ni
- Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Chitrasen Mohanty
- Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Yujia Cai
- Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Lei Zhao
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Namita Agrawal
- Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nikita Gonugunta
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Xiaohu Wang
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Liam Mccarthy
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Varshitha Kasulabada
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Akshita Pattnaik
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Atique U. Ahmed
- Department of Neurological Surgery, Northwestern University, Chicago, IL, USA
| | - James Miller
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Charles Kulwin
- Goodman Campbell Brain and Spine Neurological Surgery, Indianapolis, IN, USA
| | - Aaron Cohen-Gadol
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Troy Payner
- Goodman Campbell Brain and Spine Neurological Surgery, Indianapolis, IN, USA
| | - Chih-Ta Lin
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jesse J. Savage
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Brandon Lane
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kevin Shiue
- Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Aaron Kamer
- Department of Clinical Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mitesh Shah
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gopal Iyer
- Department of Human Oncology, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Gordon Watson
- Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
| | - Mahua Dey
- Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA
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12
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Wang L, Rivas R, Wilson A, Park YM, Walls S, Yu T, Miller AC. Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells. Cells 2023; 13:39. [PMID: 38201243 PMCID: PMC10778067 DOI: 10.3390/cells13010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
To better understand radiation-induced organ dysfunction at both high and low doses, it is critical to understand how endothelial cells (ECs) respond to radiation. The impact of irradiation (IR) on ECs varies depending on the dose administered. High doses can directly damage ECs, leading to EC impairment. In contrast, the effects of low doses on ECs are subtle but more complex. Low doses in this study refer to radiation exposure levels that are below those that cause immediate and necrotic damage. Mitochondria are the primary cellular components affected by IR, and this study explored their role in determining the effect of radiation on microvascular endothelial cells. Human dermal microvascular ECs (HMEC-1) were exposed to varying IR doses ranging from 0.1 Gy to 8 Gy (~0.4 Gy/min) in the AFRRI 60-Cobalt facility. Results indicated that high doses led to a dose-dependent reduction in cell survival, which can be attributed to factors such as DNA damage, oxidative stress, cell senescence, and mitochondrial dysfunction. However, low doses induced a small but significant increase in cell survival, and this was achieved without detectable DNA damage, oxidative stress, cell senescence, or mitochondrial dysfunction in HMEC-1. Moreover, the mitochondrial morphology was assessed, revealing that all doses increased the percentage of elongated mitochondria, with low doses (0.25 Gy and 0.5 Gy) having a greater effect than high doses. However, only high doses caused an increase in mitochondrial fragmentation/swelling. The study further revealed that low doses induced mitochondrial elongation, likely via an increase in mitochondrial fusion protein 1 (Mfn1), while high doses caused mitochondrial fragmentation via a decrease in optic atrophy protein 1 (Opa1). In conclusion, the study suggests, for the first time, that changes in mitochondrial morphology are likely involved in the mechanism for the radiation dose-dependent effect on the survival of microvascular endothelial cells. This research, by delineating the specific mechanisms through which radiation affects endothelial cells, offers invaluable insights into the potential impact of radiation exposure on cardiovascular health.
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Affiliation(s)
- Li Wang
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; (L.W.); (R.R.); (A.W.); (S.W.)
- Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA; (Y.M.P.); (T.Y.)
| | - Rafael Rivas
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; (L.W.); (R.R.); (A.W.); (S.W.)
| | - Angelo Wilson
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; (L.W.); (R.R.); (A.W.); (S.W.)
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA; (Y.M.P.); (T.Y.)
| | - Yu Min Park
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA; (Y.M.P.); (T.Y.)
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Shannon Walls
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; (L.W.); (R.R.); (A.W.); (S.W.)
| | - Tianzheng Yu
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA; (Y.M.P.); (T.Y.)
- Consortium for Health and Military Performance, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Alexandra C. Miller
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; (L.W.); (R.R.); (A.W.); (S.W.)
- Department of Radiation Science and Radiology, Uniformed Services University Health Sciences, Bethesda, MD 20889, USA
- Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
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13
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Szatmári T, Balázs K, Csordás IB, Sáfrány G, Lumniczky K. Effect of radiotherapy on the DNA cargo and cellular uptake mechanisms of extracellular vesicles. Strahlenther Onkol 2023; 199:1191-1213. [PMID: 37347291 DOI: 10.1007/s00066-023-02098-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/01/2023] [Indexed: 06/23/2023]
Abstract
In the past decades, plenty of evidence has gathered pointing to the role of extracellular vesicles (EVs) secreted by irradiated cells in the development of radiation-induced non-targeted effects. EVs are complex natural structures composed of a phospholipid bilayer which are secreted by virtually all cells and carry bioactive molecules. They can travel certain distances in the body before being taken up by recipient cells. In this review we discuss the role and fate of EVs in tumor cells and highlight the importance of DNA specimens in EVs cargo in the context of radiotherapy. The effect of EVs depends on their cargo, which reflects physiological and pathological conditions of donor cell types, but also depends on the mode of EV uptake and mechanisms involved in the route of EV internalization. While the secretion and cargo of EVs from irradiated cells has been extensively studied in recent years, their uptake is much less understood. In this review, we will focus on recent knowledge regarding the EV uptake of cancer cells and the effect of radiation in this process.
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Affiliation(s)
- Tünde Szatmári
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, 1097, Budapest, Hungary.
| | - Katalin Balázs
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, 1097, Budapest, Hungary
| | - Ilona Barbara Csordás
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, 1097, Budapest, Hungary
| | - Géza Sáfrány
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, 1097, Budapest, Hungary
| | - Katalin Lumniczky
- Department of Radiobiology and Radiohygiene, Unit of Radiation Medicine, National Public Health Centre, 1097, Budapest, Hungary
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14
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Nemzow L, Boehringer T, Bacon B, Turner HC. Development of a human peripheral blood ex vivo model for rapid protein biomarker detection and applications to radiation biodosimetry. PLoS One 2023; 18:e0289634. [PMID: 37561730 PMCID: PMC10414586 DOI: 10.1371/journal.pone.0289634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 07/21/2023] [Indexed: 08/12/2023] Open
Abstract
In the event of a widespread radiological incident, thousands of people may be exposed to a wide range of ionizing radiation. In this unfortunate scenario, there will be a need to quickly screen a large number of people to assess the amount of radiation exposure and triage for medical treatment. In our earlier work, we previously identified and validated a panel of radiosensitive protein biomarkers in blood leukocytes, using the humanized-mouse and non-human primate (NHP) models. The objective of this work was to develop a high-throughput imaging flow-cytometry (IFC) based assay for the rapid measurement of protein biomarker expression in human peripheral blood samples irradiated ex vivo. In this assay design, peripheral human blood samples from healthy adult donors were exposed to 0-5 Gy X-irradiation ex vivo and cultured for up to 2 days. Samples were stained with a cocktail of surface antigens (CD66b, CD20, and CD3), fixed and permeabilized, and intracellularly stained for BAX (Bcl-2-associated X) protein, used here as a representative biomarker. Samples were interrogated by IFC, and a uniform analysis template was created to measure biomarker expression in heterogeneous and specific leukocyte subtype populations at each time point. In this human blood ex vivo model, we show that within gated populations of leukocyte subtypes, B-cells are highly radiosensitive with the smallest surviving fraction, followed by T-cells and granulocytes. Dose-dependent biomarker responses were measured in the lymphocytes, B-, and T-cell populations, but not in the granulocytes, with dose-response curves showing increasing fold changes in BAX protein expression up to Day 2 in lymphocyte populations. We present here the successful use of this ex vivo model for the development of radiation dose-response curves of a candidate protein biomarker towards future applications of dose reconstruction and biodosimetry.
