Abstract
Background
Chronic inflammation, such as ulcerative colitis, increases the risk of developing colitis-associated cancers. Currently, mice administered with azoxymethane/dextran sodium sulfate are well-known models for colitis-associated cancers. Although human colitis-associated cancers are often flat lesions, most azoxymethane/dextran sodium sulfate mouse cancers are raised lesions.
Aims
To establish a novel mouse model for colitis-associated cancers and evaluate its characteristics.
Methods
A single dose of azoxymethane was intraperitoneally administered to CD4-dnTGFβRII mice, which are genetically modified mice that spontaneously develop inflammatory bowel disease at different doses and timings. The morphological and biological characteristics of cancers was assessed in these mice.
Results
Colorectal cancer developed with different proportions in each group. In particular, a high rate of cancer was observed at 10 and 20 weeks after administration in 12-week-old CD4-dnTGFβRII mice dosed at 15 mg/kg. Immunohistochemical staining of tumors was positive for β-catenin, ki67, and Sox9 but not for p53. Grade of inflammation was significantly higher in mice with cancer than in those without cancer (p < 0.001). In CD4-dnTGFβRII/azoxymethane mice, adenocarcinomas with flat lesions were observed, with moderate-to-severe inflammation in the non-tumor area. In comparison, non-tumor areas of azoxymethane/dextran sodium sulfate mice had less inflammation than those of CD4-dnTGFβRII/azoxymethane mice, and most macroscopic characteristics of tumors were pedunculated or sessile lesions in azoxymethane/dextran sodium sulfate mice.
Conclusions
Although feasibility and reproducibility of azoxymethane/CD4-dbTGFβRII appear to be disadvantages compared to the azoxymethane/dextran sodium sulfate model, this is the first report to demonstrate that the chronic inflammatory colitis model, CD4-dnTGFβRII also develops colitis-related colorectal cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest 2007;117:514–521.
Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571–607.
Van Assche G, Dignass A, Bokemeyer B et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis 2013;7:1–33.
Majumder S, Shivaji UN, Kasturi R et al. Inflammatory bowel disease-related colorectal cancer: past, present and future perspectives. World J Gastrointest Oncol 2022;14:547–567.
Mutaguchi M, Naganuma M, Sugimoto S et al. Difference in the clinical characteristic and prognosis of colitis-associated cancer and sporadic neoplasia in ulcerative colitis patients. Dig Liver Dis 2019;51:1257–1264.
Gillespie PE, Chambers TJ, Chan KW et al. Colonic adenomas–a colonoscopy survey. Gut 1979;20:240–245.
Heimann TM, Oh SC, Martinelli G et al. Colorectal carcinoma associated with ulcerative colitis: a study of prognostic indicators. Am J Surg 1992;164:13–17.
Tanaka T, Kohno H, Suzuki R et al. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 2003;94:965–973.
Parang B, Barrett CW, Williams CS. AOM/DSS model of colitis-associated cancer. Methods Mol Biol 2016;1422:297–307.
Odze RD. Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical, pathological, and molecular review. Am J Gastroenterol 1999;94:1746–1750.
Laine L, Kaltenbach T, Barkun A et al. SCENIC international consensus statement on surveillance and management of dysplasia in inflammatory bowel disease. Gastrointest Endosc 2015;81:489-501.e426.
Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000;12:171–181.
De Robertis M, Massi E, Poeta ML et al. The AOM/DSS murine model for the study of colon carcinogenesis: from pathways to diagnosis and therapy studies. J Carcinog 2011;10:9.
Miller JR, Moon RT. Signal transduction through beta-catenin and specification of cell fate during embryogenesis. Genes Dev 1996;10:2527–2539.
Brabletz T, Jung A, Kirchner T. Beta-catenin and the morphogenesis of colorectal cancer. Virchows Arch 2002;441:1–11.
Fujita M, Matsubara N, Matsuda I et al. Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling. Oncotarget 2018;9:969–981.
Weidner N, Moore DH 2nd, Vartanian R. Correlation of Ki-67 antigen expression with mitotic figure index and tumor grade in breast carcinomas using the novel “paraffin”-reactive MIB1 antibody. Hum Pathol 1994;25:337–342.
Furuyama K, Kawaguchi Y, Akiyama H et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011;43:34–41.
Ramalingam S, Daughtridge GW, Johnston MJ et al. Distinct levels of Sox9 expression mark colon epithelial stem cells that form colonoids in culture. Am J Physiol Gastrointest Liver Physiol 2012;302:G10-20.
Matheu A, Collado M, Wise C et al. Oncogenicity of the developmental transcription factor Sox9. Cancer Res 2012;72:1301–1315.
Sohn OS, Fiala ES, Requeijo SP et al. Differential effects of CYP2E1 status on the metabolic activation of the colon carcinogens azoxymethane and methylazoxymethanol. Cancer Res 2001;61:8435–8440.
Sugimoto S, Naganuma M, Iwao Y et al. Endoscopic morphologic features of ulcerative colitis-associated dysplasia classified according to the SCENIC consensus statement. Gastrointest Endosc 2017;85:639-646.e632.
Murthy SK, Feuerstein JD, Nguyen GC et al. AGA clinical practice update on endoscopic surveillance and management of colorectal dysplasia in inflammatory bowel diseases: expert review. Gastroenterology 2021;161:1043–1051.
Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis. Gut. 1994;35:950–954. https://doi.org/10.1136/gut.35.7.950.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
Funding
TU received a research grant D2 from Kansai Medical University.
Author information
Authors and Affiliations
Contributions
TU, YA, and KO: conceived the study. TU, YA, and MN: participated in the study design; TU, YA, MA, TF, YT, YM, SH, and HT: experienced for this study. Pathological analysis was performed by KT and HT. Statistical analysis was done by TU. TU and MN: drafted the first version of the manuscript. All authors were involved in the writing process, and read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
There are no competing interests for this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Uragami, T., Ando, Y., Aoi, M. et al. Establishment of a Novel Colitis-Associated Cancer Mouse Model Showing Flat Invasive Neoplasia. Dig Dis Sci 68, 1885–1893 (2023). https://doi.org/10.1007/s10620-022-07774-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-022-07774-4