Search Results (67)

Radiotherapy (RT) remains a cornerstone of cancer treatment, offering spatially precise cytotoxicity against malignant cells. However, emerging evidence reveals that ionizing radiation (IR) exerts biological effects beyond the targeted tumor volume, manifesting as radiation bystander effects (BEs) and other non-targeted effects (NTEs). These phenomena challenge the traditional paradigm of RT as a localized intervention, highlighting systemic and long-term consequences in non-irradiated tissues. This comprehensive review synthesizes molecular, cellular, and clinical insights about BEs, elucidating the complex intercellular signaling networks gap junctions, cytokines, extracellular vesicles, and oxidative stress that propagate damage, genomic instability, and inflammation. We explore the role of mitochondrial dysfunction, epigenetic reprogramming, immune modulation, and stem cell niche disruption in shaping BEs outcomes. Clinically, BEs contribute to neurocognitive decline, cardiovascular disease, pulmonary fibrosis, gastrointestinal toxicity, and secondary malignancies, particularly in pediatric and long-term cancer survivors. The review also evaluates countermeasures including antioxidants, COX-2 inhibitors, exosome blockers, and FLASH RT, alongside emerging strategies targeting cfCh, inflammasomes, and senescence-associated secretory phenotypes. We discuss the dual nature of BEs: their potential to both harm and heal, underscoring adaptive responses and immune priming in specific contexts. By integrating mechanistic depth with translational relevance, this work posits that radiation BEs are a modifiable axis of RT biology. Recognizing and mitigating BEs is imperative for optimizing therapeutic efficacy, minimizing collateral damage, and enhancing survivorship outcomes. This review advocates for a paradigm shift in RT planning and post-treatment care, emphasizing precision, personalization, and systemic awareness in modern oncology. Full article

Regulating tumor invasion and metastasis is pivotal for improving cancer patient prognosis. While cell migration is a key factor in these processes, the non-targeted effects of chemoradiotherapy on cell motility remain poorly understood. In this study, we employed HeLa-FUCCI cells—a cervical cancer-derived HeLa cell line integrated with the Fluorescent Ubiquitination-Based Cell Cycle Indicator (FUCCI) probe, enabling the visualization of cell cycle phases—to investigate the radiation-induced impacts, including non-targeted effects, on cell migration. To create irradiated (In-field) and non-irradiated (out-of-field) regions, half of the culture dish was shielded with a lead block during irradiation. Cells were then exposed to 2 Gy X-rays, with or without cisplatin. Following irradiation, the cells were subjected to time-lapse imaging at 15 min intervals for 24 h, and the acquired data were analyzed using cell segmentation and tracking algorithms, Cellpose 2.0 and TrackMate 7. Without cisplatin, the migration velocity and total distance traveled of Out-of-field cells were significantly reduced compared to controls, suggesting a suppressive bystander signal. In contrast, with cisplatin treatment, these parameters significantly increased in both In-field and Out-of-field cells. This suggests that chemoradiotherapy may inadvertently enhance tumor cell motility outside the target volume, a critical finding with significant implications for therapeutic outcomes. Full article

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312–CPS1–ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312–CPS1 axis to improve radiotherapy efficacy in NSCLC. Full article

Spatially fractionated radiotherapy (SFRT) offers a promising approach for debulking large tumors by delivering high-dose radiation to a fraction of the tumor volume. However, the complex tumor microenvironment necessitates models beyond traditional 2D cultures and resource-intensive animal studies for SFRT investigations. Three-dimensional (3D) scaffold-based models with an adequate cross-sectional area have emerged as uniquely suited platforms to bridge this gap, by providing a more realistic platform for GRID-based SFRT research. In this study, we employed a 3D co-culture scaffold model to dissect the contributions of the radiation-induced bystander effect, abscopal effect, and immune system response on clonogenic survival following GRID irradiation. MDA-MB-231 breast cancer cells were seeded on commercial 3D scaffolds and irradiated at a 20 Gy peak dose using lead grids with three- and six-hole patterns, exposing ~12.8% and 25.7% of the scaffold area, respectively. An assessment of reproductive cell survival revealed a significant bystander effect, as the survival was notably lower than predicted based solely on the directly irradiated fraction. Evidence of an abscopal effect was observed by culturing non-irradiated cells in media exposed to GRID irradiation. Furthermore, a co-culture with allogeneic peripheral blood mononuclear cells (PBMCs) modulated clonogenic survival, with an additive effect observed when combined with SFRT. These findings underscore the presence of a bystander effect in GRID radiotherapy and indicate an abscopal immune component, particularly with the three-hole GRID configuration. This study established the utility of in vitro 3D co-culture scaffolds as an effective model system for elucidating complex SFRT-mediated biological responses. Full article

