Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses

Abstract

Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid–ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

References

  1. Verhey LJ, Munzenrider JE . Proton beam therapy. Annu Rev Biophys Bioeng 1982; 11: 331–357.

    CAS  Article  Google Scholar 

  2. Suit HD, Goitein M, Tepper J, Koehler AM, Schmidt RA, Schneider R . Explorotory study of proton radiation therapy using large field techniques and fractionated dose schedules. Cancer 1975; 35: 1646–1657.

    CAS  Article  Google Scholar 

  3. D'angio GJ, Lawrence JH . Medical research with high-energy heavy particles. Nucleonics 1963; 21: 56–61.

    Google Scholar 

  4. Lawrence JH, Tobias CA, Born JL, Linfoot JA, Kling RP, Gottschalk A . Alpha and proton heavy particles and the Bragg peak in therapy. Trans Am Clin Climatol Assoc 1964; 75: 111–116.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Moravek Z, Bogner L . Analysis of the physical interactions of therapeutic proton beams in water with the use of Geant4 Monte Carlo calculations. Z Med Phys 2009; 19: 174–181.

    Article  Google Scholar 

  6. Dicello JF . How do we get from cell and animal data to risks for humans from space radiations? J Radiat Res 2002; 43(Suppl): S1–S6.

    Article  Google Scholar 

  7. Williams JR, Zhang Y, Zhou H, Osman M, Cha D, Kavet R et al. Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers. Mutat Res 1999; 6: 255–269.

    Article  Google Scholar 

  8. George K, Durante M, Willingham V, Wu H, Yang TC, Cucinotta FA . Biological effectiveness of accelerated particles for the induction of chromosome damage measured in metaphase and interphase human lymphocytes. Radiat Res 2003; 160: 425–435.

    CAS  Article  Google Scholar 

  9. Rithidech KN, Honikel LM, Reungpatthanaphong P, Tungjai M, Golightly M, Whorton EB . Effects of 100MeV protons delivered at 0.5 or 1cGy/min on the in vivo induction of early and delayed chromosomal damage. Mutat Res 2013; 756: 127–140.

    CAS  Article  Google Scholar 

  10. Vogelstein B, Kinzler KW . Cancer genes and the pathways they control. Nat Med 2004; 10: 789–799.

    CAS  Article  Google Scholar 

  11. Van Dyke T, Jacks T . Cancer modeling in the modern era: progress and challenges. Cell 2002; 108: 135–144.

    CAS  Article  Google Scholar 

  12. Fearon ER, Vogelstein B . A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759–767.

    CAS  Article  Google Scholar 

  13. Arnold CN, Goel A, Blum HE, Boland CR . Molecular pathogenesis of colorectal cancer: implications for molecular diagnosis. Cancer 2005; 104: 2035–2047.

    CAS  Article  Google Scholar 

  14. Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256: 668–670.

    CAS  Article  Google Scholar 

  15. Hinoi T, Akyol A, Theisen BK, Ferguson DO, Greenson JK, Williams BO et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res 2007; 67: 9721–9730.

    CAS  Article  Google Scholar 

  16. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6: 2853–2868.

    CAS  Google Scholar 

  17. Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 2013; 24: 242–256.

    CAS  Article  Google Scholar 

  18. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006; 444: 633–637.

    CAS  Article  Google Scholar 

  19. Coppe JP, Desprez PY, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010; 5: 99–118.

    CAS  Article  Google Scholar 

  20. Elyada E, Pribluda A, Goldstein RE, Morgenstern Y, Brachya G, Cojocaru G et al. CKIalpha ablation highlights a critical role for p53 in invasiveness control. Nature 2011; 470: 409–413.

    CAS  Article  Google Scholar 

  21. Kim SB, Zhang L, Barron S, Shay JW . Inhibition of microRNA-31-5p protects human colonic epithelial cells against ionizing radiation. Life Sci Space Res 2014; 1: 67–73.

    Article  Google Scholar 

  22. Kim SB, Pandita RK, Eskiocak U, Ly P, Kaisani A, Kumar R et al. Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation. Proc Natl Acad Sci USA 2012; 109: E2949–E2955.

    CAS  Article  Google Scholar 

  23. Kim SB, Ly P, Kaisani A, Zhang L, Wright WE, Shay JW . Mitigation of radiation-induced damage by targeting EGFR in noncancerous human epithelial cells. Radiat Res 2013; 180: 259–267.

    CAS  Article  Google Scholar 

  24. Kim SB, Lu Z, Shay JW . Oxygen and silicon ion particles induce neoplastic transformation in human colonic epithelial cells. Gravit Space Res 2014; 2: 32–41.

    Google Scholar 

  25. Eskiocak U, Kim SB, Roig AI, Kitten E, Batten K, Cornelius C et al. CDDO-Me protects against space radiation-induced transformation of human colon epithelial cells. Radiat Res 2010; 174: 27–36.

    CAS  Article  Google Scholar 

  26. Kudo S . Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 1993; 25: 455–461.

    CAS  Article  Google Scholar 

  27. Bahnassy AA, Zekri AR, El-Houssini S, El-Shehaby AM, Mahmoud MR, Abdallah S et al. Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients. BMC Gastroenterol 2004; 4: 22.

    Article  Google Scholar 

  28. Miyaoka Y, Chan AH, Judge LM, Yoo J, Huang M, Nguyen TD et al. Isolation of single-base genome-edited human iPS cells without antibiotic selection. Nat Methods 2014; 11: 291–293.

