Task Progress:
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The overall plan is to apply the well-characterized APC mouse models (APC1638N/+ and CDX2P Apcflox/+) of colorectal cancer (CRC) for development of risks estimates for various radiation exposures during manned space flight. We already know from studies in atomic bomb survivors that radiation is risk factor for CRC. Space radiation with its novel characteristics is expected to have greater risk relative to radiation on Earth. A standard approach in radiation biology towards risk estimation is to determine relative biologic effectiveness (RBE) of various parameters for space radiation compared to terrestrial radiation exposures. However, currently, there is much uncertainty in predicting risk of CRC in astronauts undertaking long duration space missions due to lack of sufficient in vivo mechanistic data in human or in animal models representing the human disease. Considering the limitation of acquiring human data, our study is focused on acquiring sufficient data in mouse models of human CRC with an aim to aid in risk model development for safe human space exploration. Therefore, qualitative and quantitative data on intestinal tumorigenesis in mice generated in this project will be used for quantitative dose response analyses. While such analyses will provide an estimate of risk in mouse model, our ultimate aim is to combine mouse model data from space radiation exposure and human epidemiological data from atomic bomb survivors to develop mathematical risk prediction model of CRC for astronauts.
Task progress on GI tumorigenesis (GU). We have participated in three beam runs at NASA Space Radiation Laboratory (NSRL) after our current NSCOR award in 2015 with an aim to assess tumorigenesis at doses lower than the previous ones with a broader range of ions. Greater tumorigenesis was observed with 28Si ions in our previous studies relative to other ions and gamma rays. This year we exposed APC1638N/+ mice to 5 cGy of 28-Si (300 MeV/n) and we used male mice due to higher tumor frequency in male relative to female mice. This year we have also started experiments with 16-O (325 MeV/n) and 4-He (250 MeV/n) ions, which are NASA prioritized ions of lower Z value proposed in the NSCOR. In 2017, we are also approved for proton, 28-Si, 56-Fe, and 4-He beam time and we will use the time to irradiated APC1638N/+ mice to fulfill statistical requirements. Importantly, we completed animal numbers required for our low dose rate (0.33 cGy/min) studies, data has been compiled, and tumor data from low and high (50 cGy/min) dose rate exposures were compared. We observed that differences in dose rate did not affect tumor frequency or size. An important aspect of our proposal was to study effects of genetic heterogeneity on space radiation-induced intestinal tumorigenesis. Our backcrossing of APC1638N/+ of C57BL/6J background into C3H/HeN and BALB/c background for the genetic heterogeneity study is near completion. The backcrossing was done for 10 generations and the plan is to sequence APC gene locus for detection of the mutation. We expect APC1638N/+ mice in C3H/HeN and BALB/c background to be ready for space radiation exposure during fall 2017 beam run.
We simulated a solar particle event (SPE) at the NSRL to characterize the biological effects of low dose rate protons in vivo. Using the colorectal cancer susceptible (CPC;Apc) mouse model, we studied colonic tumorigenesis after whole-body exposure to a simulated SPE with varying energies (50-150 MeV/n) using a total dose of 2 Gy over a 2 hour period (at an average dose rate of 1.67 cGy/min). We also exposed mice to 2 Gy at 20 cGy/min of acute (50 MeV/n) proton (91% of the sSPE was at 50 MeV/n) or X-ray (250 kVp, 1 mA, 1.65 mm Al filter) at a dose rate of 20 cGy/min as a reference radiation. We observed that whole-body irradiation with simulated SPE was more effective in inducing invasive adenocarcinoma incidence compared to unirradiated controls and x-rays. We started a pilot GCR simulation study in 2016 using protons, and helium and silicon ions. Using the large beam and large boxes to contain 2-3 mice each we were able to irradiate about 90 mice in about 90 minutes with the new fast switching capabilities at the NSRL. We reduced the dose rate to 0.5 cGy per minute (instead of the usual 10-20 cGy per minute) with a total dose of 30 cGy. For NRSL16C we used 20 cGy of proton, followed by 5 cGy of helium and then 5 cGy of silicon. Since 5 cGy of silicon did not increase polyp formation, these experiments were conducted to determine if adding both helium and protons to 5 cGy of silicon would increase polyp formation. We also reversed the order of ions in the GCRsim since it may affect carcinogenesis initiation and/or progression. Results from these experiments will require about 9 additional months. Going forward we will add more mice to this GCRsim for NSRL 17A.