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Affiliation(s)
- Leah Nemzow
- Center for Radiological Research, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Thomas Boehringer
- Center for Radiological Research, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Bezalel Bacon
- Center for Radiological Research, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Helen C. Turner
- Center for Radiological Research, Columbia University Irving Medical Center, New York, New York, United States of America
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15
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Zu Y, Wang Z, Yao H, Yan L. Oxygen-generating biocatalytic nanomaterials for tumor hypoxia relief in cancer radiotherapy. J Mater Chem B 2023; 11:3071-3088. [PMID: 36920849 DOI: 10.1039/d2tb02751h] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
Radiotherapy (RT), the most commonly used treatment method in clinics, shows unique advantages such as strong penetration, high energy intensity, and low systemic side effects. However, in vivo tumor hypoxia seriously hinders the therapeutic effect of RT. Hypoxia is a common characteristic of locally advanced solid tumor microenvironments, which leads to the proliferation, invasion and metastasis of tumor cells. In addition, oxygen consumption during RT will further aggravate tumor hypoxia, causing a variety of adverse side effects. In recent years, various biocatalytic nanomaterials (BCNs) have been explored to regulate and reverse tumor hypoxia microenvironments during RT. In this review, the most recent efforts toward developing oxygen-generating BCNs in relieving tumor hypoxia in RT are focused upon. The classification, engineering nanocatalytical activity of oxygen-generating BCNs and combined therapy based on these BCNs are systematically introduced and discussed. The challenges and prospects of these oxygen-generating BCNs in RT applications are also summarized.
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Affiliation(s)
- Yan Zu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
| | - Ziyu Wang
- College of Medical and Biological lnformation Engineering, Northeastern University, Shenyang 110170, China
| | - Huiqin Yao
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
| | - Liang Yan
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
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16
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Jules A, Means D, Troncoso JR, Fernandes A, Dadgar S, Siegel ER, Rajaram N. Diffuse Reflectance Spectroscopy of Changes in Tumor Microenvironment in Response to Different Doses of Radiation. Radiat Res 2022; 198:545-552. [PMID: 36240754 PMCID: PMC9798304 DOI: 10.1667/rade-21-00228.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 09/28/2022] [Indexed: 12/31/2022]
Abstract
Radiation therapy plays an important role in cancer treatment, as it is an established method used as part of the treatment plan for the majority of cancer patients. Real-time monitoring of the effects of radiation on the tumor microenvironment can contribute to the development of better treatment plans. In this study, we use diffuse reflectance spectroscopy, a non-invasive optical fiber-based technique, to determine the effects of different doses of radiation on the tumor microenvironment, as well as to determine the sensitivity of diffuse reflectance spectroscopy to low doses of radiation that are used in the treatment of certain cancers. We injected 4T1 cells into 50 Balb/c mice to generate tumor xenografts. When the tumors grew to 200 mm3, we distributed the mice into a control group or one of three radiation groups: 1, 2, or 4 Gy/fraction, and they underwent treatment for five consecutive days. We measured the tumor volume and collected diffuse reflectance spectra every day, with optical measurements being acquired both before and one h postirradiation on the five days of treatment. Based on the diffusely reflected light, we quantified vascular oxygenation, total hemoglobin content, and tissue scattering within these tumors. There was a significant increase in tumor vascular oxygenation, which was primarily due to an increase in oxygenated hemoglobin, in response to a 1 Gy/fraction of radiation, while there was a decrease in tissue scattering in response to all doses of radiation. Immunohistochemical analysis revealed that tumor cell proliferation and apoptosis were higher in irradiated groups compared to the control group. Our findings show that diffuse reflectance spectroscopy is sensitive to microenvironmental changes in tumors treated with doses of radiation as low as 1 Gy/fraction.
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Affiliation(s)
- April Jules
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas
| | - Davin Means
- Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas
| | | | - Alric Fernandes
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas
| | - Sina Dadgar
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas
| | - Eric R Siegel
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Narasimhan Rajaram
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, Arkansas
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17
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Castellano LRC, Cruz SBSC, Hier M, Bonan PRF, Alaoui-Jamali MA, da Silva SD. Implications and Emerging Therapeutic Avenues of Inflammatory Response in HPV+ Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:5406. [PMID: 36358823 PMCID: PMC9657300 DOI: 10.3390/cancers14215406] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 10/24/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC.
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Affiliation(s)
- Lúcio Roberto Cançado Castellano
- Department of Otolaryngology and Head and Neck Surgery and Lady Davis Institutes for Medical Research of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
- Human Immunology Research and Education Group, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
- Graduate Program in Dentistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
| | - Sara Brito Silva Costa Cruz
- Department of Otolaryngology and Head and Neck Surgery and Lady Davis Institutes for Medical Research of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
- Human Immunology Research and Education Group, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
- Graduate Program in Dentistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
| | - Michael Hier
- Department of Otolaryngology and Head and Neck Surgery and Lady Davis Institutes for Medical Research of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
| | - Paulo Rogério Ferreti Bonan
- Human Immunology Research and Education Group, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
- Graduate Program in Dentistry, Federal University of Paraíba, João Pessoa 58051-900, PB, Brazil
| | - Moulay A. Alaoui-Jamali
- Department of Otolaryngology and Head and Neck Surgery and Lady Davis Institutes for Medical Research of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
| | - Sabrina Daniela da Silva
- Department of Otolaryngology and Head and Neck Surgery and Lady Davis Institutes for Medical Research of the Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
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18
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Navin PJ, Olson MC, Mendiratta-Lala M, Hallemeier CL, Torbenson MS, Venkatesh SK. Imaging Features in the Liver after Stereotactic Body Radiation Therapy. Radiographics 2022; 42:2131-2148. [PMID: 36240077 DOI: 10.1148/rg.220084] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Historically, radiation therapy was not considered in treatment of liver tumors owing to the risk of radiation-induced liver disease. However, development of highly conformed radiation treatments such as stereotactic body radiation therapy (SBRT) has increased use of radiation therapy in the liver. SBRT is indicated in treatment of primary and metastatic liver tumors with outcomes comparable to those of other local therapies, especially in treatment of hepatocellular carcinoma. After SBRT, imaging features of the tumor and surrounding background hepatic parenchyma demonstrate a predictable pattern immediately after treatment and during follow-up. The goals of SBRT are to deliver a lethal radiation dose to the targeted liver tumor and to minimize radiation dose to normal liver parenchyma and other adjacent organs. Evaluation of tumor response after SBRT centers on changes in size and enhancement; however, these changes are often delayed secondary to the underlying physiologic effects of radiation. Knowledge of the underlying pathophysiologic mechanisms of SBRT should allow better understanding of the typical imaging features in detection of tumor response and avoid misinterpretation from common pitfalls and atypical imaging findings. Imaging features of radiation-induced change in the surrounding liver parenchyma are characterized by a focal liver reaction that can potentially be mistaken for no response or recurrence of tumor. Knowledge of the pattern and chronology of this phenomenon may allay any uncertainty in assessment of tumor response. Other pitfalls related to fiducial marker placement or combination therapies are important to recognize. The authors review the basic principles of SBRT and illustrate post-SBRT imaging features of treated liver tumors and adjacent liver parenchyma with a focus on avoiding pitfalls in imaging evaluation of response. Online supplemental material is available for this article. ©RSNA, 2022.
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Affiliation(s)
- Patrick J Navin
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Michael C Olson
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Mishal Mendiratta-Lala
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Christopher L Hallemeier
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Michael S Torbenson
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Sudhakar K Venkatesh
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
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19
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Blair TC, Bambina S, Kramer GF, Dowdell AK, Alice AF, Baird JR, Lund AW, Piening BD, Crittenden MR, Gough MJ. Fluorescent tracking identifies key migratory dendritic cells in the lymph node after radiotherapy. Life Sci Alliance 2022; 5:e202101337. [PMID: 35487695 PMCID: PMC9058260 DOI: 10.26508/lsa.202101337] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022] Open
Abstract
Radiation therapy generates extensive cancer cell death capable of promoting tumor-specific immunity. Within the tumor, conventional dendritic cells (cDCs) are known to carry tumor-associated antigens to the draining lymph node (TdLN) where they initiate T-cell priming. How radiation influences cDC migration is poorly understood. Here, we show that immunological efficacy of radiation therapy is dependent on cDC migration in radioimmunogenic tumors. Using photoconvertible mice, we demonstrate that radiation impairs cDC migration to the TdLN in poorly radioimmunogenic tumors. Comparative transcriptional analysis revealed that cDCs in radioimmunogenic tumors express genes associated with activation of endogenous adjuvant signaling pathways when compared with poorly radioimmunogenic tumors. Moreover, an exogenous adjuvant combined with radiation increased the number of migrating cDCs in these poorly radioimmunogenic tumors. Taken together, our data demonstrate that cDC migration play a critical role in the response to radiation therapy.
