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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 January 2023) | Viewed by 16894

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Prof. Dr. Yi-Jang Lee

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Guest Editor

Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
Interests: radiation biology; molecular radiation oncology; molecular cell biology; molecular imaging; cancer biology

Dr. Yu-Chan Chang

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Guest Editor

Department of Biomedicine Imaging and Radiological Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
Interests: cancer metabolism; radiobiology; biomolecular imaging
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Dear Colleagues,

Radiotherapy is an indispensable approach for cancer treatment. Approximately 50% of cancer patients receive radiation therapy with or without other concurrent treatments. The pitfalls and complications of radiotherapy are conspicuous, but these problems do not remove the necessity of this approach. Although medical physicists and physicians have attempted to develop different regimes and modalities to increase the therapeutic index, the basic molecular biological issues leading to unwanted effects after radiotherapy remain complex and need to be solved. Even when radiation induces apoptosis, necrosis, autophagy, and senescence in cancer cells, these events may promote regrowth or the distant migration of unirradiated malignancy. These may explain the recurrence and radioresistance of cancers after radiotherapy, but the underlying mechanisms still need to be clarified. In this Special Issue, we encourage the submission of studies involving photon therapy, particulate therapy, and FLASH radiotherapy and the molecular mechanisms induced that may be able to account for cancer relapse after treatment at the bench side and/or bedside. We also aim to provide information on the specific compounds or inhibitors that could target these molecular events to reduce radiation-induced complications and bystander effects and elevate the efficacy of radiotherapy.

Prof. Dr. Yi-Jang Lee
Dr. Yu-Chan Chang
Guest Editors

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Keywords

radiotherapy
recurrence
molecular biological mechanisms
radioresistance
bystander effects
cancer cell
apoptosis
necrosis
autophagy
senescence
radioresistance
compound
inhibitor

Published Papers (7 papers)

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Research

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12 pages, 1671 KiB

Open AccessArticle

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients

by Chih-Chia Yu, Hon-Yi Lin, Chen-Hsi Hsieh, Michael W. Y. Chan, Wen-Yen Chiou, Moon-Sing Lee, Chen-Lin Chi, Ru-Inn Lin, Feng-Chun Hsu, Liang-Cheng Chen, Chia-Hui Chew, Hsuan-Ju Yang and Shih-Kai Hung

Int. J. Mol. Sci. 2023, 24(8), 6903; https://doi.org/10.3390/ijms24086903 - 07 Apr 2023

Cited by 2 | Viewed by 1363

Abstract

Gene Ontology (GO) analysis can provide a comprehensive function analysis for investigating genes, allowing us to identify the potential biological roles of genes. The present study conducted GO analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in disease progression and mediating tumor response to RT. Methods: We performed a GO enrichment analysis on the RNA-seq data to validate radiation-induced gene expression. A total of 172 I-IVB specimens from oral squamous cell carcinoma patients were collected for clinical analysis, from which IRAK2 expression was analyzed by immunohistochemistry. This was a retrospective study conducted between IRAK2 expression and the outcomes of oral squamous cell carcinoma patients after radiotherapy treatment. We conducted Gene Ontology (GO) analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in mediating tumor response to radiotherapy. GO enrichment analysis to validate radiation-induced gene expression was performed. Clinically, 172 stage I-IVB resected oral cancer patients were used to validate IRAK2 expression in predicting clinical outcomes. GO enrichment analysis showed that IRAK2 is involved in 10 of the 14 most enriched GO categories for post-irradiation biological processes, focusing on stress response and immune modulation. Clinically, high IRAK2 expression was correlated with adverse disease features, including pT3-4 status (p = 0.01), advanced overall stage (p = 0.02), and positive bone invasion (p = 0.01). In patients who underwent radiotherapy, the IRAK2-high group was associated with reduced post-irradiation local recurrence (p = 0.025) compared to the IRAK2-low group. IRAK2 plays a crucial role in the radiation-induced response. Patients with high IRAK2 expression demonstrated more advanced disease features but predicted higher post-irradiation local control in a clinical setting. These findings support IRAK2 as a potential predictive biomarker for radiotherapy response in non-metastatic and resected oral cancer patients. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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14 pages, 2166 KiB

Open AccessArticle

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

by Yu-Chuen Huang, Pei-Ying Hsieh, Li-Ying Wang, Tung-Hu Tsai, Yu-Jen Chen and Chen-Hsi Hsieh

Int. J. Mol. Sci. 2023, 24(6), 5849; https://doi.org/10.3390/ijms24065849 - 19 Mar 2023

Viewed by 1387

Abstract

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH₂PO₄)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUC_cabozantinib) between the control group and the RT_{2Gy×3 f’x} and RT_{9Gy×3 f’x} groups in the concurrent and the sequential regimens. However, compared to those in the control group, the T_max, T_1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT_{2Gy×3 f’x} in the concurrent regimen, respectively. Additionally, the T_1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT_{9Gy×3 f’x} group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT_{2Gy×3 f’x} in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT_{9Gy×3 f’x} sequential regimen. Compared to the RT_{9Gy×3 f’x} concurrent regimen, the RT_{9Gy×3 f’x} sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT_{9Gy×3 f’x} is more significant with the sequential regimen than with the concurrent regimen. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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11 pages, 1270 KiB

Open AccessArticle

Advances in Boron Neutron Capture Therapy (BNCT) for Recurrent Intracranial Meningioma

by Tien-Li Lan, Chun-Fu Lin, Yi-Yen Lee, Ko-Han Lin, Feng-Chi Chang, Shih-Chieh Lin, Jia-Cheng Lee, Fong-In Chou, Jinn-Jer Peir, Hong-Ming Liu, Pei-Fan Mu and Yi-Wei Chen

