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EXPERIMENT INFORMATION

NSCOR: Space Radiation and Intestinal Tumorigenesis: Risk Assessment and Counter Measure Development (NNX09AU95G)
Principal Investigator
Research Area:
Radiation biology
Species Studied
Scientific Name: Species: Cells, human
Scientific Name: Mus musculus Species: Mouse

Description
OBJECTIVES:
Ionizing radiation (IR) is a known risk factor for colorectal (CR) cancer. Considering the high spontaneous incidence of gastrointestinal (GI) cancer in the US and even higher incidence of pre-malignant lesions, such as colonic polyps, an even modest increase by radiation exposure could have a significant effect on health risk estimates for manned space flight. During space travel, astronauts are exposed to levels of radiation, which increases their risk for acute short-term deleterious effects, such as during a solar storm, and for long-term deleterious effects like cancer. Long-duration space missions, like those at the International Space Station, lunar missions, or a mission to Mars, are of sufficient duration to allow for appreciable cumulative doses of cosmic radiation that could have profound health consequences. This project is important because there are no good estimates for intestinal, particularly CR, cancer by space radiation. Considering the increased CR cancer incidence in A-bomb survivors and the novel characteristics of space radiation, cancer causation by space radiation could potentially be even greater.

The overall goal of this project was to improve NASA risk estimates for space radiation-induced intestinal tumors. Investigators employed adenomatous polyposis coli (APC) mouse models that have been successfully used to demonstrate radiation-induced intestinal cancer. The APC models have inactivation of one allele of the APC gene and generally have sporadic loss or truncation mutations of the other gene. This results in mice developing intestinal tumors, called polyps or adenomas and more rarely invasive cancers. Space and terrestrial radiation could differentially perturb other factors of molecular pathways involved in intestinal tumorigenesis and thus initiate increased intestinal tumor development and/or progression.


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Publications
Suman S, Kallakury BV, Fornace AJ Jr, and Datta K. Protracted upregulation of leptin and IGF1 is associated with activation of PI3K/Akt and JAK2 pathway in mouse intestine after ionizing radiation exposure. International Journal of Biological Sciences. 2015. January 20; 11(3):274-83. pubmed.gov

Suman S, Kumar S, Fornace AJ Jr, and Datta K. Decreased RXRalpha is associated with increased ß-catenin/TCF4 in (56)Fe-induced intestinal tumors. Frontiers in Oncology. 2015. October 8; 5:218. pubmed.gov

Shay JW, Cucinotta FA, Sulzman FM, Coleman CN, and Minna JD. From mice and men to Earth and space: joint NASA-NCI workshop on lung cancer risk resulting from space and terrestrial radiation. Cancer Research. 2011. November 15; 71(22):6926-9. pubmed.gov

Constantinescu S, Hecht K, Sobotzki N, Erzinger MM, Bovet C, Shay JW, Wollscheid B, Sturla SJ, Marra G, and Beerenwinkel N. Transcriptomic responses of cancerous and noncancerous human colon cells to sulforaphane and selenium. Chemical Research in Toxicology. 2014. March 17; 27(3):377-86. pubmed.gov

Datta K, Suman S, and Fornace AJ Jr. Radiation persistently promoted oxidative stress, activated mTOR via PI3K/Akt, and downregulated autophagy pathway in mouse intestine. International Journal of Biochemistry and Cell Biology. 2014. December; 57:167-76. pubmed.gov

Suman S, Kumar S, Moon BH, Strawn SJ, Thakor H, Fan Z, Shay JW, Fornace AJ Jr, and 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. International Journal of Radiation, Oncology, Biology, Physics. 2016. May 1; 95(1):131-8. pubmed.gov

El-Ashmawy M, Delgado O, Cardentey A, Wright WE, and Shay JW. CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation. PLoS One. 2014. December 23; 9(12):e115600. pubmed.gov

Kaisani A, Delgado O, Fasciani G, Kim SB, Wright WE, Minna JD, and Shay JW. Branching morphogenesis of immortalized human bronchial epithelial cells in three-dimensional culture. Differentiation. 2014. March-April; 87(3-4):119-26. pubmed.gov

