Ishigamori Rikako, Naruse Mie, Hirata Akihiro, Maru Yoshiaki, Hippo Yoshitaka, Imai Toshio
Central Animal Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan.
Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
J Toxicol Pathol. 2022 Jul;35(3):211-223. doi: 10.1293/tox.2022-0021. Epub 2022 Apr 22.
Recently, we introduced an organoid-based chemical carcinogenesis model using mouse normal tissue-derived organoids. In the present review article, the histopathological and immunohistochemical characteristics of mouse normal tissue-derived organoids and tumors derived from these organoids after their treatment with genotoxic carcinogens and injection into nude mouse are reviewed. In organoids treated with genotoxic carcinogens, we confirmed macroscopic tumorigenicity and histopathological findings, including neoplastic characteristics, such as multilayered epithelia and/or invasion of epithelia into the surrounding interstitium. In contrast glandular/cystic structures with monolayered epithelia were clearly demarcated from the surrounding Matrigel/interstitium in the untreated control groups. In addition to macroscopic tumorigenicity, these microscopic epithelial changes, which are characteristic of the early stages of carcinogenesis, are included in the requirements for carcinogenicity-positive judgement of the organoid-based carcinogenesis model. Immunohistochemistry of cytokeratins (CKs), used to determine the origin of epithelia and distribution of extraductal invasive lesions, or oncogenic kinases, which reflect molecular activation in epithelia following chemical treatment, is helpful for accurate diagnosis and molecular evaluation in the early stages of carcinogenesis. This information improves our biological understanding of organoid-based chemical carcinogenesis models.
最近，我们引入了一种基于类器官的化学致癌模型，该模型使用小鼠正常组织来源的类器官。在本综述文章中，我们回顾了小鼠正常组织来源的类器官以及用基因毒性致癌物处理并注射到裸鼠体内后从这些类器官衍生出的肿瘤的组织病理学和免疫组化特征。在用基因毒性致癌物处理的类器官中，我们证实了宏观的肿瘤形成能力和组织病理学发现，包括肿瘤特征，如多层上皮和/或上皮向周围间质的浸润。相比之下，在未处理的对照组中，具有单层上皮的腺泡/囊性结构与周围的基质胶/间质有明显的界限。除了宏观的肿瘤形成能力外，这些微观上皮变化是致癌早期的特征，也包含在基于类器官的致癌模型致癌性阳性判断的要求中。用于确定上皮起源和导管外浸润性病变分布的细胞角蛋白（CKs）免疫组化，或反映化学处理后上皮分子激活的致癌激酶免疫组化，有助于在致癌早期进行准确诊断和分子评估。这些信息增进了我们对基于类器官的化学致癌模型的生物学理解。