Radiation therapy is a medical treatment that uses high doses of radiation to kill or damage cancer cells. It works by damaging the DNA within the cancer cells, ultimately causing cell death. Radiotherapy can be used as a primary treatment, adjuvant treatment in combination with surgery or chemotherapy or palliative treatment to relieve symptoms in advanced cancer stages. Radiation therapy is constantly improving in order to enhance the effect on cancer cells and reduce the side effects on healthy tissues. Our results clearly demonstrate that proton therapy and, even more, carbon ion therapy appear as promising alternatives to overcome the radioresistance of various tumors thanks to less dependency on oxygen and a better ability to kill cancer stem cells. Interestingly, hadrons also retain the advantages of radiosensitization approaches. These data confirm the great ability of hadrons to spare healthy tissue near the tumor via various mechanisms (reduced lymphopenia, bystander effect, etc.). Technology and machine improvements such as image-guided radiotherapy or particle therapies can improve treatment quality and efficacy (dose deposition and biological effect) in tumors while increasingly sparing healthy tissues. Radiation biology can help to understand how cancer cells resist radiation (hypoxia, DNA repair mechanisms, stem cell status, cell cycle position, etc.), how normal tissues may display sensitivity to radiation and how radiation effects can be increased with either radiosensitizers or accelerated particles. All these research topics are under investigation within the ARCHADE research community in France. By focusing on these areas, radiotherapy can become more effective, targeted and safe, enhancing the overall treatment experience and outcomes for cancer patients. Our goal is to provide biological evidence of the therapeutic advantages of hadrontherapy, according to the tumor characteristics. This article aims to give an updated view of our research in radiation biology within the frame of the French “ARCHADE association” and new perspectives on research and treatment with the C400 multi-ions accelerator prototype. Full article

Spatially fractionated radiation therapy (SFRT) has a long history of treating bulky and hypoxic tumors. Recent evidence suggests that, compared to conventional uniform dose radiation therapy, SFRT may utilize different mechanisms of tumor cell killing, potentially including bystander and immune-activating effects. The abscopal effect in radiation therapy refers to the control or even elimination of distant untreated tumors following the treatment of a primary tumor with radiation, a process believed to be immune-mediated. Such effects have been shown to be enhanced by immunotherapy, particularly immune checkpoint inhibition. In this manuscript, we explore the potential synergy of spatially fractionated radiation therapy, in the form of kV x-ray minibeam, combined with PD-L1 checkpoint inhibition in a murine mammary carcinoma model at conventional dose-rate. We found that minibeam of peak/valley doses of 50 Gy/3.7 Gy performed statistically equivalent but trending better than that of 100 Gy/7.4 Gy in its abscopal effect and so 50 Gy/3.7 Gy was selected for further studies. Our findings indicate that the abscopal effect is significantly greater in the minibeam plus anti-PD-L1 treated animals compared to those receiving uniform dose radiation therapy plus anti-PD-L1 (p = 0.04948). Immune cell profiling in the minibeam plus anti-PD-L1 group compared to uniform dose reveals a consistent trend towards greater immune cell infiltration in the primary tumor, as well as a higher percentage of CD8+ T cells, both systemically and at the abscopal tumor site. Full article