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Affiliation(s)
- Tiffany C Blair
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Shelly Bambina
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Gwen F Kramer
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Alexa K Dowdell
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Alejandro F Alice
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Jason R Baird
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Amanda W Lund
- Ronald O Perelman Department of Dermatology, Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA
| | - Brian D Piening
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
| | - Marka R Crittenden
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
- The Oregon Clinic, Portland, OR, USA
| | - Michael J Gough
- Earle A Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA
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20
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Goy E, Tomezak M, Facchin C, Martin N, Bouchaert E, Benoit J, de Schutter C, Nassour J, Saas L, Drullion C, Brodin PM, Vandeputte A, Molendi-Coste O, Pineau L, Goormachtigh G, Pluquet O, Pourtier A, Cleri F, Lartigau E, Penel N, Abbadie C. The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion. eLife 2022; 11:67190. [PMID: 35302491 PMCID: PMC8933005 DOI: 10.7554/elife.67190] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/15/2022] [Indexed: 11/13/2022] Open
Abstract
A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient’s treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.
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Affiliation(s)
- Erwan Goy
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Maxime Tomezak
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France.,Univ. Lille, CNRS, UMR8520, Institut d'Electronique, Microélectronique et Nanotechnologie, F-59652 Villeneuve d'Ascq, France
| | - Caterina Facchin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Nathalie Martin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Emmanuel Bouchaert
- Oncovet Clinical Research, Plateforme PRECI, F-59120 Loos, France.,Oncovet, Plateforme PRECI, F-59650 Villeneuve d'Ascq, France
| | - Jerome Benoit
- Oncovet Clinical Research, Plateforme PRECI, F-59120 Loos, France.,Oncovet, Plateforme PRECI, F-59650 Villeneuve d'Ascq, France
| | - Clementine de Schutter
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Joe Nassour
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Laure Saas
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Claire Drullion
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Priscille M Brodin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France
| | - Alexandre Vandeputte
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France
| | - Olivier Molendi-Coste
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Laurent Pineau
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Gautier Goormachtigh
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Olivier Pluquet
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Albin Pourtier
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Fabrizio Cleri
- Univ. Lille, CNRS, UMR8520, Institut d'Electronique, Microélectronique et Nanotechnologie, F-59652 Villeneuve d'Ascq, France
| | - Eric Lartigau
- Lille University, Medical School and Centre Oscar Lambret, Lille, France
| | - Nicolas Penel
- Lille University, Medical School and Centre Oscar Lambret, Lille, France
| | - Corinne Abbadie
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
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21
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Goel R, Ojha H, Choudhary V, Sharma D, Nair A, Sharma N, Pathak M, Shivkumar H, Sharma R, Kaushik V, Singhal R. Medical management of ionizing radiation-induced skin injury. RADIATION PROTECTION AND ENVIRONMENT 2022. [DOI: 10.4103/rpe.rpe_4_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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22
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Wahl RL, Sgouros G, Iravani A, Jacene H, Pryma D, Saboury B, Capala J, Graves SA. Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns. J Nucl Med 2021; 62:23S-35S. [PMID: 34857619 PMCID: PMC12079726 DOI: 10.2967/jnumed.121.262751] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/15/2021] [Indexed: 12/25/2022] Open
Affiliation(s)
- Richard L Wahl
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri
| | - George Sgouros
- Department of Radiology, Johns Hopkins University, Baltimore, Maryland
| | - Amir Iravani
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri
| | | | - Daniel Pryma
- Penn Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Jacek Capala
- National Institutes of Health, Bethesda, Maryland
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23
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Jiang W, Cai J, Guan J, Liao Y, Lu F, Ma J, Gao J, Zhang Y. Characterized the Adipogenic Capacity of Adipose-Derived Stem Cell, Extracellular Matrix, and Microenvironment With Fat Components Grafting. Front Cell Dev Biol 2021; 9:723057. [PMID: 34616732 PMCID: PMC8489879 DOI: 10.3389/fcell.2021.723057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/31/2021] [Indexed: 12/18/2022] Open
Abstract
Background: Autologous fat grafting has been a widely used technique; however, the role of adipose-derived stem cells (ASCs), extracellular matrix (ECM), and microenvironment in fat regeneration are not fully understood. Methods: Lipoaspirates were obtained and processed by inter-syringe shifting to remove adipocytes, yielding an adipocyte-free fat (Aff). Aff was then exposed to lethal dose of radiation to obtain decellularized fat (Df). To further remove microenvironment, Df was rinsed with phosphate-buffered saline (PBS) yielding rinsed decellularized fat (Rdf). Green fluorescent protein (GFP) lentivirus (LV-GFP)-transfected ASCs were added to Df to generate cell-recombinant decellularized fat (Crdf). Grafts were transplanted subcutaneously into nude mice and harvested over 3 months. Results: Removal of adipocytes (Aff) didn't compromise the retention of fat grafts, while additional removal of stromal vascular fraction (SVF) cells (Df) and microenvironment (Rdf) resulted in poor retention by day 90 (Aff, 82 ± 7.1% vs. Df, 28 ± 6.3%; p < 0.05; vs. Rdf, 5 ± 1.2%; p < 0.05). Addition of ASCs to Df (Crdf) partially restored its regenerative potential. Aff and Crdf exhibited rapid angiogenesis and M2-polarized macrophages infiltration, in contrast to impaired angiogenesis and M1-polarized inflammatory pattern in Df. GFP + ASCs participated in angiogenesis and displayed a phenotype of endothelial cells in Crdf. Conclusion: Adipose ECM and microenvironment have the capacity to stimulate early adipogenesis while ECM alone cannot induce adipogenesis in vivo. By directly differentiating into endothelial cells and regulating macrophage polarization, ASCs coordinate early adipogenesis with angiogenesis and tissue remodeling, leading to better long-term retention and greater tissue integrity.
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Affiliation(s)
- Wenqing Jiang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junrong Cai
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingyan Guan
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yunjun Liao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingjing Ma
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianhua Gao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuteng Zhang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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24
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Wimmer S, Deloch L, Hader M, Derer A, Grottker F, Weissmann T, Hecht M, Gostian AO, Fietkau R, Frey B, Gaipl US. Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells. Int J Mol Sci 2021; 22:ijms22179114. [PMID: 34502022 PMCID: PMC8430967 DOI: 10.3390/ijms22179114] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/11/2021] [Accepted: 08/20/2021] [Indexed: 12/21/2022] Open
Abstract
While the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy (RT) is complemented more and more by immunotherapy in clinical trials, little is known about the impact of the human papillomavirus (HPV) status or the applied RT scheme on the immune phenotype of the tumor cells. Therefore, we aimed to examine the impact of the HPV status of four human HNSCC cell lines on cell death and the expression of immune checkpoint molecules (ICMs) after RT with either hypofractionation irradiation (5x3.0Gy) or a high single dose (1x19.3Gy) via multicolor flow cytometry and quantitative PCR at an early time point after therapy. In our study, 5x3.0Gy RT induced high numbers of early and late apoptotic cells independent of the HPV status, but necrosis was only increased in the HPV-positive UM-Scc-47 cells. Generally, the immune stimulatory ICMs (CD70, CD137-L, ICOS-L) were less affected by RT compared to the immune suppressive ones (PD-L1, PD-L2, and the herpesvirus entry mediator (HVEM)). A significant higher surface expression of the analyzed ICMs was found after hypofractionated RT compared to a single high dose; however, regardless of the HPV status, with the exception of ICOS-L. Here, HPV-positive HNSCC tumor cells showed a stronger response to 5x3.0Gy than HPV-negative ones. On the RNA level, only minor alterations of ICMs were observed following RT, with the exception of the HPV negative cell line CAL33 treated with 5x3.0Gy, where PD-L2, HVEM and CD70 were significantly increased. We conclude that the HPV status may not distinctly predict immunological responses following RT, and thus cannot be used as a single predictive marker for therapy responses in HNSCC. In contrast, the patient-specific individual expression of ICMs following RT is preferable for the targeted patient selection for immune therapy directed against distinct ICM.
