| Zugriffsnummer | 41263 |
| Dokumenttyp | Zeitschriftenartikel |
| Peer Review | mit Peer Review |
| Sprache | Englisch |
| Titel | Lack of DNA damage response at low radiation doses in adult stem cells contributes to organ dysfunction |
| Autor(in); Institution |
Nagle, Peter W.; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
Hosper, Nynke A.; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
Barazzuol, Lara; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
Jellema, Anne L.; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
Baanstra, Mirjam; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
Goethem, Marc Jan van; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS; University of Groningen, KVI Center for Advanced Radiation Technology, Groningen, THE NETHERLANDS
Brandenburg, Sytze; University of Groningen, KVI Center for Advanced Radiation Technology, Groningen, THE NETHERLANDS
Giesen, Ulrich; 6.5, Strahlenwirkung, PTB-Braunschweig
Langendijk, Johannes A.; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS
van Luijk, Peter; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS
Coppes, Rob P.; University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, THE NETHERLANDS; University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, THE NETHERLANDS
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| Quelle/Jahr | Clinical Cancer Research: 24 (2018), 24, 6583 - 6593 |
| ISSN | 1078-0432 (PRINT) ; 1557-3265 (ONLINE) |
| DOI | |
| Verlag | Philadelphia, Pa.: AACR |
| Freie Schlagworte | Stem cells ; radiotherapy ; head and neck cancer ; salivary gland organoids ; thyroid gland organoids |
| Zusammenfassung | Purpose: 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 (SG), 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. Experimental Design: Post-irradiation rat SG secretory function was determined after pilocarpine induction. Murine and patient-derived SG 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. Results: Relative low-dose irradiation to the high-density stem cell region of rat SG disproportionally impaired function. Hyper-radiosensitivity at doses <1 Gy, followed by relative radioresistance at doses ≥1Gy, was observed in SG 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 SG organoid cells showed similar responses, while a single 1 Gy dose to SGderived stem cells resulted in greater survival than clinically relevant fractionated doses of 4×0.25 Gy. Conclusions: 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. |
| Themenbereich der Metrologie | Ionisierende Strahlung |
Zitierung
Nagle, P. W., Hosper, N. A., Barazzuol, L., Jellema, A. L., Baanstra, M., Goethem, M. J. V., Brandenburg, S., Giesen, U., Langendijk, J. A., van Luijk, P., & Coppes, R. P. (2018). Lack of DNA damage response at low radiation doses in adult stem cells contributes to organ dysfunction. Clinical Cancer Research, 24(24), 6583–6593. https://doi.org/10.1158/1078-0432.ccr-18-0533