Establishment of a Novel Colitis-Associated Cancer Mouse Model Showing Flat Invasive Neoplasia

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.

Keywords: CD4-dnTGFβRII mice; Chronic inflammation; Colitis-associated cancer; Ulcerative colitis.