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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 30585

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Dr. Takamitsu Kato

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Guest Editor

Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA
Interests: DNA damage; flavonoids; DNA repair; cytogenetics; radiobiology
Special Issues, Collections and Topics in MDPI journals

Dr. Hiroto Yoshikawa

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Guest Editor

Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
Interests: radiation biology; radiation physics; cancer biology

Special Issue Information

Dear Colleagues,

A major goal of radiotherapy is to control tumor mass with minimal effects on the surrounding normal tissues. To achieve this, basic radiation responses in normal and cancer cells need to be understood. In cell molecular biology, this includes DNA damage and repair, cell cycle effects, cell death, and genomic instability, including somatic mutations and epigenetic modifications. Cellular radiation responses are altered by oxygen concentrations, temperature, and other microenvironmental factors, as well as small molecules classified as radio-sensitizers and radio-protectors. Radiotherapy can be combined with other cancer treatment modalities such as chemotherapy and immunotherapy.
This Special Issue is focused on radiobiology research that can be translational to clinical radiotherapy. It includes topics from basic cell and molecular responses to radiation to clinical trials. This Special Issue will help basic radiation and cancer biology researchers as well as clinical radiation oncologists to update their knowledge for better radiotherapy.

Dr. Takamitsu Kato
Dr. Hiroto Yoshikawa
Guest Editors

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Keywords

ionizing radiation
DNA damage
DNA repair
chromosome aberrations
cell death
mutations
epigenetics
hypoxia
radiosensitizer
radioprotector
immunotherapy
tumor microenvironment
radiotherapy

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Published Papers (10 papers)

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Editorial

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4 pages, 183 KiB

Open AccessEditorial

From Basic Radiobiology to Translational Radiotherapy

by Piyawan Chailapakul and Takamitsu A. Kato

Int. J. Mol. Sci. 2022, 23(24), 15902; https://doi.org/10.3390/ijms232415902 - 14 Dec 2022

Cited by 2 | Viewed by 1434

Abstract

The Special Issue, entitled “From basic radiobiology to translational radiotherapy”, highlights recent advances in basic radiobiology and the potential to improve radiotherapy in translational research [...] Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

Research

Jump to: Editorial, Review

15 pages, 3416 KiB

Open AccessArticle

Social Hierarchy Dictates Intestinal Radiation Injury in a Gut Microbiota-Dependent Manner

by Xiaozhou Zeng, Zhihong Liu, Yanxi Dong, Jiamin Zhao, Bin Wang, Huiwen Xiao, Yuan Li, Zhiyuan Chen, Xiaojing Liu, Jia Liu, Jiali Dong, Saijun Fan and Ming Cui

Int. J. Mol. Sci. 2022, 23(21), 13189; https://doi.org/10.3390/ijms232113189 - 29 Oct 2022

Cited by 7 | Viewed by 2154

Abstract

Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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16 pages, 2817 KiB

Open AccessArticle

GDF15 Contributes to Radioresistance by Mediating the EMT and Stemness of Breast Cancer Cells

by Xinrui Zhao, Xinglong Liu, Songling Hu, Yan Pan, Jianghong Zhang, Guomei Tai and Chunlin Shao

Int. J. Mol. Sci. 2022, 23(18), 10911; https://doi.org/10.3390/ijms231810911 - 18 Sep 2022

Cited by 13 | Viewed by 3036

Abstract

Radiotherapy is one of the conventional methods for the clinical treatment of breast cancer. However, radioresistance has an adverse effect on the prognosis of breast cancer patients after radiotherapy. In this study, using bioinformatic analysis of GSE59732 and GSE59733 datasets in the Gene Expression Omnibus (GEO) database together with the prognosis database of breast cancer patients after radiotherapy, the GDF15 gene was screened out to be related to the poor prognosis of breast cancer after radiotherapy. Compared with radiosensitive parental breast cancer cells, breast cancer cells with acquired radioresistance exhibited a high level of GDF15 expression and enhanced epithelial-to-mesenchymal transition (EMT) properties of migration and invasion, as well as obvious stem-like traits, including the increases of mammosphere formation ability, the proportion of stem cells (CD44⁺ CD24⁻ cells), and the expressions of stem cell-related markers (SOX2, NANOG). Moreover, knockdown of GDF15 sensitized the radioresistance cells to irradiation and significantly inhibited their EMT and stem-like traits, indicating that GDF15 promoted the radioresistance of breast cancer by enhancing the properties of EMT and stemness. Conclusively, GDF15 may be applicable as a novel prognosis-related biomarker and a potential therapeutic target for breast cancer radiotherapy. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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16 pages, 5736 KiB

Open AccessArticle

Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

by Fahimeh Faqihi, Marcus A. Stoodley and Lucinda S. McRobb

Int. J. Mol. Sci. 2022, 23(16), 8908; https://doi.org/10.3390/ijms23168908 - 10 Aug 2022

