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Ultra-High-Dose-Rate FLASH Irradiation May Spare Hypoxic Stem Cell Niches in Normal Tissues

2019; Elsevier BV; Volume: 105; Issue: 1 Linguagem: Inglês

10.1016/j.ijrobp.2019.05.030

1879-355X

Guillem Pratx, Daniel S. Kapp,

Advanced Radiotherapy Techniques

Recent animal studies have rekindled interest in the use of ultra-high-dose-rate irradiation (also known as FLASH) to reduce normal-tissue toxicity. Using short pulses ( 15 mm Hg), the OER curve is relatively flat, and FLASH irradiation should have a marginal effect (noted as [b] in Fig. 1). Finally, at low oxygen levels (<1 mm Hg), the overall FLASH effect would be small due to complete oxygen depletion ( [c] in Fig. 1). Based on this simplified model, we conclude that the radioprotective benefits of FLASH irradiation should be circumscribed to cells that are already hypoxic and sufficiently far from blood vessels. These conditions are consistent with findings from past in vitro experiments6Berry R.J. Stedeford J.B. Reproductive survival of mammalian cells after irradiation at ultra-high dose-rates: Further observations and their importance for radiotherapy.Br J Radiol. 1972; 45: 171-177Crossref Scopus (28) Google Scholar, 7Weiss H. Epp E.R. Heslin J.M. et al.Oxygen depletion in cells irradiated at ultra-high dose-rates and at conventional dose-rates.Int J Radiat Biol Relat Stud Phys Chem Med. 1974; 26: 17-29Crossref Scopus (39) Google Scholar and mathematical modeling.10Weiss H. An equation for predicting the surviving fraction of cells irradiated with single pulses delivered at ultra-high dose rates.Radiat Res. 1972; 50: 441-452Crossref Scopus (5) Google Scholar We note that early reports of a FLASH effect in fully oxygenated cells could not be reproduced by Berry and others, possibly because of improper experimental design.6Berry R.J. Stedeford J.B. Reproductive survival of mammalian cells after irradiation at ultra-high dose-rates: Further observations and their importance for radiotherapy.Br J Radiol. 1972; 45: 171-177Crossref Scopus (28) Google Scholar The role of normal-tissue stem cells in recovery from radiation-induced damage was initially reported for cognitive dysfunction.11Acharya M.M. Christie L.A. Lan M.L. et al.Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells.Proc Natl Acad Sci USA. 2009; 106: 19150-19155Crossref PubMed Scopus (91) Google Scholar Direct measurements have demonstrated that stem cells may reside in hypoxic niches. For instance, in the bone marrow, stem-cell niches maintain a hypoxic microenviroment with local pO2 as low as 10 mm Hg.12Spencer J.A. Ferraro F. Roussakis E. et al.Direct measurement of local oxygen concentration in the bone marrow of live animals.Nature. 2014; 508: 269-273Crossref PubMed Scopus (599) Google Scholar Hypoxic niches have also been reported for mesenchymal stem cells (15-60 mm Hg), neural stem cells (<8-60 mm Hg pO2), and hematopoietic stem cells (7-50 mm Hg), as reviewed by Mohyeldin et al.13Mohyeldin A. Garzón-Muvdi T. Quiñones-Hinojosa A. Oxygen in stem cell biology: A critical component of the stem cell niche.Cell Stem Cell. 2010; 7: 150-161Abstract Full Text Full Text PDF PubMed Scopus (986) Google Scholar Stem cell niches have also been found in the colon, lung, and kidney, although the oxygen concentrations of these stem cell niches were not reported. From our simplified model (Fig. 1), the oxygen concentrations in these stem cell niches overlaps with the range of values where one would predict significant radioprotection from additional oxygen depletion associated with FLASH. We therefore hypothesize that the observed effects on normal-tissue toxicity of FLASH versus conventional radiation dose rates may be due, at least in part, to the relative sparing of stem cells residing in hypoxic niches in normal tissues. Other potential explanations for the FLASH effect have been previously proposed, including the sparing of circulating immune cells in light of the rapid treatment time, the effect on chromatin remodeling, and inflammatory/anti-inflammatory cell signaling.5Durante M. Bräuer-Krisch E. Hill M. Faster and safer? Flash ultra-high dose rate in radiotherapy.Br J Radiol. 2018; 91: 20170628Google Scholar As a corollary to our hypothesis, FLASH may also render hypoxic tumors more resistant to radiation therapy. The detrimental effect of tumor hypoxia on the control of murine and human tumors by ionizing radiation has been widely studied. Given this association between tumor hypoxia and radioresistance, concern is raised that the extent of hypoxia in such tumors may be exacerbated by FLASH-induced radiolytic oxygen depletion.9Wilson P. Jones B. Yokoi T. et al.Revisiting the ultra-high dose rate effect: Implications for charged particle radiotherapy using protons and light ions.Br J Radiol. 2012; 85: e933-e939Crossref PubMed Scopus (35) Google Scholar This potential effect on hypoxic tumors needs to be further investigated before FLASH is tested in the clinic. Download .pdf (.1 MB) Help with pdf files Supplementary Information