Dataset Information

Association of Cancer Stem Cell Radio-Resistance Under Ultra-High Dose Rate FLASH Irradiation With Lysosome-Mediated Autophagy.

ABSTRACT: Cancer stem cell (CSC) is thought to be the major cause of radio-resistance and relapse post radiotherapy (RT). Recently ultra-high dose rate "FLASH-RT" evokes great interest for its decreasing normal tissue damages while maintaining tumor responses compared with conventional dose rate RT. However, the killing effect and mechanism of FLASH irradiation (FLASH-IR) on CSC and normal cancer cell are still unclear. Presently the radiation induced death profile of CSC and normal cancer cell were studied. Cells were irradiated with FLASH-IR (∼10⁹ Gy/s) at the dose of 6-9 Gy via laser-accelerated nanosecond particles. Then the ratio of apoptosis, pyroptosis and necrosis were determined. The results showed that FLASH-IR can induce apoptosis, pyroptosis and necrosis in both CSC and normal cancer cell with different ratios. And CSC was more resistant to radiation than normal cancer cell under FLASH-IR. Further experiments tracing lysosome and autophagy showed that CSCs had higher levels of lysosome and autophagy. Taken together, our results suggested that the radio-resistance of CSC may associate with the increase of lysosome-mediated autophagy, and the decrease of apoptosis, necrosis and pyroptosis. To our limited knowledge, this is the first report shedding light on the killing effects and death pathways of CSC and normal cancer cell under FLASH-IR. By clarifying the death pathways of CSC and normal cancer cell under FLASH-IR, it may help us improve the understanding of the radio-resistance of CSC and thus help to optimize the future clinical FLASH treatment plan.

SUBMITTER: Yang G

PROVIDER: S-EPMC8116574 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Association of Cancer Stem Cell Radio-Resistance Under Ultra-High Dose Rate FLASH Irradiation With Lysosome-Mediated Autophagy.

Yang Gen G Lu Chunyang C Mei Zhusong Z Sun Xiaoyi X Han Jintao J Qian Jing J Liang Yulan Y Pan Zhuo Z Kong Defeng D Xu Shirui S Liu Zhipeng Z Gao Ying Y Qi Guijun G Shou Yinren Y Chen Shiyou S Cao Zhengxuan Z Zhao Ye Y Lin Chen C Zhao Yanying Y Geng Yixing Y Ma Wenjun W Yan Xueqing X

Frontiers in cell and developmental biology 20210429

Cancer stem cell (CSC) is thought to be the major cause of radio-resistance and relapse post radiotherapy (RT). Recently ultra-high dose rate "FLASH-RT" evokes great interest for its decreasing normal tissue damages while maintaining tumor responses compared with conventional dose rate RT. However, the killing effect and mechanism of FLASH irradiation (FLASH-IR) on CSC and normal cancer cell are still unclear. Presently the radiation induced death profile of CSC and normal cancer cell were studi ...[more]

PMID: 33996830

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Project description:Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.

Project description:Ultra-high dose rate FLASH irradiation (FLASH-IR) has got extensive attention since it may provide better protection on normal tissues while maintain tumor killing effect compared with conventional dose rate irradiation. The FLASH-IR induced protection effect on normal tissues is exhibited as radio-resistance of the irradiated normal cells, and is suggested to be related to oxygen depletion. However, the detailed cell death profile and pathways are still unclear. Presently normal mouse embryonic fibroblast cells were FLASH irradiated (∼109 Gy/s) at the dose of ∼10-40 Gy in hypoxic and normoxic condition, with ultra-fast laser-generated particles. The early apoptosis, late apoptosis and necrosis of cells were detected and analyzed at 6, 12, and 24 h post FLASH-IR. The results showed that FLASH-IR induced significant early apoptosis, late apoptosis and necrosis in normal fibroblast cells, and the apoptosis level increased with time, in either hypoxic or normoxic conditions. In addition, the proportion of early apoptosis, late apoptosis and necrosis were significantly lower in hypoxia than that of normoxia, indicating that radio-resistance of normal fibroblast cells under FLASH-IR can be enhanced by hypoxia. To further investigate the apoptosis related profile and potential pathways, mitochondria dysfunction cells resulting from loss of cytochrome c (cyt c-/-) were also irradiated. The results showed that compared with irradiated normal cells (cyt c+/+), the late apoptosis and necrosis but not early apoptosis proportions of irradiated cyt c-/- cells were significant decreased in both hypoxia and normoxia, indicating mitochondrial dysfunction increased radio-resistance of FLASH irradiated cells. Taken together, to our limited knowledge, this is the first report shedding light on the death profile and pathway of normal and cyt c-/- cells under FLASH-IR in hypoxic and normoxic circumstances, which might help us improve the understanding of the FLASH-IR induced protection effect in normal cells, and thus might potentially help to optimize the future clinical FLASH treatment.

Project description:PurposeAnimal studies with ultrahigh dose-rate radiation therapy (FLASH, >40 Gy/s) preferentially spare normal tissues without sacrificing antitumor efficacy compared with conventional dose-rate radiation therapy (CONV). At the University of Washington, we developed a cyclotron-generated preclinical scattered proton beam with FLASH dose rates. We present the technical details of our FLASH radiation system and preliminary biologic results from whole pelvis radiation.Methods and materialsA Scanditronix MC50 compact cyclotron beamline has been modified to produce a 48.7 MeV proton beam at dose rates between 0.1 and 150 Gy/s. The system produces a 6 cm diameter scattered proton beam (flat to ± 3%) at the target location. Female C57BL/6 mice 5 to 6 weeks old were used for all experiments. To study normal tissue effects in the distal colon, mice were irradiated using the entrance region of the proton beam to the whole pelvis, 18.5 Gy at different dose rates: control, CONV (0.6-1 Gy/s) and FLASH (50-80 Gy/s). Survival was monitored daily and EdU (5-ethynyl-2´-deoxyuridine) staining was performed at 24- and 96-hours postradiation. Cleaved caspase-3 staining was performed 24-hours postradiation. To study tumor control, allograft B16F10 tumors were implanted in the right flank and received 18 Gy CONV or FLASH proton radiation. Tumor growth and survival were monitored.ResultsAfter 18.5 Gy whole pelvis radiation, survival was 100% in the control group, 0% in the CONV group, and 44% in the FLASH group (P < .01). EdU staining showed cell proliferation was significantly higher in the FLASH versus CONV group at both 24-hours and 96-hours postradiation in the distal colon, although both radiation groups showed decreased proliferation compared with controls (P < .05). Lower cleaved caspase-3 staining was seen in the FLASH versus conventional group postradiation (P < .05). Comparable flank tumor control was observed in the CONV and FLASH groups.ConclusionsWe present our preclinical FLASH proton radiation system and biologic results showing improved survival after whole pelvis radiation, with equivalent tumor control.

Dataset Information

Association of Cancer Stem Cell Radio-Resistance Under Ultra-High Dose Rate FLASH Irradiation With Lysosome-Mediated Autophagy.

Publications

Association of Cancer Stem Cell Radio-Resistance Under Ultra-High Dose Rate FLASH Irradiation With Lysosome-Mediated Autophagy.

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