Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows ...the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients’ quality of life and to escalate radiation doses to tumors when necessary. High‐precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ‐specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.
Here, we discuss the complexity of radiotherapy‐induced side effects and approaches for prevention or treatment. Radiation damage develops at a cellular level, progresses to intercellular interactions resulting in intra‐ and interorgan functional responses. These need different approaches for prevention or treatment, for instance intracellular signaling modification, sparing of specific stem cell‐containing areas or contributing organs, and stem cell therapies.
Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The ...mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.
Adult stem cells are often touted as therapeutic agents in the regenerative medicine field, however data detailing both the engraftment and functional capabilities of solid tissue derived human adult ...epithelial stem cells is scarce. Here we show the isolation of adult human salivary gland (SG) stem/progenitor cells and demonstrate at the single cell level in vitro self‐renewal and differentiation into multilineage organoids. We also show in vivo functionality, long‐term engraftment, and functional restoration in a xenotransplantation model. Indeed, transplanted human salisphere‐derived cells restored saliva production and greatly improved the regenerative potential of irradiated SGs. Further selection for c‐Kit expression enriched for cells with enhanced regenerative potencies. Interestingly, interaction of transplanted cells with the recipient SG may also be involved in functional recovery. Thus, we show for the first time that salispheres cultured from human SGs contain stem/progenitor cells capable of self‐renewal and differentiation and rescue of saliva production. Our study underpins the therapeutic promise of salisphere cell therapy for the treatment of xerostomia. Stem Cells 2016;34:640–652
Human salivary gland stem cells cultured as salispheres are able to self‐renew and differentiate from single cells into salivary gland organoids. When xeno‐transplanted into an animal model of radiation‐induced hyposalivation, human salivary gland stem cells rescue saliva production.
Inter-individual variation largely influences disease susceptibility, as well as response to therapy. In a clinical context, the optimal treatment of a disease should consider inter-individual ...variation and formulate tailored decisions at an individual level. In recent years, emerging organoid technologies promise to capture part of an individual's phenotypic variability and prove helpful in providing clinically relevant molecular insights. Organoids are stem cell-derived three-dimensional models that contain multiple cell types that can self-organize and give rise to complex structures mimicking the organization and functionality of the tissue of origin. Organoids represent thus a more faithful recapitulation of the dynamics of the tissues of interest, compared to conventional monolayer cultures, thus supporting their use in evaluating disease prognosis, or as a tool to predict treatment outcomes. Additionally, the individualized nature of patient-derived organoids enables the use of autologous organoids as a source of transplantable material not limited by histocompatibility. An increasing amount of preclinical evidence has paved the way for clinical trials exploring the applications of organoid-based technologies, some of which are in phase I/II. This review focuses on the recent progress concerning the use of patient-derived organoids in personalized medicine, including (1) diagnostics and disease prognosis, (2) treatment outcome prediction to guide therapeutic advice and (3) organoid transplantation or cell-based therapies. We discuss examples of these potential applications and the challenges associated with their future implementation.
Dysfunction of the salivary gland and irreversible hyposalivation are the main side effects of radiotherapy treatment for head and neck cancer leading to a drastic decrease of the quality of life of ...the patients. Approaches aimed at regenerating damaged salivary glands have been proposed as means to provide long-term restoration of tissue function in the affected patients. In studies to elucidate salivary gland regenerative mechanisms, more and more evidence suggests that salivary gland stem/progenitor cell behavior, like many other adult tissues, does not follow that of the hard-wired professional stem cells of the hematopoietic system. In this review, we provide evidence showing that several cell types within the salivary gland epithelium can serve as stem/progenitor-like cells. While these cell populations seem to function mostly as lineage-restricted progenitors during homeostasis, we indicate that upon damage specific plasticity mechanisms might be activated to take part in regeneration of the tissue. In light of these insights, we provide an overview of how recent developments in the adult stem cell research field are changing our thinking of the definition of salivary gland stem cells and their potential plasticity upon damage. These new perspectives may have important implications on the development of new therapeutic approaches to rescue radiation-induced hyposalivation.
FLASH radiotherapy International Workshop Vozenin, Marie-Catherine; Baumann, Michael; Coppes, Rob P. ...
Radiotherapy and oncology,
October 2019, 2019-10-00, 20191001, Letnik:
139
Journal Article
On the mechanism of salivary gland radiosensitivity Konings, Antonius W T; Coppes, Rob P; Vissink, Arjan
International journal of radiation oncology, biology, physics,
07/2005, Letnik:
62, Številka:
4
Journal Article
Recenzirano
Odprti dostop
To contribute to the understanding of the enigmatic radiosensitivity of the salivary glands by analysis of appropriate literature, especially with respect to mechanisms of action of early radiation ...damage, and to supply information on the possibilities of amelioration of radiation damage to the salivary glands after radiotherapy of head-and-neck cancer.
Selected published data on the mechanism of salivary gland radiosensitivity and radioprotection were studied and analyzed.
From a classical point of view, the salivary glands should not respond as rapidly to radiation as they appear to do. Next to the suggestion of massive apoptosis, the leakage of granules and subsequent lysis of acinar cells was suggested to be responsible for the acute radiation-induced function loss of the salivary glands. The main problem with these hypotheses is that recently performed assays show no cell loss during the first days after irradiation, while saliva flow is dramatically diminished. The water secretion is selectively hampered during the first days after single-dose irradiation. Literature is discussed that shows that the compromised cells suffer selective radiation damage to the plasma membrane, disturbing signal transduction primarily affecting watery secretion. Although the cellular composition of the submandibular gland and the parotid gland are different, the damage response is very alike. The acute radiation-induced function loss in both salivary glands can be ameliorated by prophylactic treatment with specific receptor agonists.
