NASA Specialized Center of Research (NSCOR)

Intestinal Tumorigenesis Risks of Space Radiation

NSCOR TEAM

GEORGETOWN TEAM

PROJECT LEADERS
 

Ionizing Radiation in Space

High-energy ionizing radiation (IR) is constantly streaming through space; however, the geomagnetic field around Earth protects us from its harmful effects. Consequently, any journeys into outer space beyond the Earth's magnetosphere would expose traveling astronauts to this highly-penetrating type of radiation. Major sources of ionizing radiation in space include:

-galactic cosmic radiation (GCR) originating from beyond our solar system,

-solar particle events (SPEs) or solar storms,

-radiation trapped in orbit around earth's magnetosphere (Van Allen Belt).

The radiation field in space, unlike that found on Earth, is heterogeneous and predominantly composed of high-energy protons and high-energy, high-charge particles, such as iron, silicon and oxygen ions. For more detailed information on space radiation, please click here.

Space Radiation and GI Cancer Risk

A major goal of the National Aeronautics and Space Administration's (NASA) life-science research program is to enable human exploration of space with risks from space radiation as low as reasonably possible. In a joint effort with the University of Texas Southwestern, the goal of our NASA Specialized Center of Research (NSCOR) is to assess in vivo the risks and molecular characteristics of increased intestinal carcinogenesis following space radiation exposure.

Gastrointestinal (GI) tumors are frequent in the U.S. and colorectal cancer (CRC) is the third most common cancer, accounting for 10% of all cancer deaths. The American Cancer Society estimates that in the year 2010, 142,570 people were diagnosed with colorectal cancer, and 53,194 people died from it (the American Cancer Society). Precancerous lesions are present in about 10% of adults at age 40 (approximately the average age of a typical astronaut) and their incidence increases to ~25% in older adults. Moreover, IR is a known risk factor for colorectal cancer based on studies such as the A-bomb survivor cohort. Therefore, even a modest exposure to space radiation could have a significant effect on health risk estimates for future manned space flights.

Project Overview

Previous studies based on mathematical and statistical modeling have demonstrated an individual having significant probability of developing cancer after a mission to Mars, secondary to chronic radiation exposure. Despite these findings, large uncertainties still exist when making risk projections mainly because there are limited biological data to describe the effects of protons and galactic cosmic rays on mouse or human tissues. Because of these uncertainties, the safety margins have to remain high, limiting how long an astronaut can remain in space. The overarching goal of our proposed studies is to improve the understanding of GI cancer initiation, promotion and progression due to space-type radiation and to contribute to reducing the margin of uncertainty regarding GI cancer following space travel.

The application of scaling factors is probably the only practical approach to human cancer risk estimation for space radiation where the carcinogenic relative biological effectiveness (RBE) of space-type radiation is determined in animal models, and then extrapolated for use in human risk estimation, which is itself derived using epidemiologic risk estimates from terrestrial exposures.

Mutations in the adenomatous polyposis coli (APC) gene are involved early in development of both sporadic and familial colon cancer (familial adenomatous polyposis, FAP). Loss of wild-type APC function initiates polyp formation, probably due to cells migrating along the crypt-villus axis continuing to proliferate, rather than differentiate and cease to further divide as happens in healthy tissue. The ApcMin mouse (ApcMin/+), which has a truncation mutation at codon 850, is the most studied of the APC mutants and there is a large literature that has shown its utility as a model for intestinal cancer initiation and prevention studies. Additional mouse models are available for key target genes in colorectal cancer and will also be employed in this program.
 

Project Objectives

-To quantitatively analyze intestinal tumor incidence and grade following exposure to high-energy heavy ions (HZE) and protons of different energies, and compare to equitoxic doses of γ-rays in the ApcMin (multiple intestinal neoplasia) and Apc1638N/+ mouse models.

-To assess potential gender and age variation in tumor incidence after space-type radiation.

-To characterize the effects of space-type radiation in triggering persistent stress responses in intestinal epithelial cells and their potential effects on tumorigenesis.

-To delineate cancer progression-specific biological changes and genomic, proteomic and metabolomic signatures associated with radiation-induced tumorigenesis.

Recent Publications

2016

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. doi: 10.1038/srep31853. PMID: 27558773.

Datta K, Suman S, Kumar S, Fornace AJ Jr. Colorectal Carcinogenesis, Radiation Quality, and the Ubiquitin-Proteasome Pathway. J Cancer. 2016 Jan 1;7(2):174-83. doi: 10.7150/jca.13387. eCollection 2016. Review. PubMed PMID: 26819641; PubMed Central PMCID: PMC4716850.

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 Tumorgenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC(1638N/+) Mice. 2016 May 1;95(1):131-8. doi: 10.1016/j.ijrobp.2015.10.057. Epub 2015 Oct 31. PMID: 26725728.