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Affiliation(s)
- Sebastian Wimmer
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Lisa Deloch
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Michael Hader
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Anja Derer
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Fridolin Grottker
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Thomas Weissmann
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Markus Hecht
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Antoniu-Oreste Gostian
- Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany;
| | - Rainer Fietkau
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Benjamin Frey
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Udo S. Gaipl
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (S.W.); (L.D.); (M.H.); (A.D.); (F.G.); (T.W.); (M.H.); (R.F.); (B.F.)
- Translational Radiobiology, Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-8544-258; Fax: +49-9131-8539-335
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25
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McMahon SJ, Prise KM. A Mechanistic DNA Repair and Survival Model (Medras): Applications to Intrinsic Radiosensitivity, Relative Biological Effectiveness and Dose-Rate. Front Oncol 2021; 11:689112. [PMID: 34268120 PMCID: PMC8276175 DOI: 10.3389/fonc.2021.689112] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/31/2021] [Indexed: 01/04/2023] Open
Abstract
Variations in the intrinsic radiosensitivity of different cells to ionizing radiation is now widely believed to be a significant driver in differences in response to radiotherapy. While the mechanisms of radiosensitivity have been extensively studied in the laboratory, there are a lack of models which integrate this knowledge into a predictive framework. This paper presents an overview of the Medras model, which has been developed to provide a mechanistic framework in which different radiation responses can be modelled and individual responses predicted. This model simulates the repair of radiation-induced DNA damage, incorporating the overall kinetics of repair and its fidelity, to predict a range of biological endpoints including residual DNA damage, mutation, chromosome aberration, and cell death. Validation of this model against a range of exposure types is presented, including considerations of varying radiation qualities and dose-rates. This approach has the potential to inform new tools to deliver mechanistic predictions of radiation sensitivity, and support future developments in treatment personalization.
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Affiliation(s)
- Stephen Joseph McMahon
- Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
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26
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Batista Napotnik T, Polajžer T, Miklavčič D. Cell death due to electroporation - A review. Bioelectrochemistry 2021; 141:107871. [PMID: 34147013 DOI: 10.1016/j.bioelechem.2021.107871] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022]
Abstract
Exposure of cells to high voltage electric pulses increases transiently membrane permeability through membrane electroporation. Electroporation can be reversible and is used in gene transfer and enhanced drug delivery but can also lead to cell death. Electroporation resulting in cell death (termed as irreversible electroporation) has been successfully used as a new non-thermal ablation method of soft tissue such as tumours or arrhythmogenic heart tissue. Even though the mechanisms of cell death can influence the outcome of electroporation-based treatments due to use of different electric pulse parameters and conditions, these are not elucidated yet. We review the mechanisms of cell death after electroporation reported in literature, cell injuries that may lead to cell death after electroporation and membrane repair mechanisms involved. The knowledge of membrane repair and cell death mechanisms after cell exposure to electric pulses, targets of electric field in cells need to be identified to optimize existing and develop of new electroporation-based techniques used in medicine, biotechnology, and food technology.
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Affiliation(s)
- Tina Batista Napotnik
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia
| | - Tamara Polajžer
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia
| | - Damijan Miklavčič
- University of Ljubljana, Faculty of Electrical Engineering, Tržaška cesta 25, 1000 Ljubljana, Slovenia.
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27
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Adnan M, Rasul A, Shah MA, Hussain G, Asrar M, Riaza A, Sarfraza I, Hussaina A, Khorsandid K, Laie NS, Hussaina SM. Radioprotective Role of Natural Polyphenols: From Sources to Mechanisms. Anticancer Agents Med Chem 2021; 22:30-39. [PMID: 33874875 DOI: 10.2174/1871520621666210419095829] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/22/2020] [Accepted: 10/19/2020] [Indexed: 11/22/2022]
Abstract
The identification and development of radioprotective agents has emerged as a subject matter of research during recent years due to the growing usage of ionizing radiation in different areas of human life. Previous work on synthetic radioprotectors has achieved limited progress because of the numerous issues associated with toxicity. Compounds extracted from plants have potential to serve as lead candidates for developing ideal radioprotectors due to their low cost, safety and selectivity. Polyphenols are the most abundant and commonly dispersed group of biologically active molecules possessing broad range of pharmacological activities. Polyphenols have displayed efficacy for radioprotection during various investigations and can be administered at high doses with lesser toxicity. Detoxification of free radicals, modulating inflammatory responses, DNA repair, stimulation of hematopoietic recovery, and immune functions are the main mechanisms for radiation protection with polyphenols. Epicatechin, epigallocatechin-3-gallate, apigenin, caffeic acid phenylethylester, and silibinin provide cytoprotection together with the suppression of many pro-inflammatory cytokines owing to their free radical scavenging, anti-oxidant, and anti-inflammatory properties. Curcumin, resveratrol, quercetin, gallic acid, and rutin's radioprotective properties are regulated primarily by direct or indirect decline in cellular stress. Thus, polyphenols may serve as potential candidates for radioprotection in the near future, however, extensive investigations are still required to better understand their protection mechanisms.
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Affiliation(s)
- Muhammad Adnan
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Azhar Rasul
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Muhammad A Shah
- Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Government College University Faisalabad 38000. Pakistan
| | - Ghulam Hussain
- Neurochemical biology and Genetics Laboratory, Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Muhammad Asrar
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Ammara Riaza
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Iqra Sarfraza
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Arif Hussaina
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
| | - Khatereh Khorsandid
- Department of Photodynamic, Medical Laser Research Center, Yara Institute, ACECR, Tehran. Iran
| | - Ngit S Laie
- Institute for Research in Molecular Medicine Universiti Sains Malaysia, Pulau Pinang. Malaysia
| | - Syed M Hussaina
- Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000. Pakistan
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28
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Sharma S, Srivastava M. Inhibition of the DNA damage response to activate immune responses toward tumors. FEBS J 2021; 288:4503-4506. [PMID: 33811455 DOI: 10.1111/febs.15836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/22/2021] [Indexed: 11/29/2022]
Abstract
Cancer immunotherapy represents a very encouraging mode of treatment for cancer where one's immune system is utilized to eliminate tumor cells. Wayne et al. explore inhibition of DNA damage response (DDR) pathways with small molecule inhibitors as a means to prime cells with immune response. These findings suggest that a one-size-fits-all approach cannot be used when harnessing immune response via DDR inhibitors and genotoxic agents, which are required ultimately for the success of immunotherapy. Comment on: https://doi.org/10.1111/febs.15747.
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Affiliation(s)
- Sheetal Sharma
- Department of Experimental Medicine and Biotechnology, Post-graduate Institute of Medical Research & Education, Chandigarh, India
| | - Mrinal Srivastava
- TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research (TIFR) Hyderabad, India
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29
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Sabloff M, Tisseverasinghe S, Babadagli ME, Samant R. Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on? ACTA ACUST UNITED AC 2021; 28:903-917. [PMID: 33617507 PMCID: PMC7985756 DOI: 10.3390/curroncol28010089] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/19/2021] [Accepted: 02/02/2021] [Indexed: 01/23/2023]
Abstract
Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.