Kim SB, Bozeman RG, Kaisani A, Kim W, Zhang L, Richardson JA, Wright WE, and Shay JW. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses. Oncogene. 2016. June 30; 35(26):3365-75. pubmed.gov

Laiakis EC, Trani D, Moon BH, Strawn SJ, and Fornace AJ Jr. Metabolomic profiling of urine samples from mice exposed to protons reveals radiation quality and dose specific differences. Radiation Research. 2015. April; 183(4):382-90. pubmed.gov

Suman S, Moon B-H, Thakor H, Fornace AJ Jr, and Datta K. Wip1 abrogation decreases intestinal tumor frequency in APC(Min/+) mice irrespective of radiation quality. Radiation Research. 2014. September; 182(3):345-9. pubmed.gov

Zhang L, Kim SB, Gaoxiang J, Buhemeida A, Dallol A, Wright WE, Al-Qahtani M, and Shay JW. Exome sequencing of normal and isogenic transformed human colonic epithelial cells (HCECs) reveals novel genes potentially involved in the early stages of colorectal tumorigenesis. BMC Genomics. 2015;16 Suppl 1:S8. pubmed.gov

Cheema AK, Suman S, Kaur P, Singh R, Fornace AJ Jr, and Datta K. Long-term differential changes in mouse intestinal metabolomics after gamma and heavy ion radiation exposure. PLoS One. 2014. January 27; 9(1):e87079. pubmed.gov

Trani D, Nelson SA, Moon BH, Swedlow JJ, Williams EM, Strawn SJ, Appleton PL, Kallakury B, Näthke I, and Fornace AJ Jr. High-energy particle-induced tumorigenesis throughout the gastrointestinal tract. Radiation Research. 2014. February; 181(2):162-71. pubmed.gov

Kim SB, Zhang L, Barron S, and Shay JW. Inhibition of microRNA-31-5p protects human colonic epithelial cells against ionizing radiation. Life Sciences in Space Research. 2014. April; 1:67-73. [DOI]

Ng WL, Chen G, Wang M, Wang H, Story M, Shay JW, Zhang X, Wang J, Amin AR, Hu B, Cucinotta FA, and Wang Y. OCT4 as a target of miR-34a stimulates p63 but inhibits p53 to promote human cell transformation. Cell Death and Disease. 2014. January 23; 5:e1024. pubmed.gov

Suman S, Rodriguez OC, Winters TA, Fornace AJ Jr, Albanese C, and Datta K. Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production. Aging. 2013. August; 5(8):607-22. pubmed.gov

Kim SB, Ly P, Kaisani A, Zhang L, Wright WE, and Shay JW. Mitigation of radiation-induced damage by targeting EGFR in non-cancerous human epithelial cells. Radiation Research. 2013. September; 180(3):259-67. pubmed.gov

Keywords
Cell differentiation
Colon
Cosmic radiation
DNA damage
Dose-response relationship, radiation
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Data Information
Data Availability
Archive is complete. No data sets are available for this experiment. Please Contact LSDA if you know of available data for this investigation.

Parameters
Bardoxolone methyl (CDDO-Me)
CDDO-ethyl amide (CDDO-EA)
HCT116 3-6
Human colonic epithelial cells (HCEC CT7)
Human mutL homolog 1 (hMLH1)
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Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Ground 05/01/2009 In Progress

Human Research Program (HRP) Human Research Roadmap (HRR) Information
Crew health and performance is critical to successful human exploration beyond low Earth orbit. The Human Research Program (HRP) investigates and mitigates the highest risks to human health and performance, providing essential countermeasures and technologies for human space exploration. Risks include physiological and performance effects from hazards such as radiation, altered gravity, and hostile environments, as well as unique challenges in medical support, human factors, and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify the approach and research activities planned to address these risks, which are assigned to specific Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.

The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/

+ Click here for information of how this experiment is contributing to the HRP's path for risk reduction.

Additional Information
Managing NASA Center
Johnson Space Center (JSC)
Responsible NASA Representative
Johnson Space Center LSDA Office
Project Manager: Jessica Keune
Institutional Support
National Aeronautics and Space Administration (NASA)
Proposal Date
10/01/2009
Proposal Source
2008 NSCOR Space Radiation NNJ08ZSA003N