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The Lancet. Oncology May 2017Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all... (Review)
Review
Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all patients with the same TNM stage receive the same therapy. We believe there is a substantial opportunity to improve radiotherapy delivery beyond just technological and anatomical precision. In this Series paper, we explore several new ideas that could improve understanding of the phenotypic and genotypic differences that exist between patients and their tumours. We discuss how exploiting these differences and taking advantage of precision medicine tools-such as genomics, radiomics, and mathematical modelling-could open new doors to personalised radiotherapy adaptation and treatment. We propose a new treatment shift that moves away from an era of empirical dosing and fractionation to an era focused on the development of evidence to guide personalisation and biological adaptation of radiotherapy. We believe these approaches offer the potential to improve outcomes and reduce toxicity.
Topics: Biomarkers, Tumor; Combined Modality Therapy; Genotype; Head and Neck Neoplasms; Humans; Immunotherapy; Models, Theoretical; Phenotype; Precision Medicine; Radiation Tolerance; Radiotherapy; Radiotherapy Dosage
PubMed: 28456586
DOI: 10.1016/S1470-2045(17)30252-8 -
Radiation Research Apr 2010The body senses "danger" from "damaged self" molecules through members of the same receptor superfamily it uses for microbial "non-self", triggering canonical signaling... (Review)
Review
The body senses "danger" from "damaged self" molecules through members of the same receptor superfamily it uses for microbial "non-self", triggering canonical signaling pathways that lead to the generation of acute inflammatory responses. For this reason, the biology of normal tissue responses to moderate and clinically relevant doses of radiation is inextricably connected to innate immunity. The complex sequence of inflammatory events that ensues causes further cell and tissue damage to eliminate potential invaders but also leads to cytoprotective responses that limit the spread of damage and to wound healing through tissue regeneration or replacement. These sequential processes are orchestrated through multiple feedback control mechanisms involving cyclical production of free radicals and cytokines that are common to both radiation and immune signaling. This requires a concerted effort by resident tissue and inflammatory cell types, with macrophages apparently leading the way. The initial response to moderate doses of radiation therefore feeds into a pro-inflammatory paradigm whose eventual outcome is critically dependent upon the properties of the immune cells that are involved in tissue damage, regeneration and repair and that are in part under genetic influence. Importantly, these canonical pathways provide targets for interventions aimed at modifying normal tissue radiation responses. In this review, we examine areas of intersection between innate immunity and normal tissue radiobiology.
Topics: Animals; Humans; Immunity, Innate; Immunologic Factors; Inflammation; Models, Immunological; Radiation Tolerance; Receptors, Pattern Recognition
PubMed: 20334512
DOI: 10.1667/RR1931.1 -
The British Journal of Radiology Jan 2017Tumours contain multiple different cell populations, including cells derived from the bone marrow as well as cancer-associated fibroblasts and various stromal... (Review)
Review
Tumours contain multiple different cell populations, including cells derived from the bone marrow as well as cancer-associated fibroblasts and various stromal populations including the vasculature. The microenvironment of the tumour cells plays a significant role in the response of the tumour to radiation treatment. Low levels of oxygen (hypoxia) caused by the poorly organized vasculature in tumours have long been known to affect radiation response; however, other aspects of the microenvironment may also play important roles. This article reviews some of the old literature concerning tumour response to irradiation and relates this to current concepts about the role of the tumour microenvironment in tumour response to radiation treatment. Included in the discussion are the role of cancer stem cells, radiation damage to the vasculature and the potential for radiation to enhance immune activity against tumour cells. Radiation treatment can cause a significant influx of bone marrow-derived cell populations into both normal tissues and tumours. Potential roles of such cells may include enhancing vascular recovery as well as modulating immune reactivity.
Topics: Animals; Cell Cycle; Cell Death; Cell Hypoxia; Cell Survival; Humans; Neoplasms; Neoplastic Stem Cells; Radiation Dosage; Radiation Tolerance; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 27416998
DOI: 10.1259/bjr.20160474 -
Frontiers in Immunology 2019In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has... (Review)
Review
In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.
Topics: Animals; Cancer-Associated Fibroblasts; Extracellular Matrix; Humans; Immunity; Immunomodulation; Neoplasms; Radiation Tolerance; Radiotherapy; Stromal Cells; Tumor Microenvironment
PubMed: 30828330
DOI: 10.3389/fimmu.2019.00193 -
FEMS Microbiology Letters Mar 2018Four facultative anaerobic and two obligate anaerobic bacteria were isolated from extreme environments (deep subsurface halite mine, sulfidic anoxic spring, mineral-rich...