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Affiliation(s)
- Mitchell Sabloff
- Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada;
- The Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | | | - Mustafa Ege Babadagli
- Division of Radiation Oncology, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada;
- Correspondence:
| | - Rajiv Samant
- Division of Radiation Oncology, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada;
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Ebahimzadeh K, Shoorei H, Mousavinejad SA, Anamag FT, Dinger ME, Taheri M, Ghafouri-Fard S. Emerging role of non-coding RNAs in response of cancer cells to radiotherapy. Pathol Res Pract 2020; 218:153327. [PMID: 33422780 DOI: 10.1016/j.prp.2020.153327] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023]
Abstract
Radiotherapy is an effective method for treatment of a large proportion of human cancers. Yet, the efficacy of this method is precluded by the induction of radioresistance in tumor cells and the radiation-associated injury of normal cells surrounding the field of radiation. These restrictions necessitate the introduction of modalities for either radiosensitization of cancer cells or protection of normal cells against adverse effects of radiation. Non-coding RNAs (ncRNAs) have essential roles in the determination of radiosensitivity. Moreover, ncRNAs can modulate radiation-induced side effects in normal cells. Several microRNAs (miRNAs) such as miR-620, miR-21 and miR-96-5p confer radioresistance, while other miRNAs including miR-340/ 429 confer radiosensitivity. The expression levels of a number of miRNAs are associated with radiation-induced complications such as lung fibrosis or oral mucositis. The expression patterns of several long non-coding RNAs (lncRNAs) such as MALAT1, LINC00630, HOTAIR, UCA1 and TINCR are associated with response to radiotherapy. Taken together, lncRNAs and miRNAs contribute both in modulation of response of cancer cells to radiotherapy and in protection of normal cells from the associated side effects. The current review provides an overview of the roles of these transcripts in these aspects.
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Affiliation(s)
- Kaveh Ebahimzadeh
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Seyed Ali Mousavinejad
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Soudeh Ghafouri-Fard
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Stephen Inbaraj B, Chen BH. An overview on recent in vivo biological application of cerium oxide nanoparticles. Asian J Pharm Sci 2020; 15:558-575. [PMID: 33193860 PMCID: PMC7610205 DOI: 10.1016/j.ajps.2019.10.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/25/2019] [Accepted: 10/05/2019] [Indexed: 12/13/2022] Open
Abstract
Cerium oxide nanoparticles (CNPs) possess a great potential as therapeutic agents due to their ability to self-regenerate by reversibly switching between two valences +3 and +4. This article reviews recent articles dealing with in vivo studies of CNPs towards Alzheimer's disease, obesity, liver inflammation, cancer, sepsis, amyotrophic lateral sclerosis, acute kidney injury, radiation-induced tissue damage, hepatic ischemia reperfusion injury, retinal diseases and constipation. In vivo anti-cancer studies revealed the effectiveness of CNPs to reduce tumor growth and angiogenesis in melanoma, ovarian, breast and retinoblastoma cancer cell-induced mice, with their conjugation with folic acid, doxorubicin, CPM, or CXC receptor-4 antagonist ligand eliciting higher efficiency. After conjugation with triphenylphosphonium or magnetite nanoparticles, CNPs were shown to combat Alzheimer's disease by reducing amyloid-β, glial fibrillary acidic protein, inflammatory and oxidative stress markers in mice. By improving muscle function and longevity, the citrate/EDTA-stabilized CNPs could ameliorate amyotrophic lateral sclerosis. Also, they could effectively reduce obesity in mice by scavenging ROS and reducing adipogenesis, triglyceride synthesis, GAPDH enzyme activity, leptin and insulin levels. In CCl4-induced rats, stress signaling pathways due to inflammatory cytokines, liver enzymes, oxidative and endoplasmic reticulum messengers could be attenuated by CNPs. Commercial CNPs showed protective effects on rats with hepatic ischemia reperfusion and peritonitis-induced hepatic/cardiac injuries by decreasing oxidative stress and hepatic/cardiac inflammation. The same CNPs could improve kidney function by diminishing renal superoxide, hyperglycemia and tubular damage in peritonitis-induced acute kidney injury in rats. Radiation-induced lung and testicular tissue damage could be alleviated in mice, with the former showing improvement in pulmonary distress and bronchoconstriction and the latter exhibiting restoration in spermatogenesis rate and spermatid/spermatocyte number. Through enhancement of gastrointestinal motility, the CNPs could alleviate constipation in both young and old rats. They could also protect rat from light-induced retinal damage by slowing down neurodegenerative process and microglial activation.
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Affiliation(s)
| | - Bing-Huei Chen
- Department of Food Science, Fu Jen Catholic University, Taipei 242
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32
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Modulation of DNA Damage Response by Sphingolipid Signaling: An Interplay that Shapes Cell Fate. Int J Mol Sci 2020; 21:ijms21124481. [PMID: 32599736 PMCID: PMC7349968 DOI: 10.3390/ijms21124481] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/11/2022] Open
Abstract
Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of evidence points to a fundamental role for the sphingolipid metabolic pathway in modulating the DNA damage response (DDR). The interplay between these two elements of cell signaling determines cell fate when cells are exposed to metabolic stress or ionizing radiation among other genotoxic agents. In this review, we aim to dissect the mediators of the DDR and how these interact with the different sphingolipid metabolites to mount various cellular responses.
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33
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Feng X, Tubbs A, Zhang C, Tang M, Sridharan S, Wang C, Jiang D, Su D, Zhang H, Chen Z, Nie L, Xiong Y, Huang M, Nussenzweig A, Chen J. ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways. EMBO J 2020; 39:e104036. [PMID: 32484965 DOI: 10.15252/embj.2019104036] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 03/21/2020] [Accepted: 05/08/2020] [Indexed: 12/20/2022] Open
Abstract
Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation-induced innate immune responses. Using a series of mammalian knockout cell lines, we demonstrate that, surprisingly, both the cGAS/STING-dependent DNA-sensing pathway and the MAVS-dependent RNA-sensing pathway are responsible for type I interferon signaling induced by ionizing radiation in the presence or absence of ATR inhibitors. The relative contributions of these two pathways in type I interferon signaling depend on cell type and/or genetic background. We propose that DNA damage-elicited double-strand DNA breaks releases DNA fragments, which may either activate the cGAS/STING-dependent pathway or-especially in the case of AT-rich DNA sequences-be transcribed and initiate MAVS-dependent RNA sensing and signaling. Together, our results suggest the involvement of two distinct pathways in type I interferon signaling upon DNA damage. Moreover, radiation plus ATR inhibition may be a promising new combination therapy against cancer.
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Affiliation(s)
- Xu Feng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anthony Tubbs
- Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Chunchao Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mengfan Tang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sriram Sridharan
- Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Chao Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dadi Jiang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dan Su
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Huimin Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhen Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Litong Nie
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Xiong
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Min Huang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - André Nussenzweig
- Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Junjie Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Vigneswara V, Ahmed Z. The Role of Caspase-2 in Regulating Cell Fate. Cells 2020; 9:cells9051259. [PMID: 32438737 PMCID: PMC7290664 DOI: 10.3390/cells9051259] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022] Open
Abstract
Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life.