The most probable mechanism of action, explaining the enigmatic high radiosensitivity for early effects, is selective radiation damage to the plasma membrane of the secretory cells, disturbing muscarinic receptor stimulated watery secretion. Later damage is mainly due to classical mitotic cell death of progenitor cells, leading to a hampered replacement capacity of the gland for secretory cells, but is also caused by damage to the extracellular environment, preventing proper cell functioning.
Radiotherapy for head and neck cancer may result in serious side effects, such as hyposalivation, impairing the patient's quality of life. Modern radiotherapy techniques attempt to reduce the dose to ...salivary glands, which, however, results in low-dose irradiation of the tissue stem cells. Here we assess the low-dose sensitivity of tissue stem cells and the consequences for tissue function.
Postirradiation rat salivary gland secretory function was determined after pilocarpine induction. Murine and patient-derived salivary gland and thyroid gland organoids were irradiated and clonogenic survival was assessed. The DNA damage response (DDR) was analyzed in organoids and modulated using different radiation modalities, chemical inhibition, and genetic modification.
Relative low-dose irradiation to the high-density stem cell region of rat salivary gland disproportionally impaired function. Hyper-radiosensitivity at doses <1 Gy, followed by relative radioresistance at doses ≥1 Gy, was observed in salivary gland and thyroid gland organoid cultures. DDR modulation resulted in diminished, or even abrogated, relative radioresistance. Furthermore, inhibition of the DDR protein ATM impaired DNA repair after 1 Gy, but not 0.25 Gy. Irradiation of patient-derived salivary gland organoid cells showed similar responses, whereas a single 1 Gy dose to salivary gland-derived stem cells resulted in greater survival than clinically relevant fractionated doses of 4 × 0.25 Gy.
We show that murine and human glandular tissue stem cells exhibit a dose threshold in DDR activation, resulting in low-dose hyper-radiosensitivity, with clinical implications in radiotherapy treatment planning. Furthermore, our results from patient-derived organoids highlight the potential of organoids to study normal tissue responses to radiation.
Over half of patients with brain tumors experience debilitating and often progressive cognitive decline after radiotherapy treatment. Microglia, the resident macrophages in the brain, have been ...implicated in this decline. In response to various insults, microglia can develop innate immune memory (IIM), which can either enhance (priming or training) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigate whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats show a stronger immune response to a secondary inflammatory insult, demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of postmortem normal-appearing non-tumor brain tissue of patients with glioblastoma indicates that radiation-induced microglial priming is likely conserved in humans. Targeting microglial priming or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.
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•Radiation causes microglial priming, enhancing the response to secondary insults•Radiation-induced microglial priming is persistent over time•The extent of radiation-induced microglial priming is age and dose dependent•Primed microglia are likely present in patients with brain tumors after treatment
Survivors of brain tumors experience radiotherapy-induced cognitive decline. Voshart et al. show that radiation can affect the innate immune memory of rat microglia, leading to persistent priming and hence an exaggerated response to subsequent inflammatory insults. This response is likely conserved in humans and could be targeted to decrease radiotherapy-related neurotoxicity.
Abstract
Radiotherapy involves unavoidable co-irradiation of the normal tissue, often resulting in side effects that limit the dose to the tumor and/or reduce quality of life of cancer survivors. The ...response of normal tissues to irradiation is mainly determined by the survival and regenerative potential of the tissue stem cells, and modulated by inflammatory processes, vasculature damage, altered neuronal innervation and fibrosis. Indeed, transplantation of tissue specific stem cells has been shown to restores tissue homeostasis and prevent late radiation effects. However, the radiation-induced senescence, fibrosis, and chronic inflammation may chance the stem cell niche engender an unfavorable environment for the regenerative potential of the tissue’s stem cells. Here changes in the salivary gland stem cell niche will be discussed using irradiated murine submandibular salivary gland tissue and derived organoids. Recently, we have developed methods to culture murine and patient specific tissue resembling salivary gland organoids (SGO). SGO contain all the glandular lineages, are able to extensively self-renew and up on transplantation rescue salivary gland function, allowing the study of radiation responses. The role of stemness factors, senescence and inflammatory processes in stem cell self-renewal and differentiation and post-irradiation regeneration will be discussed. Using SGO formation efficiency (OFE) as a measure of regenerative potential it is shown that stem cell potency after in vivo irradiation, is time dependent reduced. Interestingly, the conditioned medium of irradiated SGO reduced the OFE of unirradiated SGO. The potential role of radiation-induced senescence-associated secretory phenotype, hippo-signaling and inflammation through activation of cytosolic DNA sensing pathways on stem cells function will be addressed. Radiation-induced environmental changes in the stem cells niche have a severe impact on stem cell function. Modulation of these effect may enhance regenerative potential of surviving stem cells and improve engraftment and regeneration after stem cell transplantation. Supported by the Dutch Cancer Society (KWF, grant No. 10650 and 12092) and The Netherlands Organisation for Health Research and Development (ZonMw, Grant nrs. 11.600.1023 and 40-43600-98-14003).
Citation Format: Rob P. Coppes. Optimizing stem cell niche for post-irradiation regeneration abstract. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-020.
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