Four facultative anaerobic and two obligate anaerobic bacteria were isolated from extreme environments (deep subsurface halite mine, sulfidic anoxic spring, mineral-rich river) in the frame MASE (Mars Analogues for Space Exploration) project. The isolates were investigated under anoxic conditions for their survivability after desiccation up to 6 months and their tolerance to ionizing radiation up to 3000 Gy. The results indicated that tolerances to both stresses are strain-specific features. Yersinia intermedia MASE-LG-1 showed a high desiccation tolerance but its radiation tolerance was very low. The most radiation-tolerant strains were Buttiauxella sp. MASE-IM-9 and Halanaerobium sp. MASE-BB-1. In both cases, cultivable cells were detectable after an exposure to 3 kGy of ionizing radiation, but cells only survived desiccation for 90 and 30 days, respectively. Although a correlation between desiccation and ionizing radiation resistance has been hypothesized for some aerobic microorganisms, our data showed that there was no correlation between tolerance to desiccation and ionizing radiation, suggesting that the physiological basis of both forms of tolerances is not necessarily linked. In addition, these results indicated that facultative and obligate anaerobic organisms living in extreme environments possess varied species-specific tolerances to extremes.
Topics: Adaptation, Biological; Bacteria; Bacterial Physiological Phenomena; Desiccation; Environmental Microbiology; Extreme Environments; Hypoxia; Microbial Viability; Radiation Tolerance; Radiation, Ionizing
PubMed: 29474542
DOI: 10.1093/femsle/fny044 -
International Journal of Molecular... Jan 2021Following exposure to high doses of ionizing radiation, diverse strains of vertebrate species will manifest varying levels of radiation sensitivity. To understand the...
Following exposure to high doses of ionizing radiation, diverse strains of vertebrate species will manifest varying levels of radiation sensitivity. To understand the inter-strain cellular and molecular mechanisms of radiation sensitivity, two mouse strains with varying radiosensitivity (C3H/HeN, and CD2F1), were exposed to total body irradiation (TBI). Since Insulin-like Growth Factor-1 (IGF-1) signaling pathway is associated with radiosensitivity, we investigated the link between systemic or tissue-specific IGF-1 signaling and radiosensitivity. Adult male C3H/HeN and CD2F1 mice were irradiated using gamma photons at Lethal Dose-70/30 (LD), 7.8 and 9.35 Gy doses, respectively. Those mice that survived up to 30 days post-irradiation, were termed the survivors. Mice that were euthanized prior to 30 days post-irradiation due to deteriorated health were termed decedents. The analysis of non-irradiated and irradiated survivor and decedent mice showed that inter-strain radiosensitivity and post-irradiation survival outcomes are associated with activation status of tissue and systemic IGF-1 signaling, nuclear factor erythroid 2-related factor 2 (Nrf2) activation, and the gene expression profile of cardiac mitochondrial energy metabolism pathways. Our findings link radiosensitivity with dysregulation of IGF-1 signaling, and highlight the role of antioxidant gene response and mitochondrial function in radiation sensitivity.
Topics: Animals; Antioxidants; Dose-Response Relationship, Radiation; Gamma Rays; Gene Expression; Insulin-Like Growth Factor I; Male; Mice; Mice, Inbred C3H; Mitochondria; NF-E2-Related Factor 2; Radiation Tolerance; Radiation, Ionizing; Signal Transduction; Whole-Body Irradiation
PubMed: 33466349
DOI: 10.3390/ijms22010451 -
Bulletin Du Cancer May 2006Hypoxia is now recognized as a major explanation of tumor radioresistance and is an important prognostic factor in head and neck and cervical cancers. Anemia, which had... (Review)
Review
Hypoxia is now recognized as a major explanation of tumor radioresistance and is an important prognostic factor in head and neck and cervical cancers. Anemia, which had also a negative impact on cancer prognosis, increase tumor hypoxia. But we do not know actually if anemia has a direct role in tumor resistance or if it only reflect aggressiveness of the disease. Some trials have demonstrated that erythropoietin could increase the hemoglobin level during radiation courses. The only published randomised trial, performed in head and neck cancers, did not find any benefit for erythropoietin ; moreover, a deleterious effect was demonstrated. Possible explanations for this paradoxal result were discussed, particularly biological hypothesis and statistical bias.
