A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential.
A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential.
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发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
N. Masumori;T. Thomas;P. Chaurand;T. Case;M. Paul;S. Kasper;R. Caprioli;T. Tsukamoto;S. Shappell;R. Matusik
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作者：
N. Masumori;T. Thomas;P. Chaurand;T. Case;M. Paul;S. Kasper;R. Caprioli;T. Tsukamoto;S. Shappell;R. Matusik
神经内分泌（NE）细胞不仅参与正常前列腺的生长和分化，而且参与前列腺癌（Pca）的发生和发展，包括雄激素抵抗的发展。然而，确切的病理生理NE细胞在Pca仍然知之甚少。在这里，我们描述了一个Pca的转基因模型进行性NE分化。已经建立了七种转基因小鼠品系，其具有与发展前列腺肿瘤的SV 40-大T抗原（Tag）连接的大鼠前列腺特异性大probasin启动子。在本研究中，通过对52只2-12月龄小鼠进行检查，对7个品系之一（12 T-10）进行了表征。随着年龄的增长，前列腺中依次出现低级别前列腺上皮内瘤变、高级别前列腺上皮内瘤变、微浸润、浸润性癌、低分化或未分化癌伴NE分化。而标签是均匀地表达在前列腺上皮细胞，只有一个增加的前列腺上皮内瘤变的细胞亚群显示NE分化嗜铬粒蛋白免疫染色。随后发展的明显浸润性癌偶尔表现出明确的腺分化（腺癌），特别是未分化癌，其NE组织学特征与人类NE癌中观察到的相似。NE癌发生在背外侧叶和腹侧叶，通常雄激素受体阴性。如通过组织学和/或Tag免疫组织化学所证实的，32只（66%）年龄>或= 6个月的小鼠中的21只和17只（88%）年龄>或= 9个月的小鼠中的15只发展了转移性肿瘤。转移发生在较晚的时间点，转移到区域淋巴结、肝脏和肺特别常见。嗜铬粒蛋白免疫染色和电子显微镜证实，转移瘤表现出NE分化的组织学特征。接受皮下注射的无胸腺裸鼠。原发性NE肿瘤植入物发展为具有相似NE分化的Tag阳性转移性肿瘤。基质辅助激光解吸电离飞行时间质谱鉴定出原发性NE肿瘤和前列腺外器官病变之间相同的蛋白质谱。因此，在12 T-10大probasin启动子-Tag小鼠中，高级别前列腺上皮内瘤形成逐渐发展为更大的NE分化，并进展为浸润性腺癌和NE癌，具有高转移百分比。通过这些阶段的可预测的进展将允许测试治疗干预以及可能进一步描绘NE细胞在Pca进展中的作用。
Neuroendocrine (NE) cells may be involved not only in growth and differentiation of the normal prostate but also in carcinogenesis and progression of prostate adenocarcinoma (Pca), including development of androgen resistance. However, the exact pathophysiology of NE cells in Pca remains poorly understood. Here we describe a transgenic model of Pca with progressive NE differentiation. Seven lines of transgenic mice with the rat prostate-specific large probasin promoter linked to the SV40-large T antigen (Tag) that develop prostatic neoplasia have been established. In this study, one of the seven lines (12T-10) was characterized by examination of 52 mice aged from 2-12 months. With advancing age, low-grade prostatic intraepithelial neoplasia, high-grade prostatic intraepithelial neoplasia, microinvasion, invasive carcinoma, and poorly or undifferentiated carcinoma with NE differentiation appeared in the prostates in sequential order. Whereas Tag is expressed uniformly in prostate epithelium, only an increasing subset of cells in prostatic intraepithelial neoplasia showed NE differentiation by chromogranin immunostaining. Frankly invasive carcinoma developing subsequently showed occasional definitive glandular differentiation (adenocarcinoma) and particularly undifferentiated carcinoma with NE histological features similar to those observed in NE carcinomas in humans. The NE carcinomas occurred in the dorsolateral and ventral lobes and were generally androgen receptor negative. Twenty-one of 32 (66%) mice aged > or = 6 months and 15 of 17 (88%) mice aged > or = 9 months developed metastatic tumors, as confirmed by histology and/or Tag immunohistochemistry. Metastases occurred at the later time points, with metastasis to regional lymph nodes, liver, and lung being particularly common. Metastases showed histological features of NE differentiation, as confirmed by chromogranin immunostaining and electron microscopy. An athymic nude mouse that received a s.c. implant of a primary NE tumor developed Tag-positive metastatic tumors with similar NE differentiation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified identical protein profiles between the primary NE tumor and lesions in the extraprostatic organs. Hence, in the 12T-10 large probasin promoter-Tag mouse, high-grade prostatic intraepithelial neoplasia develops progressively greater NE differentiation and progresses to invasive adenocarcinoma and NE carcinoma, with a high percentage of metastases. The predictable progression through these stages will allow testing of therapeutic interventions as well as possible further delineation of the role of NE cells in Pca progression.