This year we focused on assessing long-term effects of heavy ion radiation on GI epithelial cell migration up to two months after exposure and compare the results to gamma radiation. The generated data is expected to contribute towards developing GI risk estimates of heavy ion radiation, which is qualitatively high linear energy transfer (high-LET) in outer space relative to gamma-rays, which is low-LET. Mice (C57BL/6J) were exposed to sham, or 0.5 Gy of gamma or 56Fe radiation and small intestine, which is organized into well-defined crypts and villi and is considered a model system to study GI cell migration, and collected 7 and 60 d after exposure. Rate of IEC migration was assessed using BrdU pulse labeling 24 h prior to sacrificing the mice. We analyzed key signaling molecules involved in cell polarity, microtubule dynamics, and cell adhesion dynamics using immunoblots, immunofluorescence, immunohistochemistry. Our data from this study suggests that heavy ion radiation could impede GI epithelial cell migration persistently. Overall, these studies in normal GI tissues indicate a profound and persistent perturbation of normal GI physiology and cellular homeostasis, and has implications for space travel-related GI pathophysiological changes.
At the genomics level we are using laboratory and bioinformatics tools of systems genomics to identify the features of gastrointestinal tumors arising in our murine models. Using next generation sequencing (NGS) based methods we are determining the global mutation burden, and mutation types including small mutations and structural variations in these tumors. To further inform mechanistic interpretation of HZE effects, we are planning to use NGS technologies to examine transcriptomic and epigenomic changes in colonocytes recovered after space radiation. Our overarching goal is to utilize integrative genomics analyses to identify the signatures of space radiation exposure, tumorigenesis, and the mechanistic consequences of these disturbances so that this information can be utilized to support risk assessment and mitigation studies. We are using formalin fixed paraffin embedded (FFPE) tumor samples for sequencing. As an initial step, FFPE sections were H&E stained for pathology evaluation and areas representing adenoma or carcinoma are marked for dissection. DNA is extracted from the dissected tissue using our standard protocols. We have developed a methodology for molecular quality control that will allow an estimate of sample purity and comprehensive sequencing for space radiation genomic signature identification.
Analyses of mouse model data of simulated space radiation, using mechanistically-motivated mathematical models of carcinogenesis, are needed to better understand and potentially mitigate these risks. We have used data on heavy ions (12-C, 28-Si, and 56-Fe) and gamma-ray induced intestinal tumor frequency in APC1638N/+ mice. Our mathematical model includes: (1) targeted effects (TE), caused by ionizations within/close to nuclear DNA; (2) non-targeted effects (NTE), caused by radiation damage to other cell structures (e.g., mitochondria) and/or activation of stress signaling pathways; (3) cytotoxic effects. We used the model to estimate the NTE contribution to the dose response for each ion. According to our model, NTE cause the steep initial rise of the heavy ion dose responses observed between 0 and 0.1 Gy. Because at low fluences of heavy ions many cell nuclei will not be traversed by the cores of ion tracks, the contribution of NTE to the dose response at low doses is expected to be high. Model-based estimates of NTE contributions were consistent with this expectation: they dominated the dose response below 0.1 Gy. Non targeted effects may therefore play an important role in low-dose carcinogenesis from heavy ions. Overall, we plan to generate in vivo data on tumor frequency and mechanisms of tumor development using NASA mandated additional priority space radiation beams at lower doses relevant to space environment. These data will be used to reduce uncertainty in CRC risk prediction and develop reliable risk prediction model for human.
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Bibliography Type:
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Description: (Last Updated: 12/03/2021)
Show Cumulative Bibliography Listing
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Abstracts for Journals and Proceedings
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Shay JW. "Mouse models of cancer risk and prevention from space radiation." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Abstracts for Journals and Proceedings
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Kim SB, Bozeman R, Kim W, Zhang L, Richardson J, Wright WE, Fornace A, Shay JW. "Simulated solar particle events (SPE) promotes senescence-associated inflammatory responses in colorectal cancer susceptible mice." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Abstracts for Journals and Proceedings
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Suman S, Kumar S, Fornace AJ Jr, Datta K. "Persistent oxidative stress in mouse intestinal and colonic epithelial cells after exposure to 12C-ion exposure." To be presented in 2017 AACR (American Association of Cancer Research) Annual Meeting, Washington DC, April 1-5, 2017. 2017 AACR (American Association of Cancer Research) Annual Meeting, Washington DC, April 1-5, 2017. , Apr-2017
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Abstracts for Journals and Proceedings
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Kumar S, Suman S, Moon B-H, Fornace AJ Jr, Datta K. "Low-dose ionizing radiation induces persistent activation of NADPH oxidase pathway in mouse colon." To be presented in 2017 AACR (American Association of Cancer Research) Annual Meeting, Washington DC, April 1-5, 2017. 2017 AACR (American Association of Cancer Research) Annual Meeting, Washington DC, April 1-5, 2017. , Apr-2017
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Abstracts for Journals and Proceedings