Cited by 1 | Viewed by 1854

Abstract

Endothelial cells are highly sensitive to ionizing radiation, and exposure leads to multiple adaptive changes. Remarkably, part of this response is the translocation of normally intracellular proteins to the cell surface. It is unclear whether this ectopic expression has a protective or deleterious function, but, regardless, these surface-exposed proteins may provide unique discriminatory targets for radiation-guided drug delivery to vascular malformations or tumor vasculature. We investigated the ability of an antibody–thrombin conjugate targeting mitochondrial PDCE2 (E2 subunit of pyruvate dehydrogenase) to induce precision thrombosis on irradiated endothelial cells in a parallel-plate flow system. Click-chemistry was used to create antibody–thrombin conjugates targeting PDCE2 as the vascular targeting agent (VTA). VTAs were injected into the parallel-plate flow system with whole human blood circulating over irradiated cells. The efficacy and specificity of fibrin-thrombus formation was assessed relative to non-irradiated controls. The PDCE2-targeting VTA dose-dependently increased thrombus formation: minimal thrombosis was induced in response to 5 Gy radiation; doses of 15 and 25 Gy induced significant thrombosis with equivalent efficacy. Negligible VTA binding or thrombosis was demonstrated in the absence of radiation or with non-targeted thrombin. PDCE2 represents a unique discriminatory target for radiation-guided drug delivery and precision thrombosis in pathological vasculature. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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11 pages, 3254 KiB

Open AccessArticle

Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol

by Felix Jaekel, Elke Bräuer-Krisch, Stefan Bartzsch, Jean Laissue, Hans Blattmann, Marten Scholz, Julia Soloviova, Guido Hildebrandt and Elisabeth Schültke

Int. J. Mol. Sci. 2022, 23(15), 8319; https://doi.org/10.3390/ijms23158319 - 28 Jul 2022

Cited by 4 | Viewed by 1803

Abstract

Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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22 pages, 4161 KiB

Open AccessArticle

Micro-RNA and Proteomic Profiles of Plasma-Derived Exosomes from Irradiated Mice Reveal Molecular Changes Preventing Apoptosis in Neonatal Cerebellum

by Simonetta Pazzaglia, Barbara Tanno, Ilaria De Stefano, Paola Giardullo, Simona Leonardi, Caterina Merla, Gabriele Babini, Seda Tuncay Cagatay, Ammar Mayah, Munira Kadhim, Fiona M. Lyng, Christine von Toerne, Zohaib N. Khan, Prabal Subedi, Soile Tapio, Anna Saran and Mariateresa Mancuso

Int. J. Mol. Sci. 2022, 23(4), 2169; https://doi.org/10.3390/ijms23042169 - 16 Feb 2022

Cited by 13 | Viewed by 3158

Abstract

Cell communication via exosomes is capable of influencing cell fate in stress situations such as exposure to ionizing radiation. In vitro and in vivo studies have shown that exosomes might play a role in out-of-target radiation effects by carrying molecular signaling mediators of radiation damage, as well as opposite protective functions resulting in resistance to radiotherapy. However, a global understanding of exosomes and their radiation-induced regulation, especially within the context of an intact mammalian organism, has been lacking. In this in vivo study, we demonstrate that, compared to sham-irradiated (SI) mice, a distinct pattern of proteins and miRNAs is found packaged into circulating plasma exosomes after whole-body and partial-body irradiation (WBI and PBI) with 2 Gy X-rays. A high number of deregulated proteins (59% of WBI and 67% of PBI) was found in the exosomes of irradiated mice. In total, 57 and 13 miRNAs were deregulated in WBI and PBI groups, respectively, suggesting that the miRNA cargo is influenced by the tissue volume exposed to radiation. In addition, five miRNAs (miR-99b-3p, miR-200a-3p, miR-200a, miR-182-5p, miR-182) were commonly overexpressed in the exosomes from the WBI and PBI groups. In this study, particular emphasis was also given to the determination of the in vivo effect of exosome transfer by intracranial injection in the highly radiosensitive neonatal cerebellum at postnatal day 3. In accordance with a major overall anti-apoptotic function of the commonly deregulated miRNAs, here, we report that exosomes from the plasma of irradiated mice, especially in the case of WBI, prevent radiation-induced apoptosis, thus holding promise for exosome-based future therapeutic applications against radiation injury. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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Review

Jump to: Editorial, Research

23 pages, 909 KiB

Open AccessReview

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

by Fabio Busato, Badr El Khouzai and Maddalena Mognato

Int. J. Mol. Sci. 2022, 23(18), 10211; https://doi.org/10.3390/ijms231810211 - 6 Sep 2022

