Division of Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Reconstructive Surgery, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan; Division of Anatomical and Cellular Pathology, Department of Pathology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan.
Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
J Oral Biosci. 2024 Dec;66(4):88-97. doi: 10.1016/j.job.2024.08.002. Epub 2024 Aug 17.
Details about salivary gland tumor histogenesis remain unknown. Here, we established a newly generated murine salivary gland tumor model that could overexpress pleomorphic adenoma gene 1 (PLAG1) and attempted to clarify the events that occur during the early phase of salivary gland tumor histogenesis.
Salivary gland tumors were generated using murine models (Sox9IRES-CreERT2; ROSA26-PLAG1). Lineage tracing of Sox9-expressing cells was performed using Sox9IRES-CreERT2; ROSA26-tdTomato mice, which were generated by crossing Sox9 and ROSA26-tdTomato mice (expressing the tdTomato fluorescent protein). Organ-cultured embryonic salivary glands from the murine model were morphologically analyzed, and mRNA sequencing was conducted two days after tumor induction for gene enrichment and functional annotation analysis.
Salivary gland tumors exhibited epithelial features with acinar-like structures because of gene rearrangements in the luminal cells. Structural disturbances in the duct-acinar unit of the salivary gland were observed and cancer-related pathways were enriched among the differentially upregulated genes in the early phase of tumor induction in an organ-cultured embryonic salivary gland tumor model.
The newly generated murine salivary gland tumor model may show that the tumorization of luminal stem/progenitor cells can result in the development of salivary gland tumors comprising only luminal cells.
唾液腺肿瘤发生的详细机制仍不清楚。本研究建立了一种新的可过表达多形性腺瘤基因 1（PLAG1）的小鼠唾液腺肿瘤模型，并试图阐明唾液腺肿瘤发生早期的相关事件。
利用 Sox9IRES-CreERT2；ROSA26-PLAG1 小鼠模型生成唾液腺肿瘤。通过 Sox9 和 ROSA26-tdTomato 小鼠（表达 tdTomato 荧光蛋白）杂交，生成 Sox9IRES-CreERT2；ROSA26-tdTomato 小鼠，对 Sox9 表达细胞进行谱系追踪。对来自该模型的胚胎唾液腺器官培养进行形态分析，并在肿瘤诱导后两天进行 mRNA 测序，进行基因富集和功能注释分析。
由于腔细胞中的基因重排，唾液腺肿瘤表现出具有腺样结构的上皮特征。在胚胎唾液腺肿瘤器官培养模型中，观察到唾液腺导管-腺泡单位的结构紊乱，并且在肿瘤诱导的早期阶段，差异上调基因中富集了与癌症相关的通路。
新建立的小鼠唾液腺肿瘤模型可能表明，腔干细胞/祖细胞的肿瘤化可导致仅由腔细胞组成的唾液腺肿瘤的发展。
