Abstract
Carcinogenesis induced by space radiation is considered a major risk factor in manned interplanetary and other extended missions. The models presently used to estimate the risk for cancer induction following deep space radiation exposure are based on data from A-bomb survivor cohorts and do not account for important biological differences existing between high-linear energy transfer (LET) and low-LET-induced DNA damage. High-energy and charge (HZE) radiation, the main component of galactic cosmic rays (GCR), causes highly complex DNA damage compared to low-LET radiation, which may lead to increased frequency of chromosomal rearrangements, and contribute to carcinogenic risk in astronauts. Gastrointestinal (GI) tumors are frequent in the United States, and colorectal cancer (CRC) is the third most common cancer accounting for 10% of all cancer deaths. On the basis of the aforementioned epidemiological observations and the frequency of spontaneous precancerous GI lesions in the general population, even a modest increase in incidence by space radiation exposure could have a significant effect on health risk estimates for future manned space flights. Ground-based research is necessary to reduce the uncertainties associated with projected cancer risk estimates and to gain insights into molecular mechanisms involved in space-induced carcinogenesis. We investigated in vivo differential effects of γ-rays and HZE ions on intestinal tumorigenesis using two different murine models, ApcMin/+ and Apc1638N/+. We showed that γ- and/or HZE exposure significantly enhances development and progression of intestinal tumors in a mutant-line-specific manner, and identified suitable models for in vivo studies of space radiation–induced intestinal tumorigenesis.
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References
Bertario L, Russo A, Sala P, Varesco L, Giarola M, Mondini P et al (2003) Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21(9):1698–1707
Bisgaard ML, Fenger K, Bulow S, Niebuhr E, Mohr J (1994) Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 3(2):121–125
Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russell R et al (2003) Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 124(3):762–777
Cachon-Gonzalez MB, Delhanty JD, Burn J, Tsioupra K, Davis MB, Attwood J et al (1991) Linkage analysis in adenomatous polyposis coli: the use of four closely linked DNA probes in 20 UK families. J Med Genet 28(10):681–685
Cucinotta FA, Durante M (2006) Cancer risk from exposure to galactic cosmic rays: implications for space exploration by human beings. Lancet Oncol 7(5):431–435
Durante M, Cucinotta FA (2008) Heavy ion carcinogenesis and human space exploration. Nat Rev Cancer 8(6):465–472
Ellender M, Harrison JD, Kozlowski R, Szluinska M, Bouffler SD, Cox R (2006) In utero and neonatal sensitivity of ApcMin/+ mice to radiation-induced intestinal neoplasia. Int J Radiat Biol 82(3):141–151
Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B et al (1994) A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 91(19):8969–8973
Fotiadis C, Tsekouras DK, Antonakis P, Sfiniadakis J, Genetzakis M, Zografos GC (2005) Gardner’s syndrome: a case report and review of the literature. World J Gastroenterol 11(34):5408–5411
Grady WM, Markowitz SD (2002) Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet 3:101–128
Haines J, Dunford R, Moody J, Ellender M, Cox R, Silver A (2000) Loss of heterozygosity in spontaneous and X-ray-induced intestinal tumors arising in F1 hybrid min mice: evidence for sequential loss of APC(+) and Dpc4 in tumor development. Genes Chromosomes Cancer 28(4):387–394
Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170
Kwong LN, Shedlovsky A, Biehl BS, Clipson L, Pasch CA, Dove WF (2007) Identification of Mom7, a novel modifier of Apc(Min/+) on mouse chromosome 18. Genetics 176(2):1237–1244
Moser AR, Luongo C, Gould KA, McNeley MK, Shoemaker AR, Dove WF (1995) ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J Cancer 31A(7–8):1061–1064
Nathke IS (2004) The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Annu Rev Cell Dev Biol 20:337–366
Okamoto M, Yonekawa H (2005) Intestinal tumorigenesis in Min mice is enhanced by X-irradiation in an age-dependent manner. J Radiat Res (Tokyo) 46(1):83–91
Pawel D, Preston D, Pierce D, Cologne J (2008) Improved estimates of cancer site-specific risks for A-bomb survivors. Radiat Res 169(1):87–98
Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M et al (2007) Solid cancer incidence in atomic bomb survivors: 1958–1998. Radiat Res 168(1):1–64
Shoemaker AR, Moser AR, Midgley CA, Clipson L, Newton MA, Dove WF (1998) A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice. Proc Natl Acad Sci USA 95(18):10826–10831
Smits R, van Oordt W, Luz A, Zurcher C, Jagmohan-Changur S, Breukel C et al (1998) Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts. Gastroenterology 114(2):275–283
Taketo MM (2006) Mouse models of gastrointestinal tumors. Cancer Sci 97(5):355–361
Taketo MM, Edelmann W (2009) Mouse models of colon cancer. Gastroenterology 136(3):780–798
Thompson DE, Mabuchi K, Ron E, Soda M, Tokunaga M, Ochikubo S et al (1994) Cancer incidence in atomic bomb survivors. Part II: solid tumors, 1958–1987. Radiat Res 137(2 Suppl):S17–S67
Uronis JM, Threadgill DW (2009) Murine models of colorectal cancer. Mamm Genome 20(5):261–268
van der Houven van Oordt CW, Smits R, Williamson SL, Luz A, Khan PM, Fodde R et al (1997) Intestinal and extra-intestinal tumor multiplicities in the Apc1638N mouse model after exposure to X-rays. Carcinogenesis 18(11):2197–2203
Acknowledgments
The work was supported by NASA Grant NNX-7AH70G. Daniela Trani was partially supported by the National Space Biomedical Research Institute (NSBRI) through NASA NCC9-58. The authors are grateful to Adam Rusek, the NASA Space Radiation Laboratory (NSRL) and the Brookhaven National Laboratory (BNL) staff for valuable assistance. The authors wish to thank Deborah Berry and the team of the Histopathology and Tissue Shared Resource at Georgetown University for technical support.
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This manuscript is based on a contribution given at the “Heavy Ions in Therapy and Space Symposium 2009,” July 6–10, 2009, Cologne (Germany).
D. Trani and K. Datta contributed equally to the manuscript.
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Trani, D., Datta, K., Doiron, K. et al. Enhanced intestinal tumor multiplicity and grade in vivo after HZE exposure: mouse models for space radiation risk estimates. Radiat Environ Biophys 49, 389–396 (2010). https://doi.org/10.1007/s00411-010-0292-2
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DOI: https://doi.org/10.1007/s00411-010-0292-2