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35
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Fujimoto M, Bo T, Yamamoto K, Yasui H, Yamamori T, Inanami O. Radiation-induced abnormal centrosome amplification and mitotic catastrophe in human cervical tumor HeLa cells and murine mammary tumor EMT6 cells. J Clin Biochem Nutr 2020; 67:240-247. [PMID: 33293764 PMCID: PMC7705082 DOI: 10.3164/jcbn.19-80] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 02/18/2020] [Indexed: 12/14/2022] Open
Abstract
Mitotic catastrophe is a form of cell death linked to aberrant mitosis caused by improper or uncoordinated mitotic progression. Abnormal centrosome amplification and mitotic catastrophe occur simultaneously, and some cells with amplified centrosomes enter aberrant mitosis, but it is not clear whether abnormal centrosome amplification triggers mitotic catastrophe. Here, to investigate whether radiation-induced abnormal centrosome amplification is essential for induction of radiation-induced mitotic catastrophe, centrinone-B, a highly selective inhibitor of polo-like kinase 4, was utilized to inhibit centrosome amplification, since polo-like kinase 4 is an essential kinase in centrosome duplication. When human cervical tumor HeLa cells and murine mammary tumor EMT6 cells were irradiated with 2.5 Gy of X-rays, cells with morphological features of mitotic catastrophe and the number of cells having >2 centrosomes increased in both cell lines. Although centrinone-B significantly inhibited radiation-induced abnormal centrosome amplification in both cell lines, such treatment did not change cell growth and significantly enhanced mitotic catastrophe in HeLa cells exposed to X-rays. In contrast, inhibition of centrosome amplification reduced cell growth and mitotic catastrophe in EMT6 cells exposed to X-rays. These results indicated that the role of radiation-induced abnormal centrosome amplification in radiation-induced mitotic catastrophe changes, depending on the cell type.
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Affiliation(s)
- Masaki Fujimoto
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Tomoki Bo
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Kumiko Yamamoto
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Hironobu Yasui
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Tohru Yamamori
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
| | - Osamu Inanami
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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36
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Jing S, Guo H, Qi Y, Yang G, Huang Y. A portable fast neutron irradiation system for tumor therapy. Appl Radiat Isot 2020; 160:109138. [PMID: 32351230 DOI: 10.1016/j.apradiso.2020.109138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 06/06/2019] [Accepted: 03/18/2020] [Indexed: 12/25/2022]
Abstract
A portable neutron tube was introduced as a small-sized (weight≤14.4 kg, power consumption ≤50W and cost≤ $100,000) neutron accelerator and applied for irradiation therapy on cancer. The effect of growth-inhibiting in vitro by neutrons irradiation on HeLa cells (human cervical cancer cells) was evaluated by colony formation assays, and cell apoptosis was evaluated by Flow Cytometry. A polyethylene protection device as the neutron moderator was designed and connected to the neutron tube to shield normal tissue and organs of the test animals from scatter radiation. Hematology and blood biochemistry were investigated to evaluate the protective effect of polyethylene. U14 (mice cervical cancer cell) tumor-bearing mice were further investigated to determine the tumor suppression effect of neutron irradiation. We found that cells showed a dose-dependent relationship after fast neutrons irradiation at different dose (1.11 Gy, 2.23 Gy, 3.34 Gy and 4.45Gy). Furthermore, in vivo experiments showed that the anti-tumor effect on U14 tumor-bearing mice greatly depended on the neutron irradiation dose. A high dose of fast neutron irradiation (26.73 Gy) could have tumor growth rate only 12.31% compared to 56.07% with control group. All the blood cell counts and blood biochemistry parameters were in the standard value ranges. Immunohistochemistry examinations clearly indicated the apoptosis cells in tumor tissues by the TUNEL assay. This work provides useful evidences on cancer irradiation therapy using fast neutron in pre-clinical study. And the neutron therapy system device has great potential to be a more convenient tool in clinical application with significantly lower power consumption, irradiation toxicity and cost.
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Affiliation(s)
- Shiwei Jing
- Northeast Normal University, Changchun, 130024, PR China
| | - Huanhuan Guo
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Yanxin Qi
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China; Yanbian University Medical College, Yanji, 133002, PR China.
| | - Guifu Yang
- Northeast Normal University, Changchun, 130024, PR China.
| | - Yubin Huang
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
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Sia J, Szmyd R, Hau E, Gee HE. Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer. Front Cell Dev Biol 2020; 8:41. [PMID: 32117972 PMCID: PMC7031160 DOI: 10.3389/fcell.2020.00041] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 01/17/2020] [Indexed: 12/19/2022] Open
Abstract
Radiation therapy (RT) is responsible for at least 40% of cancer cures, however treatment resistance remains a clinical problem. There have been recent advances in understanding the molecular mechanisms of radiation-induced cell death. The type of cell death after radiation depends on a number of factors including cell type, radiation dose and quality, oxygen tension, TP53 status, DNA repair capacity, cell cycle phase at time of radiation exposure, and the microenvironment. Mitotic catastrophe (a pathway preceding cell death that happens in mitosis or as a consequence of aberrant mitotic progression) is the primary context of radiation-induced cell death in solid cancers, although in a small subset of cancers such as haematopoietic malignancies, radiation results in immediate interphase apoptosis, occurring within hours after exposure. There is intense therapeutic interest in using stereotactic ablative body radiotherapy (SABR), a precise, high-dose form of RT given in a small number of fractions, to prime the immune system for cancer cell killing, but the optimal radiation dose and fractionation remain unclear. Additionally, promising novel radiosensitisers targeting the cell cycle and DNA repair pathways are being trialled. In the context of the increasing use of SABR and such novel agents in the clinic, we provide an updated primer on the major types of radiation-induced cell death, focussing on their molecular mechanisms, factors affecting their initiation, and their implications on immunogenicity.
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Affiliation(s)
- Joseph Sia
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Radoslaw Szmyd
- Children's Medical Research Institute, Sydney, NSW, Australia.,Sydney West Radiation Oncology Network, Sydney, NSW, Australia
| | - Eric Hau
- Sydney West Radiation Oncology Network, Sydney, NSW, Australia.,The University of Sydney, Sydney, NSW, Australia
| | - Harriet E Gee
- Sydney West Radiation Oncology Network, Sydney, NSW, Australia.,The University of Sydney, Sydney, NSW, Australia
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38
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Peng Y, Fu S, Hu W, Qiu Y, Zhang L, Tan R, Sun LQ. Glutamine synthetase facilitates cancer cells to recover from irradiation-induced G2/M arrest. Cancer Biol Ther 2019; 21:43-51. [PMID: 31526079 PMCID: PMC7012188 DOI: 10.1080/15384047.2019.1665394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 08/13/2019] [Accepted: 09/01/2019] [Indexed: 01/08/2023] Open
Abstract
Resistance to radiation of cancer cells can be either intrinsic or acquired, leading to treatment failure. In response to DNA damage caused by IR, cancer cells are arrested in cell cycle showing limited proliferation and increased apoptosis. However, radiation-resistant cells are able to overcome the cell cycle block and proceed to proliferation, for which the detailed mechanism remains to be elucidated. In the present study, we showed that radioresistant cells exhibited a recoverable G2/M phase during prolonged cell cycle and manifested lower apoptosis rate and more colony formation. RNA-seq analysis revealed that glutamine synthetase (GS, GLUL) gene was highly expressed in radioresistant cancer cells in comparison with the parental cells, which was in accordance with the G2/M arrest after ionizing radiation. Knocking out of GS in radioresistant cells resulted in a delayed G2/M recovery and lowered proliferation rate after ionizing radiation treatment, which was accompanied with increased inhibitory phosphorylation of CDK1 at Y15 and downregulated Cdc25B, a dual specific phosphatase of CDK1. Moreover, there was an enhanced complex formation of CDK1 and Cyclin B1 when the cells were rescued by re-introducing GS. In vivo, knocking down of GS significantly sensitized CNE2-R xenografts to RT in mice. In this study, we demonstrate a novel role of glutamine synthetase independent of metabolic function in promoting recovery from G2/M arrest caused by ionizing radiation, thus, causing cancer cell resistance to radiotherapy.