Int. J. Mol. Sci. 2023, 24(5), 4978; https://doi.org/10.3390/ijms24054978 - 04 Mar 2023

Cited by 3 | Viewed by 2256

Abstract

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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20 pages, 3899 KiB

Open AccessArticle

Application of Gold Nanoparticles as Radiosensitizer for Metastatic Prostate Cancer Cell Lines

by Sílvia Soares, Isabel Faria, Fátima Aires, Armanda Monteiro, Gabriela Pinto, Maria Goreti Sales, Miguel A. Correa-Duarte, Susana G. Guerreiro and Rúben Fernandes

Int. J. Mol. Sci. 2023, 24(4), 4122; https://doi.org/10.3390/ijms24044122 - 18 Feb 2023

Cited by 6 | Viewed by 2417

Abstract

More than 50% of all prostate cancer (PCa) patients are treated by radiotherapy (RT). Radioresistance and cancer recurrence are two consequences of the therapy and are related to dose heterogeneity and non-selectivity between normal and tumoral cells. Gold nanoparticles (AuNPs) could be used as potential radiosensitizers to overcome these therapeutic limitations of RT. This study assessed the biological interaction of different morphologies of AuNPs with ionizing radiation (IR) in PCa cells. To achieve that aim, three different amine-pegylated AuNPs were synthesized with distinct sizes and shapes (spherical, AuNP_sp-PEG, star, AuNP_st-PEG, and rods, AuNP_r-PEG) and viability, injury and colony assays were used to analyze their biological effect on PCa cells (PC3, DU145, and LNCaP) when submitted to the accumulative fraction of RT. The combinatory effect of AuNPs with IR decreased cell viability and increased apoptosis compared to cells treated only with IR or untreated cells. Additionally, our results showed an increase in the sensitization enhancement ratio by cells treated with AuNPs and IR, and this effect is cell line dependent. Our findings support that the design of AuNPs modulated their cellular behavior and suggested that AuNPs could improve the RT efficacy in PCa cells. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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23 pages, 7943 KiB

Open AccessArticle

High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer’s Disease Mutations

by Robert G. Hinshaw, Maren K. Schroeder, Jason Ciola, Curran Varma, Brianna Colletti, Bin Liu, Grace Geyu Liu, Qiaoqiao Shi, Jacqueline P. Williams, M. Kerry O’Banion, Barbara J. Caldarone and Cynthia A. Lemere

Int. J. Mol. Sci. 2023, 24(4), 3615; https://doi.org/10.3390/ijms24043615 - 10 Feb 2023

Cited by 2 | Viewed by 1654

Abstract

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer’s-like and wildtype littermate mice 7–8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer’s model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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25 pages, 2761 KiB

Open AccessArticle

Quantitative Correlations between Radiosensitivity Biomarkers Show That the ATM Protein Kinase Is Strongly Involved in the Radiotoxicities Observed after Radiotherapy

by Eymeric Le Reun, Larry Bodgi, Adeline Granzotto, Laurène Sonzogni, Mélanie L. Ferlazzo, Joëlle Al-Choboq, Laura El-Nachef, Juliette Restier-Verlet, Elise Berthel, Clément Devic, Audrey Bouchet, Michel Bourguignon and Nicolas Foray

Int. J. Mol. Sci. 2022, 23(18), 10434; https://doi.org/10.3390/ijms231810434 - 09 Sep 2022

Cited by 11 | Viewed by 1515

Abstract

Tissue overreactions (OR), whether called adverse effects, radiotoxicity, or radiosensitivity reactions, may occur during or after anti-cancer radiotherapy (RT). They represent a medical, economic, and societal issue and raise the question of individual response to radiation. To predict and prevent them are among the major tasks of radiobiologists. To this aim, radiobiologists have developed a number of predictive assays involving different cellular models and endpoints. To date, while no consensus has been reached to consider one assay as the best predictor of the OR occurrence and severity, radiation oncologists have proposed consensual scales to quantify OR in six different grades of severity, whatever the organ/tissue concerned and their early/late features. This is notably the case with the Common Terminology Criteria for Adverse Events (CTCAE). Few radiobiological studies have used the CTCAE scale as a clinical endpoint to evaluate the statistical robustness of the molecular and cellular predictive assays in the largest range of human radiosensitivity. Here, by using 200 untransformed skin fibroblast cell lines derived from RT-treated cancer patients eliciting OR in the six CTCAE grades range, correlations between CTCAE grades and the major molecular and cellular endpoints proposed to predict OR (namely, cell survival at 2 Gy (SF2), yields of micronuclei, recognized and unrepaired DSBs assessed by immunofluorescence with γH2AX and pATM markers) were examined. To our knowledge, this was the first time that the major radiosensitivity endpoints were compared together with the same cohort and irradiation conditions. Both SF2 and the maximal number of pATM foci reached after 2 Gy appear to be the best predictors of the OR, whatever the CTCAE grades range. All these major radiosensitivity endpoints are mathematically linked in a single mechanistic model of individual response to radiation in which the ATM kinase plays a major role. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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Review

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23 pages, 1538 KiB

Open AccessReview

Natural Radiosensitizers in Radiotherapy: Cancer Treatment by Combining Ionizing Radiation with Resveratrol

by Dominika Komorowska, Tomasz Radzik, Sebastian Kalenik and Aleksandra Rodacka

Int. J. Mol. Sci. 2022, 23(18), 10627; https://doi.org/10.3390/ijms231810627 - 13 Sep 2022

Cited by 13 | Viewed by 5471

Abstract

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies. Full article

(This article belongs to the Special Issue Recent Advances in Radiotherapy)

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