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

Oncogene volume 35, pages 3365–3375 (2016)Cite this article

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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.

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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.

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Authors and Affiliations

  1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    S B Kim, R G Bozeman, A Kaisani, W Kim, L Zhang, W E Wright & J W Shay

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J A Richardson

  3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J A Richardson

  4. Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J A Richardson

  5. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    J W Shay

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Correspondence to J W Shay.

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

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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

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