Inflammation Enhanced X-irradiation-Induced Colonic Tumorigenesis in the Min mouse

  • Nojiri, Ayumi (Division of Oncological Pathology, Aichi Cancer Center Research Institute) ;
  • Toyoda, Takeshi (Division of Oncological Pathology, Aichi Cancer Center Research Institute) ;
  • Tanaka, Takuji (The Tohkai Cytopathology Institute, Cancer Research and Prevention) ;
  • Yoshida, Toshimichi (Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine) ;
  • Tatematsu, Masae (Division of Oncological Pathology, Aichi Cancer Center Research Institute) ;
  • Tsukamoto, Tetsuya (Division of Oncological Pathology, Aichi Cancer Center Research Institute)
  • Published : 2013.07.30


Inflammation is potential risk factor of various human malignancies. Inflammatory bowel syndromes such as ulcerative colitis are well known as risk factors for colon cancer. Here, we examined enhancing effects of dextran sulfate sodium (DSS)-associated inflammation on X-irradiation induced colonic tumorigenesis in Min and wild-type (WT) mice. Animals were X-irradiated at 1.5 Gy at 5 weeks of age (at 0 experimental week) and 2% DSS in drinking water was administered at 5 or 11 experimental weeks. Mice were sacrificed at 16 weeks and incidence and multiplicity of colonic tumors were assessed. Incidence of colonic tumors in Min mouse was increased from 33.3% to 100% (p<0.05) with X-irradiation alone, whereas no tumors were developed in WT mice. In DSS-treated Min mice, X-irradiation increased the number of colonic tumors. Total number of colonic tumors was increased 1.57 times to $30.7{\pm}3.83$ tumors/mouse with X-irradiation+DSS at 5 weeks comapared to $19.6{\pm}2.9$ in corresponding DSS alone group (p<0.05). When the duration of inflammation was compared, longer period of DSS effect promoted more colonic tumorigenesis. Collectively, we conclude that X-irradiation and DSS-induced inflammation act synergistically for colonic tumorigenesis.


Min mouse;X-irradiation;DSS;colon


  1. Balkwill F, Mantovani A (2001). Inflammation and cancer: back to Virchow? Lancet, 357, 539-45.
  2. Bolla M, Verry C, Long JA (2013). High-risk prostate cancer: combination of high-dose, high-precision radiotherapy and androgen deprivation therapy. Curr Opin Urol, 23, 349-54.
  3. Brown AP, Neeley ES, Werner T, et al (2010). A population-based study of subsequent primary malignancies after endometrial cancer: genetic, environmental, and treatment-related associations. Int J Radiat Oncol Biol Phys, 78, 127-35.
  4. Chang ML, Hou JK (2011). Cancer risk related to gastrointestinal diagnostic radiation exposure. Curr Gastroenterol Rep, 13, 449-57.
  5. Choi KH, Ha M, Lee WJ, et al (2013). Cancer risk in diagnostic radiation workers in Korea from 1996-2002. Int J Environ Res Public Health, 10, 314-27.
  6. Kinzler KW, Vogelstein B (1996). Lessons from hereditary colorectal cancer. Cell, 87, 159-70.
  7. Kohno H, Suzuki R, Sugie S, et al (2005). Beta-Catenin mutations in a mouse model of inflammation-related colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sodium sulfate. Cancer Sci, 96, 69-76.
  8. Luongo C, Dove WF (1996). Somatic genetic events linked to the Apc locus in intestinal adenomas of the Min mouse. Genes Chromosomes Cancer, 17, 194-8.<194::AID-GCC2870170302>3.0.CO;2-E
  9. Moser AR, Pitot HC, Dove WF (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science, 247, 322-4.
  10. Munkholm P (2003). Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther, 18, 1-5.
  11. Nottage K, McFarlane J, Krasin MJ, et al (2012). Secondary colorectal carcinoma after childhood cancer. J Clin Oncol, 30, 2552-8.
  12. Ohshima H, Tatemichi M, Sawa T (2003). Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys, 417, 3-11.
  13. Okamoto M, Yonekawa H (2005). Intestinal tumorigenesis in Min mice is enhanced by X-irradiation in an age-dependent manner. J Radiat Res, 46, 83-91.
  14. Okayasu I, Hatakeyama S, Yamada M, et al (1990). A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology, 98, 694-702.
  15. Ozasa K, Shimizu Y, Suyama A, et al (2012). Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases. Radiat Res, 177, 229-43.
  16. Paulsen JE, Steffensen IL, Namork E, et al (2003). Age-dependent susceptibility to azoxymethane-induced and spontaneous tumorigenesis in the Min/+ mouse. Anticancer Res, 23, 259-65.
  17. Powell SM, Petersen GM, Krush AJ, et al (1993). Molecular diagnosis of familial adenomatous polyposis. N Engl J Med, 329, 1982-7.
  18. Rydberg B (1996) Clusters of DNA damage induced by ionizing radiation: formation of short DNA fragments. II. Experimental detection. Radiat Res, 145, 200-9.
  19. Samartzis D, Nishi N, Cologne J, et al (2013). Ionizing radiation exposure and the development of soft-tissue sarcomas in atomic-bomb survivors. J Bone Joint Surg Am, 95, 222-9.
  20. Shoemaker AR, Moser AR, Dove WF (1995) N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts, and epidermoid cysts. Cancer Res, 55, 4479-85.
  21. Steffensen IL, Paulsen JE, Eide TJ, et al (1997). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine increases the numbers of tumors, cystic crypts and aberrant crypt foci in multiple intestinal neoplasia mice. Carcinogenesis, 18, 1049-54.
  22. Su LK, Kinzler KW, Vogelstein B, et al (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science, 256, 668-70.
  23. Tamai O, Nozato E, Miyazato H, et al (1999). Radiation-associated rectal cancer: report of four cases. Dig Surg, 16, 238-43.
  24. Tanaka T, Kohno H, Suzuki R, et al (2006). Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer, 118, 25-34.
  25. Tanaka T, Kohno H, Suzuki R, et al (2003). A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci, 94, 965-73.
  26. Tanaka T, Suzuki R, Kohno H, et al (2005). Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess beta-catenin gene mutations and increases immunoreactivity for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase. Carcinogenesis, 26, 229-38.

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