Classical radiation biology as we understand it clearly identifies genomic DNA as the primary target of ionizing radiation. The evidence appears rock-solid: ionizing radiation typically induces DSBs with a yield of ~30 per cell per Gy, and unrepaired DSBs are a very cytotoxic lesion. We know very well the kinetics of induction and repair of different types of DNA damage in different organisms and cell lines. And yet, higher organisms differ in their radiation sensitivity—humans can be unpredictably radiosensitive during radiotherapy; this can be due to genetic defects (e.g., ataxia telangiectasia (AT), Fanconi anemia, Nijmegen breakage syndrome (NBS), and the xeroderma pigmentosum spectrum, among others) but most often is unexplained. Among other mammals, goats (Capra hircus) appear to be very radiosensitive (LD₅₀ = 2.4 Gy), while Mongolian gerbils (Meriones unguiculatus) are radioresistant and withstand quadruple that dose (LD₅₀ = 10 Gy). Primary radiation lethality in mammals is due most often to hematopoietic insufficiency, which is, in the words of Dr. Theodor Fliedner, one of the pioneers of radiation hematology, “a disturbance in cellular kinetics”. And yet, what makes one cell type, or one particular organism, more sensitive to ionizing radiation? The origins of radiosensitivity go above and beyond the empirical evidence and models of DNA damage and repair—as scientists, we must consider other phenomena: the radiation-induced bystander effect (RIBE), abscopal effects, and, of course, genomic instability and immunomodulation. It seems that radiosensitivity is not entirely determined by the mathematics of DNA damage and repair, and it is conceivable that radiation biology may benefit from an informed enquiry into physiology and organism-level signaling affecting radiation responses. The current article is a review of several key aspects of radiosensitivity beyond DNA damage induction and repair; it presents evidence supporting new potential venues of research for radiation biologists. Full article

With the improvement of medical devices for diagnosis and radiotherapy, concerns about the effects of low doses of ionizing radiation are also growing. There is no consensus among scientists on whether they might have beneficial effects on humans in certain cases or pose more risks, making the exposure unreasonable. While the damaging consequences of high-dose radiation have been known since the discovery of radioactivity, low-dose effects present a much bigger investigative challenge. They are highly specific and include radio-adaptive responses, bystander effects, and genomic instability. Current data regarding the consequences of exposure to low-dose radiation on the quality of male gametes and fertility potential are contradictory. The reports suggest two directions: indirect impact on male gametes—through spermatogenesis—or direct effects at low doses on already mature spermatozoa. Although mature gametes are used for observation in both models, they are fundamentally different, leading to varied results. Due to their unique physiological characteristics, in certain cases, exposure of spermatozoa to low-dose ionizing radiation could have positive effects. Despite the findings indicating no beneficial effects of low-dose exposure on male fertility, it is essential to research its impact on mature spermatozoa, as well. Full article

Esophageal squamous cell carcinoma (ESCC) is a deadly consequence of radiation exposure to the esophagus. ESCC arises from esophageal epithelial cells that undergo malignant transformation and features a perturbed squamous cell differentiation program. Understanding the dose- and radiation quality-dependence of the esophageal epithelium response to radiation may provide insights into the ability of radiation to promote ESCC. We have explored factors that may play a role in esophageal epithelial radiosensitivity and their potential relationship to ESCC risk. We have utilized a murine three-dimensional (3D) organoid model that recapitulates the morphology and functions of the stratified squamous epithelium of the esophagus to study persistent dose- and radiation quality-dependent changes. Interestingly, although high-linear energy transfer (LET) Fe ion exposure induced a more intense and persistent alteration of squamous differentiation and 53BP1 DNA damage foci levels as compared to Cs, the MAPK/SAPK stress pathway signaling showed similar altered levels for most phospho-proteins with both radiation qualities. In addition, the lower dose of high-LET exposure also revealed nearly the same degree of morphological changes, even though only ~36% of the cells were predicted to be hit at the lower 0.1 Gy dose, suggesting that a bystander effect may be induced. Although p38 and ERK/MAPK revealed the highest levels following high-LET exposure, the findings reveal that even a low dose (0.1 Gy) of both radiation qualities can elicit a persistent stress signaling response that may critically impact the differentiation gradient of the esophageal epithelium, providing novel insights into the pathogenesis of radiation-induced esophageal injury and early stage esophageal carcinogenesis. Full article

Tumor hypoxia is the most common feature of radioresistance to the radiotherapy (RT) of lung cancer and results in poor clinical outcomes. High-linear energy transfer (LET) radiation is a novel RT technique to overcome this problem. However, a limited number of studies have been elucidated on the underlying mechanism(s) of RIBE and RISBE in cancer cells exposed to high-LET radiation under hypoxia. Here, we developed a new method to investigate the RIBE and RISBE under hypoxia using the SPICE-QST proton microbeams and a layered tissue co-culture system. Normal lung fibroblast (WI-38) and lung cancer (A549) cells were exposed in the range of 06 Gy of proton microbeams, wherein only ~0.04–0.15% of the cells were traversed by protons. Subsequently, primary bystander A549 cells were co-cultured with secondary bystander A549 cells in the presence or absence of a GJIC and NO inhibitor using co-culture systems. Studies show that there are differences in RIBE in A549 and WI-38 primary bystander cells under normoxia and hypoxia. Interestingly, treatment with a GJIC inhibitor showed an increase in the toxicity of primary bystander WI-38 cells but a decrease in A549 cells under hypoxia. Our results also show the induction of RISBE in secondary bystander A549 cells under hypoxia, where GJIC and NO inhibitors reduced the stressful effects on secondary bystander A549 cells. Together, these preliminary results, for the first time, represented the involvement of intercellular communications through GJIC in propagation of RIBE and RISBE in hypoxic cancer cells. Full article