2015

Suman S, Kallakury BV, Fornace AJ Jr, 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. Int J Biol Sci. 2015 Jan 20;11(3):274-83. doi: 10.7150/ijbs.10684. eCollection 2015. PubMed PMID:25678846; PubMed Central PMCID: PMC4323367.

Suman S, Kumar S, Fornace AJ Jr, Datta K. Decreased RXRα is Associated with Increased β-Catenin/TCF4 in (56)Fe-Induced Intestinal Tumors. Front Oncol. 2015 Oct 8;5:218. doi: 10.3389/fonc.2015.00218. eCollection 2015. PubMed PMID: 26500891; PubMed Central PMCID: PMC4597120.

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. 2015 Oct 31. pii: S0360-3016(15)26654-0. doi: 10.1016/j.ijrobp.2015.10.057. [Epub ahead of print] PubMed PMID: 26725728.

2014

Cheema AK, Suman S, Kaur P, Singh R, Fornace AJ Jr, Datta K. Long-term differential changes in mouse intestinal metabolomics after γ and heavy ion radiation exposure. PLoS One. 2014 Jan 27;9(1):e87079. doi: 10.1371/journal.pone.0087079. eCollection 2014.

Datta K, Suman S, Fornace AJ Jr. Radiation persistently promoted oxidative stress, activated mTOR via PI3K/Akt, and downregulated autophagy pathway in mouse intestine. Int J Biochem Cell Biol. 2014 Dec;57:167-76. doi:10.1016/j.biocel.2014.10.022. Epub 2014 Oct 23. PubMed PMID: 25449263; PubMed Central PMCID: PMC4363107.

Trani D, Nelson SA, Moon BH, Swedlow JJ, Williams EM, Strawn SJ, Appleton PL, Kallakury B, Näthke I, Fornace AJ Jr. High-energy particle-induced tumorigenesis throughout the gastrointestinal tract. Radiat Res. 2014 Feb;181(2):162-71. doi: 10.1667/RR13502.1.

Suman S, Moon BH, Thakor H, Fornace AJ Jr, Datta K. Wip1 abrogation decreases intestinal tumor frequency in APC(Min/+) mice irrespective of radiation quality. Radiat Res. 2014 Sep;182(3):345-9. doi: 10.1667/RR13770.1. Epub 2014 Aug 12. PubMed PMID: 25117622.

2013

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

2012

Datta, K., Hyduke, D. R., Suman, S., Moon, B. H., Johnson, M. D., and Fornace, A. J. J. Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland. Radiat Oncol 7: 205, 2012.

Datta, K., Suman, S., Kallakury, B. V., and Fornace, A. J., Jr. Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS ONE 7: e42224, 2012.

Datta, K., Suman, S., Kallakury, B. V., and Fornace, A. J., Jr. Heavy Ion Radiation Exposure Triggered Higher Intestinal Tumor Frequency and Greater beta-Catenin Activation than gamma Radiation in APC(Min/+) Mice. PLoS ONE 8: e59295, 2013.

Datta, K., Suman, S., Trani, D., Doiron, K., Rotolo, J. A., Kallakury, B. V., Kolesnick, R., Cole, M. F., and Fornace, A. J., Jr. Accelerated hematopoietic toxicity by high energy (56)Fe radiation. Int. J. Radiat. Biol. 88: 213-222, 2012.

Suman, S., Datta, K., Trani, D., Laiakis, E. C., Strawn, S. J., and Fornace, A. J. J. Relative biological effectiveness of (12)C and (28)Si radiation in C57BL/6J mice. Radiat. Environ. Biophys. 51: 303-309, 2012.

Suman, S., Fornace, A. J. Jr., and Datta, K. Animal Models of Colorectal Cancer in Chemoprevention and Therapeutics Development, in Colorectal Cancer - From Prevention to Patient Care, Rajunor Ettarh (Ed.), 277-300, 2012; ISBN: 978-953-51-0028-7.

Suman, S., Johnson, M. D., and Fornace, A. J., Jr. Exposure to Ionizing Radiation Causes Long-Term Increase in Serum Estradiol and Activation of PI3K-Akt Signaling Pathway in Mouse Mammary Gland. Int J Radiat Oncol Biol Phys 84: 500-507, 2012.

Trani, D., Moon, B. H., Kallakury, B., Hartmann, D. P., Datta, K., and Fornace, A. J., Jr. Sex-dependent Differences in Intestinal Tumorigenesis Induced in Apc1638N/+ Mice by Exposure to Gamma Rays. Int. J. Radiat. Oncol. Biol. Phys. in press: 2012.

                                                NSCOR Team, Face to Face Meeting, August 2016,                                              plus Tony Dritschilo, Scientific Advisor

NSCOR Team plus Jon Minna, Scientific Advisor
Human Research Program Meeting, February 2016