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Affiliation(s)
- Yanni Peng
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Shujun Fu
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of MolecularRadiation Oncology Hunan Province, Changsha, China
| | - Wenfeng Hu
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of MolecularRadiation Oncology Hunan Province, Changsha, China
| | - Yanfang Qiu
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Lu Zhang
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of MolecularRadiation Oncology Hunan Province, Changsha, China
| | - Rong Tan
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of MolecularRadiation Oncology Hunan Province, Changsha, China
- Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, China
| | - Lun-Quan Sun
- Departmen of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of MolecularRadiation Oncology Hunan Province, Changsha, China
- Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, China
- National Clinical Research Center for Gerontology, Changsha, China
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Przystupski D, Górska A, Rozborska P, Bartosik W, Michel O, Rossowska J, Szewczyk A, Drąg-Zalesińska M, Kasperkiewicz P, Górski J, Kulbacka J. The Cytoprotective Role of Antioxidants in Mammalian Cells Under Rapidly Varying UV Conditions During Stratospheric Balloon Campaign. Front Pharmacol 2019; 10:851. [PMID: 31427965 PMCID: PMC6687761 DOI: 10.3389/fphar.2019.00851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
The current age of dynamic development of the space industry brings the mankind closer to routine manned space flights and space tourism. This progress leads to a demand for intensive astrobiological research aimed at improving strategies of the pharmacological protection of the human cells against extreme conditions. Although routine research in space remains out of our reach, it is worth noticing that the unique severe environment of the Earth's stratosphere has been found to mimic subcosmic conditions, giving rise to the opportunity to use the stratospheric surface as a research model for the astrobiological studies. Our study included launching into the stratosphere a balloon containing mammalian normal and cancer cells treated with various compounds to examine whether these substances are capable of protecting the cells against stress caused by rapidly varying temperature, pressure, and radiation, especially UV. Owing to oxidative stress caused by irradiation and temperature shock, we used natural compounds which display antioxidant properties, namely, catechin isolated from green tea, honokiol derived from magnolia, curcumin from turmeric, and cinnamon extract. "After-flight" laboratory tests have shown the most active antioxidants as potential agents which can minimize harmful impact of extreme conditions on human cells.
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Affiliation(s)
| | - Agata Górska
- Department of Biological Sciences, Institute of Experimental Biology, University of Wroclaw, Wroclaw, Poland
| | - Paulina Rozborska
- Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland
| | | | - Olga Michel
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Joanna Rossowska
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Szewczyk
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Wroclaw, Poland
- Department of Animal Developmental Biology, Institute of Experimental Biology, University of Wroclaw, Wroclaw, Poland
| | | | - Paulina Kasperkiewicz
- Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw, Poland
| | - Jędrzej Górski
- Faculty of Mechanical Engineering, Wroclaw University of Science and Technology, Wroclaw, Poland
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Wroclaw, Poland
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40
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Wéra AC, Lobbens A, Stoyanov M, Lucas S, Michiels C. Radiation-induced synthetic lethality: combination of poly(ADP-ribose) polymerase and RAD51 inhibitors to sensitize cells to proton irradiation. Cell Cycle 2019; 18:1770-1783. [PMID: 31238782 DOI: 10.1080/15384101.2019.1632640] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Although improvements in radiation therapy were made over the years, radioresistance is still a major challenge. Cancer cells are often deficient for DNA repair response, a feature that is currently exploited as a new anti-cancer strategy. In this context, combination of inhibitors targeting complementary pathways is of interest to sensitize cells to radiation. In this work, we used PARP (Olaparib) and RAD51 (B02) inhibitors to radiosensitize cancer cells to proton and X-ray radiation. More particularly, Olaparib and B02 were used at concentration leading to limited cytotoxic (alone or in combination) but increasing cell death when the cells were irradiated. We showed that, although at limited concentration, Olaparib and B02 were able to radiosensitize different cancer cell lines, i.e. lung and pancreatic cancer cells. Antagonistic, additive or synergistic effects were observed and correlated to cell proliferation rate. The inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. These results demonstrated that radiation-induced synthetic lethality might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.
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Buglewicz DJ, Banks AB, Hirakawa H, Fujimori A, Kato TA. Monoenergetic 290 MeV/n carbon-ion beam biological lethal dose distribution surrounding the Bragg peak. Sci Rep 2019; 9:6157. [PMID: 30992482 PMCID: PMC6467899 DOI: 10.1038/s41598-019-42600-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 03/06/2019] [Indexed: 01/30/2023] Open
Abstract
The sharp high dose Bragg peak of a carbon-ion beam helps it to deliver the highest dosage to the malignant cells while leaving the normal cells relatively unharmed. However, the precise range in which it distributes dosages that significantly induce cell death or genotoxicity surrounding its Bragg peak remains unclear. To evaluate biological effects of carbon-ion radiation through entrance to post Bragg peak in a single biological system, CHO and xrs5 cells were cultured in T-175 cell culture flasks and irradiated with 290 MeV/n monoenergetic carbon-ions with initial dosages upon entrance to the flask of 1, 2, or 3 Gy for cell survival assays or 1 Gy for cytokinesis block micronuclei assays. Under all initial dosages, the biological Bragg peak and the highest micronuclei formation was observed at the depth of 14.5 cm. Moreover, as the initial dosage increased the range displaying a significant decrease in survival fraction increased as well (P < 0.0001). Intriguingly from 1 Gy to 3 Gy, we observed a significant increase in reappearance of colony formation depth (P < 0.05), possibly indicating the nuclear fragmentation lethality potential of the carbon-ion. By means of our single system approach, we can achieve a more comprehensive understanding of biological effects surrounding of carbon-ions Bragg peak.
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Affiliation(s)
- Dylan J Buglewicz
- Department of Environmental & Radiological Health Sciences, Colorado State University, Colorado, 80523, USA
| | - Austin B Banks
- Department of Environmental & Radiological Health Sciences, Colorado State University, Colorado, 80523, USA
| | - Hirokazu Hirakawa
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, 263-8555, Japan
| | - Akira Fujimori
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, 263-8555, Japan
| | - Takamitsu A Kato
- Department of Environmental & Radiological Health Sciences, Colorado State University, Colorado, 80523, USA.
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Jiang X, Xu J, Gore JC. Quantitative temporal diffusion spectroscopy as an early imaging biomarker of radiation therapeutic response in gliomas: A preclinical proof of concept. Adv Radiat Oncol 2019; 4:367-376. [PMID: 31011683 PMCID: PMC6460331 DOI: 10.1016/j.adro.2018.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/07/2018] [Indexed: 12/17/2022] Open
Abstract
PURPOSE This study aims to test the ability of quantitative temporal diffusion spectroscopy (qTDS) to assess cellular changes associated with radiation-induced cell death in a rat glioma model. METHODS AND MATERIALS Tumor response to a single fraction of 20 Gy of x-ray radiation was investigated in a rat glioma (9L) model. Tumor response was monitored longitudinally at postinoculation days 21, 23, and 25, using a specific implementation of qTDS with acronym IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion), as well as conventional diffusion and high-resolution anatomic imaging. IMPULSED method combines diffusion-weighted signals acquired over a range of diffusion times that are then analyzed and interpreted using a theoretical model of water diffusion in tissues, which generates parametric maps depicting cellular and subcellular structural information on a voxel-wise basis. Results from different metrics were compared statistically. RESULTS A single dose of 20 Gy x-ray radiation significantly prolonged survival of 9L-bearing rats. The mean cell sizes of irradiated tumors decreased (P < .005) after radiation treatment, which we associate with cell shrinkage and the formation of small cellular bodies during apoptosis and necrosis. A combination of IMPULSED-derived parameters (mean cell size d and extracellular structural parameter β ex ) separated 90% of irradiated tumors from the nonirradiated cases at post inoculation day 23, whereas a combination of tumor growth and conventional apparent diffusion coefficient did not differentiate irradiated tumors from nonirradiated tumors. CONCLUSIONS This proof-of-concept study demonstrates the IMPULSED method to be a new method for deriving quantitative microstructural parameters in a preclinical tumor model. The method provides unique information based on the diffusion time dependency of diffusion magnetic resonance imaging, which cannot be obtained by conventional diffusion weighted imaging methods, and the results have a close correlation with primary biologic markers of treatment efficacy, such as cell death and survival.