Cited by 23 | Viewed by 5393

Abstract

Cancer treatment with ionizing radiation (IR) is a well-established and effective clinical method to fight different types of tumors and is a palliative treatment to cure metastatic stages. Approximately half of all cancer patients undergo radiotherapy (RT) according to clinical protocols that employ two types of ionizing radiation: sparsely IR (i.e., X-rays) and densely IR (i.e., protons). Most cancer cells irradiated with therapeutic doses exhibit radio-induced cytotoxicity in terms of cell proliferation arrest and cell death by apoptosis. Nevertheless, despite the more tailored advances in RT protocols in the last few years, several tumors show a relatively high percentage of RT failure and tumor relapse due to their radioresistance. To counteract this extremely complex phenomenon and improve clinical protocols, several factors associated with radioresistance, of both a molecular and cellular nature, must be considered. Tumor genetics/epigenetics, tumor microenvironment, tumor metabolism, and the presence of non-malignant cells (i.e., fibroblast-associated cancer cells, macrophage-associated cancer cells, tumor-infiltrating lymphocytes, endothelial cells, cancer stem cells) are the main factors important in determining the tumor response to IR. Here, we attempt to provide an overview of how such factors can be taken advantage of in clinical strategies targeting radioresistant tumors. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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14 pages, 811 KiB

Open AccessReview

Identification of Novel Regulators of Radiosensitivity Using High-Throughput Genetic Screening

by Rosette N. Tamaddondoust, Alicia Wong, Megha Chandrashekhar, Edouard I. Azzam, Tommy Alain and Yi Wang

Int. J. Mol. Sci. 2022, 23(15), 8774; https://doi.org/10.3390/ijms23158774 - 7 Aug 2022

Cited by 5 | Viewed by 2966

Abstract

The biological impact of ionizing radiation (IR) on humans depends not only on the physical properties and absorbed dose of radiation but also on the unique susceptibility of the exposed individual. A critical target of IR is DNA, and the DNA damage response is a safeguard mechanism for maintaining genomic integrity in response to the induced cellular stress. Unrepaired DNA lesions lead to various mutations, contributing to adverse health effects. Cellular sensitivity to IR is highly correlated with the ability of cells to repair DNA lesions, in particular coding sequences of genes that affect that process and of others that contribute to preserving genomic integrity. However, accurate profiling of the molecular events underlying individual sensitivity requires techniques with sensitive readouts. Here we summarize recent studies that have used whole-genome analysis and identified genes that impact individual radiosensitivity. Whereas microarray and RNA-seq provide a snapshot of the transcriptome, RNA interference (RNAi) and CRISPR-Cas9 techniques are powerful tools that enable modulation of gene expression and characterizing the function of specific genes involved in radiosensitivity or radioresistance. Notably, CRISPR-Cas9 has altered the landscape of genome-editing technology with its increased readiness, precision, and sensitivity. Identifying critical regulators of cellular radiosensitivity would help tailor regimens that enhance the efficacy of therapeutic treatments and fast-track prediction of clinical outcomes. It would also contribute to occupational protection based on average individual sensitivity, as well as the formulation of countermeasures to the harmful effects of radiation. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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30 pages, 1332 KiB

Open AccessReview

Microglia as Therapeutic Target for Radiation-Induced Brain Injury

by Qun Liu, Yan Huang, Mengyun Duan, Qun Yang, Boxu Ren and Fengru Tang

Int. J. Mol. Sci. 2022, 23(15), 8286; https://doi.org/10.3390/ijms23158286 - 27 Jul 2022

Cited by 21 | Viewed by 4318

Abstract

Radiation-induced brain injury (RIBI) after radiotherapy has become an increasingly important factor affecting the prognosis of patients with head and neck tumor. With the delivery of high doses of radiation to brain tissue, microglia rapidly transit to a pro-inflammatory phenotype, upregulate phagocytic machinery, and reduce the release of neurotrophic factors. Persistently activated microglia mediate the progression of chronic neuroinflammation, which may inhibit brain neurogenesis leading to the occurrence of neurocognitive disorders at the advanced stage of RIBI. Fully understanding the microglial pathophysiology and cellular and molecular mechanisms after irradiation may facilitate the development of novel therapy by targeting microglia to prevent RIBI and subsequent neurological and neuropsychiatric disorders. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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14 pages, 300 KiB

Open AccessReview

Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer

by Siqi Liang, Guangming Zhou and Wentao Hu

Int. J. Mol. Sci. 2022, 23(4), 2316; https://doi.org/10.3390/ijms23042316 - 19 Feb 2022

Cited by 11 | Viewed by 3168

Abstract

Non-small-cell lung cancer (NSCLC) has a high incidence and poses a serious threat to human health. However, the treatment outcomes of concurrent chemoradiotherapy for non-small-cell lung cancer are still unsatisfactory, especially for high grade lesions. As a new cancer treatment, heavy ion radiotherapy has shown promising efficacy and safety in the treatment of non-small-cell lung cancer. This article discusses the clinical progress of heavy ion radiotherapy in the treatment of non-small-cell lung cancer mainly from the different cancer stages, the different doses of heavy ion beams, and the patient’s individual factors, and explores the deficiency of heavy ion radiotherapy in the treatment of non-small-cell lung cancer and the directions of future research, in order to provide reference for the wider and better application of heavy ion radiotherapy in the future. Full article

(This article belongs to the Special Issue From Basic Radiobiology to Translational Radiotherapy)

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