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Suman S, Kumar S, Fornace AJ Jr, Datta K. "Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Abstracts for Journals and Proceedings
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Kumar S, Suman S, Moon B-H, Fornace AJ Jr, Datta K. "Adverse effects of radiation on murine intestinal epithelial cell migration is dependent on radiation quality." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Abstracts for Journals and Proceedings
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Suman S, Kumar S, Moon B-H, Fornace AJ Jr, Datta K. "Parental exposure to ionizing radiation elicits gastrointestinal tumorigenesis in offspring with higher male preponderance." Presented at the 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016
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Abstracts for Journals and Proceedings
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Suman S, Kumar S, Fornace AJ Jr, Datta K. "Exposure to gamma and 12-C radiation-induced differential long-term oxidative stress in mouse intestinal and colonic epithelial cells." Presented at the 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016
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Abstracts for Journals and Proceedings
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Kumar S, Suman S, Moon B-H, Fornace AJ Jr, Datta K. "Low dose ionizing radiation induces persistent oxidative stress in mouse colon through the NADPH oxidase pathway." Presented at the 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. , Oct-2016
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Abstracts for Journals and Proceedings
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Shuryak I, Fornace AJ, Datta K, Suman S, Kumar S, Sachs RK, Brenner DJ. "Scaling human cancer risks from low LET to high LET when dose-effect relations are complex." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Abstracts for Journals and Proceedings
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Meltzer PS, Shay JW, Fornace AJ Jr. "Genome Abnormalities in Space Radiation Driven Gastrointestinal Carcinogenesis." Presented at the 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. 2017 NASA Human Research Program Investigators’ Workshop, Galveston, Texas, January 23-26, 2017. , Jan-2017
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Articles in Peer-reviewed Journals
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Jafri MA, Al-Qahtani MH, Shay JW. "Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention." Semin Cancer Biol. 2017 Feb 8. [Epub ahead of print] Review. http://dx.doi.org/10.1016/j.semcancer.2017.02.004 ; PubMed PMID: 28188828 , Feb-2017
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Articles in Peer-reviewed Journals
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Norbury JW, Schimmerling W, Slaba TC, Azzam E, Badavi FF, Baiocco G, Benton E, Bindi V, Blakely EA, Blattnig SR, Boothman DA, Borak TB, Britten RA, Curtis S, Dingfelder M, Durante M, Dynan W, Eisch AJ, Robin Elgart S, Goodhead DT, Guida PM, Heilbronn LH, Hellweg CE, Huff JL, Kronenberg A, La Tessa C, Lowenstein D, Miller J, Morita T, Narici L, Nelson GA, Norman RB, Ottolenghi A, Patel ZS, Reitz G, Rusek A, Schreurs A-S, Scott-Carnell LA, Semones E, Shay JW, Shurshakov VA, Sihver L, Simonsen LC, Story M, Turker MS, Uchihori Y, Williams J, Zeitlin CJ. "Galactic cosmic ray simulation at the NASA Space Radiation Laboratory." Life Sci Space Res (Amst). 2016 Feb;8:38-51. http://dx.doi.org/10.1016/j.lssr.2016.02.001 ; PubMed PMID: 26948012 , Feb-2016
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Articles in Peer-reviewed Journals
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Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S; ICRP. "ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection." Annals of the ICRP (International Commission on Radiological Protection). 2015 Dec;44(3-4):7-357. Review. http://dx.doi.org/10.1177/0146645315595585 ; PubMed PMID: 26637346 , Dec-2015
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Articles in Peer-reviewed Journals
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El-Ashmawy M, Coquelin M, Luitel K, Batten K, Shay JW. "Organotypic culture in three dimensions prevents radiation-induced transformation in human lung epithelial cells." Nature Scientific Reports. 2016 Aug 19;6:31669. http://dx.doi.org/10.1038/srep31669 ; PubMed
PMID: 27539227; PubMed Central PMCID: PMC4990973
, Aug-2016
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Articles in Peer-reviewed Journals
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Suman S, Kumar S, Fornace AJ, Datta K. "Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine." Sci Rep. 2016 Aug 25;6:31853. http://dx.doi.org/10.1038/srep31853 ; PubMed PMID: 27558773; PubMed Central PMCID: PMC4997262 , Aug-2016
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Articles in Peer-reviewed Journals
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Suman S, Kumar S, Moon BH, Strawn SJ, Thakor H, Fan Z, Shay JW, Fornace AJ Jr, Datta K. "Relative biological effectiveness of energetic heavy ions for intestinal tumorigenesis shows male preponderance and radiation type and energy dependence in APC(1638N/+) mice." Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):131-8. http://dx.doi.org/10.1016/j.ijrobp.2015.10.057 ; PubMed PMID: 26725728 (Was in press/advance online in 2016 report.).
, May-2016
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Articles in Peer-reviewed Journals
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Shuryak I, Fornace AJ, Datta K, Suman S, Kumar S, Sachs RK, Brenner DJ. "Scaling human cancer risks from low LET to high LET when dose-effect relationships are complex." Radiation Resarch. 2017 Apr;187(4):476-82. Epub 2017 Feb 20. http://dx.doi.org/10.1667/RR009CC.1 ; PubMed PMID: 28218889 , Apr-2017
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