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Affiliation(s)
- Xiaoyu Jiang
- Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee
- Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, Tennessee
| | - Junzhong Xu
- Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee
- Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
- Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - John C. Gore
- Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee
- Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
- Department of Physics and Astronomy, Vanderbilt University, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
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Rajani KR, Carlstrom LP, Parney IF, Johnson AJ, Warrington AE, Burns TC. Harnessing Radiation Biology to Augment Immunotherapy for Glioblastoma. Front Oncol 2019; 8:656. [PMID: 30854331 PMCID: PMC6395389 DOI: 10.3389/fonc.2018.00656] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 12/12/2018] [Indexed: 12/22/2022] Open
Abstract
Glioblastoma is the most common adult primary brain tumor and carries a dismal prognosis. Radiation is a standard first-line therapy, typically deployed following maximal safe surgical debulking, when possible, in combination with cytotoxic chemotherapy. For other systemic cancers, standard of care is being transformed by immunotherapies, including checkpoint-blocking antibodies targeting CTLA-4 and PD-1/PD-L1, with potential for long-term remission. Ongoing studies are evaluating the role of immunotherapies for GBM. Despite dramatic responses in some cases, randomized trials to date have not met primary outcomes. Challenges have been attributed in part to the immunologically "cold" nature of glioblastoma relative to other malignancies successfully treated with immunotherapy. Radiation may serve as a mechanism to improve tumor immunogenicity. In this review, we critically evaluate current evidence regarding radiation as a synergistic facilitator of immunotherapies through modulation of both the innate and adaptive immune milieu. Although current preclinical data encourage efforts to harness synergistic biology between radiation and immunotherapy, several practical and scientific challenges remain. Moreover, insights from radiation biology may unveil additional novel opportunities to help mobilize immunity against GBM.
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Affiliation(s)
- Karishma R. Rajani
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
| | - Lucas P. Carlstrom
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
| | - Ian F. Parney
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
| | - Aaron J. Johnson
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| | | | - Terry C. Burns
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
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Mechanistic Modelling of Radiation Responses. Cancers (Basel) 2019; 11:cancers11020205. [PMID: 30744204 PMCID: PMC6406300 DOI: 10.3390/cancers11020205] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/04/2019] [Accepted: 02/06/2019] [Indexed: 12/30/2022] Open
Abstract
Radiobiological modelling has been a key part of radiation biology and therapy for many decades, and many aspects of clinical practice are guided by tools such as the linear-quadratic model. However, most of the models in regular clinical use are abstract and empirical, and do not provide significant scope for mechanistic interpretation or making predictions in novel cell lines or therapies. In this review, we will discuss the key areas of ongoing mechanistic research in radiation biology, including physical, chemical, and biological steps, and review a range of mechanistic modelling approaches which are being applied in each area, highlighting the possible opportunities and challenges presented by these techniques.
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Emerging Functional Imaging Biomarkers of Tumour Responses to Radiotherapy. Cancers (Basel) 2019; 11:cancers11020131. [PMID: 30678055 PMCID: PMC6407112 DOI: 10.3390/cancers11020131] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/11/2019] [Accepted: 01/13/2019] [Indexed: 12/11/2022] Open
Abstract
Tumour responses to radiotherapy are currently primarily assessed by changes in size. Imaging permits non-invasive, whole-body assessment of tumour burden and guides treatment options for most tumours. However, in most tumours, changes in size are slow to manifest and can sometimes be difficult to interpret or misleading, potentially leading to prolonged durations of ineffective treatment and delays in changing therapy. Functional imaging techniques that monitor biological processes have the potential to detect tumour responses to treatment earlier and refine treatment options based on tumour biology rather than solely on size and staging. By considering the biological effects of radiotherapy, this review focusses on emerging functional imaging techniques with the potential to augment morphological imaging and serve as biomarkers of early response to radiotherapy.
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Abstract
Combining metallo-drugs with ionising radiation for synergistic cancer cell killing: chemical design principles, mechanisms of action and emerging applications.
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Affiliation(s)
- Martin R. Gill
- CRUK/MRC Oxford Institute for Radiation Oncology
- Department of Oncology
- University of Oxford
- Oxford
- UK
| | - Katherine A. Vallis
- CRUK/MRC Oxford Institute for Radiation Oncology
- Department of Oncology
- University of Oxford
- Oxford
- UK
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47
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de Andrade Carvalho H, Villar RC. Radiotherapy and immune response: the systemic effects of a local treatment. Clinics (Sao Paulo) 2018; 73:e557s. [PMID: 30540123 PMCID: PMC6257057 DOI: 10.6061/clinics/2018/e557s] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 10/23/2018] [Indexed: 12/14/2022] Open
Abstract
Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects by triggering many molecular signaling pathways. There is still a lack of knowledge of this issue. This review focuses on the current literature about the effects of ionizing radiation on the immune system, either suppressing or stimulating the host reactions against the tumor, and the factors that interact with these responses, such as the radiation dose and dose / fraction effects in the tumor microenvironment and vasculature. In addition, some implications of these effects in cancer treatment, mainly in combined strategies, are addressed from the perspective of their interactions with the more advanced technology currently available, such as heavy ion therapy and nanotechnology.
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Affiliation(s)
- Heloisa de Andrade Carvalho
- Departamento de Radiologia e Oncologia, Divisao de Radioterapia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Servico de Radioterapia, Centro de Oncologia, Hospital Sirio-Libanes, Sao Paulo, SP, BR
| | - Rosangela Correa Villar
- Departamento de Radiologia e Oncologia, Divisao de Radioterapia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Servico de Radioterapia, Centro Infantil Boldrini, Campinas, SP, BR
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Das S, Neal CJ, Ortiz J, Seal S. Engineered nanoceria cytoprotection in vivo: mitigation of reactive oxygen species and double-stranded DNA breakage due to radiation exposure. NANOSCALE 2018; 10:21069-21075. [PMID: 30226515 DOI: 10.1039/c8nr04640a] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Cerium oxide nanomaterials are known to absorb ionizing radiation energy, as well as to neutralize free radicals in solution, by undergoing redox changes. We, therefore, proposed that ceria nanoparticles could be used in biomedical applications as an injectable, radio-protectant material. In this study, we examine the effectiveness of engineered nanoparticles in protecting germ cells from the damaging effects of irradiation-induced cell death, in vivo. C57BL/6J male mice were used as a model and irradiation was localized to the scrotal region at 2.5, 5, and/or 10 Gy intensities. Ceria nanoparticles were introduced as 100 μL injections at 100 nM and 100 μM via tail vein injections, weekly, for one month. Following this, the animals were sacrificed and their organs (heart, brain, kidneys) were harvested. Tissues were fixed, sectioned, and stained for instances of cell death, DNA damage (TUNEL assay), and ROS (nitro-tyrosine evolution). Tissues from mice treated with ceria nanoparticles showed significantly less (∼13% decrease; *P < 0.05) tissue damage (per immunohistochemistry) over controls at up to 5 Gy radiation. DNA damage and ROS also decrease substantially with ceria treatment, confirming ceria's capacity as an injectable, radio-protectant material. The study also highlights the ability of ceria nanoparticles to protect cells/tissues from both direct and indirect effects of ionizing radiation.
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Affiliation(s)
- Soumen Das
- Materials Science and Engineering, Advanced Materials Processing Center, University of Central Florida, Orlando, FL 32816, USA.
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49
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Bioluminescence Tomography Guided Small-Animal Radiation Therapy and Tumor Response Assessment. Int J Radiat Oncol Biol Phys 2018. [DOI: 10.1016/j.ijrobp.2018.01.068] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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50
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Mirrahimi M, Hosseini V, Shakeri-Zadeh A, Alamzadeh Z, Kamrava SK, Attaran N, Abed Z, Ghaznavi H, Hosseini Nami SMA. Modulation of cancer cells’ radiation response in the presence of folate conjugated Au@Fe2O3 nanocomplex as a targeted radiosensitizer. Clin Transl Oncol 2018; 21:479-488. [DOI: 10.1007/s12094-018-1947-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/06/2018] [Indexed: 12/19/2022]
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