Topics: Anemia; Blood Transfusion; Cell Hypoxia; Erythropoietin; Hematinics; Humans; Neoplasms; Otorhinolaryngologic Neoplasms; Radiation Tolerance; Randomized Controlled Trials as Topic; Recombinant Proteins
PubMed: 16777628
DOI: No ID Found -
Clinical Cancer Research : An Official... Jul 2015DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation-induced cell killing. Thus, the ability of tumor cells to elicit a... (Review)
Review
DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation-induced cell killing. Thus, the ability of tumor cells to elicit a DNA damage response following radiation, via activation of DNA repair and cell-cycle checkpoints, promotes radiation resistance and tumor cell survival. Consequently, agents that target these DNA damage response pathways are being developed to overcome radiation resistance. Overall, these agents are effective radiosensitizers; however, their mechanisms of tumor cell selectivity are not fully elucidated. In this review, we focus on the crucial radiation-induced DNA damage responses as well as clinical and translational advances with agents designed to inhibit these responses. Importantly, we describe how synthetic lethality can provide tumor cell-selective radiosensitization by these agents and expand the therapeutic window for DNA damage response-targeted agents used in combination with radiotherapy.
Topics: DNA Damage; DNA Repair; Humans; Molecular Targeted Therapy; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents
PubMed: 26133775
DOI: 10.1158/1078-0432.CCR-13-3229 -
Breast Cancer Research : BCR 2010Holliday junction recognition protein (HJURP) levels in breast cancer associate with both poor prognosis and an increased sensitivity to irradiation. Whilst, in part,...
Holliday junction recognition protein (HJURP) levels in breast cancer associate with both poor prognosis and an increased sensitivity to irradiation. Whilst, in part, this could be explained in relation to proliferation, it would not entirely account for the association with sensitivity to radiation. Thus, HJURP may have clinical potential as a marker of prognosis and radiation sensitivity; further validation with tissues from randomised controlled trials is needed. HJURP may represent the first in a class of proteins with roles in chromosome segregation and DNA repair that act as predictive biomarkers.
Topics: Biomarkers, Tumor; Breast Neoplasms; DNA Repair; DNA-Binding Proteins; Female; Humans; Prognosis; Radiation Tolerance
PubMed: 20497617
DOI: 10.1186/bcr2567 -
International Journal of Molecular... Jan 2019Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these...
Combination radiation and chemotherapy are commonly used to treat locoregionally advanced head and neck squamous cell carcinoma (HNSCC). Aggressive dosing of these therapies is significantly hampered by side effects due to normal tissue toxicity. Selenium represents an adjuvant that selectively sensitizes cancer cells to these treatments modalities, potentially by inducing lipid peroxidation (LPO). This study investigated whether one such selenium compound, methylseleninic acid (MSA), induces LPO and radiation sensitivity in HNSCC cells. Results from 4,4-difluoro-4-bora-3a,4a-diaza--indacene (BODIPY) C11 oxidation and ferric thiocyanate assays revealed that MSA induced LPO in cells rapidly and persistently. Propidium iodide (PI) exclusion assay found that MSA was more toxic to cancer cells than other related selenium compounds; this toxicity was abrogated by treatment with α-tocopherol, an LPO inhibitor. MSA exhibited no toxicity to normal fibroblasts at similar doses. MSA also sensitized HNSCC cells to radiation as determined by clonogenic assay. Intracellular glutathione in cancer cells was depleted following MSA treatment, and supplementation of the intracellular glutathione pool with -acetylcysteine sensitized cells to MSA. The addition of MSA to a cell-free solution of glutathione resulted in an increase in oxygen consumption, which was abrogated by catalase, suggesting the formation of H₂O₂. Results from this study identify MSA as an inducer of LPO, and reveal its capability to sensitize HNSCC to radiation. MSA may represent a potent adjuvant to radiation therapy in HNSCC.
Topics: Acetylcysteine; Apoptosis; Cell Line, Tumor; Gamma Rays; Glutathione; Head and Neck Neoplasms; Humans; Lipid Peroxidation; Organoselenium Compounds; Oxygen Consumption; Radiation Tolerance; Time Factors
PubMed: 30626124
DOI: 10.3390/ijms20010225