An organoid-based carcinogenesis model induced by in vitro chemical treatment
An organoid-based carcinogenesis model induced by in vitro chemical treatment
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DOI：
10.1093/carcin/bgaa011
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发表时间：
2020-10-01
期刊：
影响因子：
4.7
通讯作者：
Imai, Toshio
中科院分区：
文献类型：
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作者：
Naruse, Mie;Masui, Ryoichi;Imai, Toshio
环境化学物质诱发的动物致癌模型已被广泛应用于基础和应用癌症研究。然而，体外或体外模型的建立对于从分子机制上阐明癌症发生的早期事件，从而澄清总的作用模式是必不可少的。为了建立一种基于有机化合物的化学致癌模型，用甲基磺酸乙酯(EMS)、丙烯酰胺(AA)、二乙基亚硝胺(DEN)和7，12-二甲基苯并菲(DMBA)等4种遗传毒性化学物质体外处理小鼠有机类化合物，观察其对裸鼠的致瘤性。据报道，这四种化学物质可以在小鼠模型中诱发肺癌、肝癌或乳腺癌。DMBA处理的具有np53杂合敲除的乳腺组织衍生有机化合物显示出致瘤性，但那些带有野生型Trp53的乳腺组织没有显示出致瘤性，这反映了先前关于相应动物模型的报道。用EMS或AA处理带有或不带有Try53基因敲除的肺组织的致癌组织病理学特征，并在裸鼠皮下结节中显示出致癌蛋白的激活。DEN处理的肝脏(胆道)类有机物也有更多类似的变化。总之，使用正常小鼠组织衍生的有机化合物建立了化学致癌的体外模型。该模型将被应用于检测早期分子事件，从而澄清化学致癌的作用模式。
Animal carcinogenesis models induced by environmental chemicals have been widely used for basic and applied cancer research. However, establishment of in vitro or ex vivo models is essential for molecular mechanistic elucidation of early events in carcinogenesis, leading to clarification of the total mode of action. In the present study, to establish an organoid-based chemical carcinogenesis model, mouse organoids were treated in vitro with 4 genotoxic chemicals, e.g. ethyl methanesulfonate (EMS), acrylamide (AA), diethylnitrosamine (DEN) and 7,12-dimethylbenzIalanthracene (DMBA) to examine their tumorigenicity after injection to nude mice. The four chemicals were reported to induce lung, liver or mammary carcinomas in mouse models. DMBA-treated mammary tissue-derived organoids with np53 heterozygous knockout exhibited tumorigenicity, but not those with wild-type Trp53, reflecting previous reports of corresponding animal models. Treatment of lung organoids with or without Try53 knockout with EMS or AA resulted in carcinogenic histopathological characteristics, and the activation of oncogenic kinases was demonstrated in the nodules from the nude mouse subcutis. DEN-treated liver (binary tract) organoids also had an increased number of similar changes. In conclusion, an ex vivo model for chemical carcinogenesis was established using normal mouse tissue-derived organoids. This model will be applied to detect early molecular events, leading to clarification of the mode of action of chemical carcinogenesis.