Establishment of a Novel Colitis-Associated Cancer Mouse Model Showing Flat Invasive Neoplasia
Establishment of a Novel Colitis-Associated Cancer Mouse Model Showing Flat Invasive Neoplasia
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建立显示扁平侵袭性肿瘤的新型结肠炎相关癌症小鼠模型
DOI：
10.1007/s10620-022-07774-4
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发表时间：
2022
影响因子：
3.1
通讯作者：
Naganuma Makoto
中科院分区：
文献类型：
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作者：
Uragami Tomio;Ando Yugo;Aoi Mamiko;Fukui Toshiro;Matsumoto Yasushi;Horitani Shunsuke;Tomiyama Takashi;Okazaki Kazuichi;Tsuneyama Koichi;Tanaka Hajime;Naganuma Makoto
背景慢性炎症，如溃疡性结肠炎，增加了结肠炎相关癌症的发病风险。目前，给予氧化偶氮甲烷/葡聚糖硫酸钠的小鼠是结肠炎相关癌症的公知模型。虽然人类结肠炎相关的癌症往往是平坦的病变，大多数氧化偶氮甲烷/葡聚糖硫酸钠小鼠的癌症是凸起的lesions.AimsTo建立一种新的结肠炎相关的癌症小鼠模型，并评估其characteristics.MethodsA单剂量的氧化偶氮甲烷腹腔注射给CD 4-dnTGFβRII小鼠，这是遗传修饰的小鼠，自发发展炎症性肠病，在不同的剂量和时间。癌症的形态学和生物学特性进行了评估，在这些小鼠。ResultsColorectal cancer developed with different proportions in each group.特别是，在以15 mg/kg剂量给药的12周龄CD 4-dnTGFβRII小鼠中，在给药后10周和20周观察到较高的癌症发生率。肿瘤的免疫组织化学染色为β-catenin、ki 67和Sox 9阳性，但不为p53阳性。患癌小鼠的炎症分级显著高于未患癌小鼠（p< 0.001）。在CD 4-dnTGFβRII/氧化偶氮甲烷小鼠中，观察到具有扁平病变的腺癌，在非肿瘤区域中具有中度至重度炎症。相比之下，氧化偶氮甲烷/葡聚糖硫酸钠小鼠的非肿瘤区域的炎症比CD 4-dnTGFβRII/氧化偶氮甲烷小鼠的炎症少，并且氧化偶氮甲烷/葡聚糖硫酸钠小鼠的肿瘤的大多数宏观特征是有蒂或无蒂病变。这是第一个证明慢性炎症性结肠炎模型，CD 4-dnTGFβRII也发展结肠炎相关的结肠直肠癌的报告。
BackgroundChronic 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.AimsTo establish a novel mouse model for colitis-associated cancers and evaluate its characteristics.MethodsA 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.ResultsColorectal 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.ConclusionsAlthough 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.