    CAS  Article  Google Scholar 

  29. Simone CB 2nd, Rengan R . The use of proton therapy in the treatment of lung cancers. Cancer J 2014; 20: 427–432.

    CAS  Article  Google Scholar 

  30. Ahn PH, Lukens JN, Teo BK, Kirk M, Lin A . The use of proton therapy in the treatment of head and neck cancers. Cancer J 2014; 20: 421–426.

    CAS  Article  Google Scholar 

  31. Pugh TJ, Lee AK . Proton beam therapy for the treatment of prostate cancer. Cancer J 2014; 20: 415–420.

    CAS  Article  Google Scholar 

  32. Keole S, Ashman JB, Daniels TB . Proton therapy for sarcomas. Cancer J 2014; 20: 409–414.

    CAS  Article  Google Scholar 

  33. Eaton BR, Yock T . The use of proton therapy in the treatment of benign or low-grade pediatric brain tumors. Cancer J 2014; 20: 403–408.

    CAS  Article  Google Scholar 

  34. Hall EJ, Giaccia AJ . Radiobiology for the Radiologist. Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2006.

    Google Scholar 

  35. Parsons JL, Townsend LW . Interplanetary crew dose rates for the August 1972 solar particle event. Radiat Res 2000; 153: 729–733.

    CAS  Article  Google Scholar 

  36. Townsend LW, Shinn JL, Wilson JW . Interplanetary crew exposure estimates for the August 1972 and October 1989 solar particle events. Radiat Res 1991; 126: 108–110.

    CAS  Article  Google Scholar 

  37. Collis SJ, Schwaninger JM, Ntambi AJ, Keller TW, Nelson WG, Dillehay LE et al. Evasion of early cellular response mechanisms following low level radiation-induced DNA damage. J Biol Chem 2004; 279: 49624–49632.

    CAS  Article  Google Scholar 

  38. Breuer H, Smit BJ . Proton Therapy and Radiosurgery. Springer Science & Business Media: New York, NY, USA, 2013.

    Google Scholar 

  39. Wilson JW, Cucinotta FA, Shinn JL, Simonsen LC, Dubey RR, Jordan WR et al. Shielding from solar particle event exposures in deep space. Radiat Meas 1999; 30: 361–382.

    Article  Google Scholar 

  40. Hellweg CE, Baumstark-Khan C . Getting ready for the manned mission to Mars: the astronauts' risk from space radiation. Naturwissenschaften 2007; 94: 517–526.

    CAS  Article  Google Scholar 

  41. Delgado O, Batten KG, Richardson JA, Xie XJ, Gazdar AF, Kaisani AA et al. Radiation-enhanced lung cancer progression in a transgenic mouse model of lung cancer is predictive of outcomes in human lung and breast cancer. Clin Cancer Res 2014; 20: 1610–1622.

    CAS  Article  Google Scholar 

  42. Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW . Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis. Radiat Res 2014; 181: 512–520.

    CAS  Article  Google Scholar 

  43. Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH et al. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 2007; 9: 1963–1970.

    CAS  Article  Google Scholar 

  44. Petronelli A, Pannitteri G, Testa U . Triterpenoids as new promising anticancer drugs. Anticancer Drugs 2009; 20: 880–892.

    CAS  Article  Google Scholar 

  45. Vannini N, Lorusso G, Cammarota R, Barberis M, Noonan DM, Sporn MB et al. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol Cancer Ther 2007; 6(12 pt 1): 3139–3146.

    CAS  Article  Google Scholar 

  46. Liby K, Royce DB, Williams CR, Risingsong R, Yore MM, Honda T et al. The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res 2007; 67: 2414–2419.

    CAS  Article  Google Scholar 

  47. Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med 2011; 51: 88–96.

    CAS  Article  Google Scholar 

  48. Boivin GP, Washington K, Yang K, Ward JM, Pretlow TP, Russell R et al. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 2003; 124: 762–777.

    Article  Google Scholar 

  49. Ludlow AT, Robin JD, Sayed M, Litterst CM, Shelton DN, Shay JW et al. Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res 2014; 42: e104.

    CAS  Article  Google Scholar 

  50. Rutter MD . A practical guide and review of colonoscopic surveillance and chromoendoscopy in patients with colitis. Frontline Gastroenterol 2010; 1: 126–130.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the support team at Brookhaven National Laboratory (BNL) and NASA Space Radiation Laboratory (NSRL) (Upton, NY, USA) for helping with the Proton and HZE particles delivery to animals. We thank Dr Michael Sporn (Hanover, NH, USA) and Reata Pharmaceuticals (Irving, TX, USA) for providing CDDO-EA reagent, Summer Barron (UT Southwestern, Dallas, TX, USA) for mouse colony maintenance and Gail Fasciani (UT Southwestern, Dallas, TX, USA) for histological processing. This work was performed in laboratories constructed with support from NIH grant C06 RR30414. This work was supported by NASA Grant nos. NNX15AI21G, NNX11AC15G, NNJ05HD36G and NNX09AU95G to JWS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J W Shay.

Ethics declarations

Competing interests

JWS is on the SAB of Reata Pharmaceuticals (Irving, TX, USA). The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, S., Bozeman, R., Kaisani, A. et al. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses. Oncogene 35, 3365–3375 (2016). https://doi.org/10.1038/onc.2015.395

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.395

Further reading

Search

Quick links