It is well established that cells, tissues, and organisms exposed to low doses of ionizing radiation can induce effects in non-irradiated neighbors (non-targeted effects or NTE), but the mechanisms remain unclear. This is especially true of the initial steps leading to the release of signaling molecules contained in exosomes. Voltage-gated ion channels, photon emissions, and calcium fluxes are all involved but the precise sequence of events is not yet known. We identified what may be a quantum entanglement type of effect and this prompted us to consider whether aspects of quantum biology such as tunneling and entanglement may underlie the initial events leading to NTE. We review the field where it may be relevant to ionizing radiation processes. These include NTE, low-dose hyper-radiosensitivity, hormesis, and the adaptive response. Finally, we present a possible quantum biological-based model for NTE. Full article

This study aimed to determine the mechanism underlying the modulation of radiosensitivity in cancer cells by the radiation-induced bystander effect (RIBE). We hypothesized that the RIBE mediates cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in elevating radioresistance in unirradiated cells. In this study, we used the SPICE-QST microbeam irradiation system to target 0.07–0.7% cells by 3.4-MeV proton microbeam in the cell culture sample, such that most cells in the dish became bystander cells. Twenty-four hours after irradiation, we observed COX-2 protein upregulation in microbeam-irradiated cells compared to that of controls. Additionally, 0.29% of the microbeam-irradiated cells exhibited increased cell survival and a reduced micronucleus rate against X-ray irradiation compared to that of non-microbeam irradiated cells. The radioresistance response was diminished in both cell groups with the hemichannel inhibitor and in COX-2-knockout cells under cell-to-cell contact and sparsely distributed conditions. The results indicate that the RIBE upregulates the cell radioresistance through COX-2/PGE2 intercellular responses, thereby contributing to issues, such as the risk of cancer recurrence. Full article

Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal effects have also been observed at high doses of IR) relevant to antitumor radiation therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead to short-ranging bystander effects and distant long-ranging extracellular signaling abscopal effects. Internal and “spontaneous” cellular stress is mostly due to metabolic oxidative stress involving mitochondrial energy production (ATP) through oxidative phosphorylation and/or anaerobic pathways accompanied by the leakage of O₂⁻ and other radicals from mitochondria during normal or increased cellular energy requirements or to mitochondrial dysfunction. Among external stressors, ionizing radiation (IR) has been shown to very rapidly perturb mitochondrial functions, leading to increased energy supply demands and to ROS/NOS production. Depending on the dose, this affects all types of cell constituents, including DNA, RNA, amino acids, proteins, and membranes, perturbing normal inner cell organization and function, and forcing cells to reorganize the intracellular metabolism and the network of organelles. The reorganization implies intracellular cytoplasmic-nuclear shuttling of important proteins, activation of autophagy, and mitophagy, as well as induction of cell cycle arrest, DNA repair, apoptosis, and senescence. It also includes reprogramming of mitochondrial metabolism as well as genetic and epigenetic control of the expression of genes and proteins in order to ensure cell and tissue survival. At low doses of IR, directly irradiated cells may already exert non-targeted effects (NTE) involving the release of molecular mediators, such as radicals, cytokines, DNA fragments, small RNAs, and proteins (sometimes in the form of extracellular vehicles or exosomes), which can induce damage of unirradiated neighboring bystander or distant (abscopal) cells as well as immune responses. Such non-targeted effects (NTE) are contributing to low-dose phenomena, such as hormesis, adaptive responses, low-dose hypersensitivity, and genomic instability, and they are also promoting suppression and/or activation of immune cells. All of these are parts of the main defense systems of cells and tissues, including IR-induced innate and adaptive immune responses. The present review is focused on the prominent role of mitochondria in these processes, which are determinants of cell survival and anti-tumor RT. Full article