Origin of androgen-insensitive poorly differentiated tumors in the Transgenic adenocarcinoma of mouse prostate model
Origin of androgen-insensitive poorly differentiated tumors in the Transgenic adenocarcinoma of mouse prostate model
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DOI：
10.1593/neo.07562
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发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Smith, Gary J.
中科院分区：
文献类型：
--
作者：
Huss, Wendy J.;Grayy, Danny R.;Smith, Gary J.
去势后，转基因小鼠前列腺腺癌（TRAMP）模型显示sv40标签驱动的表达神经内分泌细胞标记物的低分化肿瘤快速发展。通过分析5-溴脱氧尿苷（BrdUrd）的掺入以及SV40-Tag、synaptophysin和雄激素受体（AR）的表达，研究去势小鼠前列腺内的细胞群体动态。去势14天后，剩余的上皮细胞和腺癌细胞无增殖，缺乏可检测到的SV40-Tag或synaptophysin表达。相反，在形态学上不同的腺体内灶被发现表达SV40-Tag、synaptophysin和Ki67，但缺乏AR表达。这些增生的SV40-Tag和表达突触素的腺体内灶与罕见的brdurd保留细胞有关。这些灶在去势后前列腺环境中迅速扩大，而表达AR-和SV40-Tag的腺癌细胞在去势后失去SV40-Tag表达并发生凋亡。在完整的TRAMP小鼠的前列腺中，也以相似的频率观察到表达突触素的细胞的腺体内灶；然而，直到小鼠生命的后期，它们才发展成快速扩张的肿瘤。这表明，表达SV40-Tag和synaptophysin但缺乏AR的神经内分泌样细胞的灶不依赖于雄激素剥夺而产生，并且代表了低分化肿瘤的来源，而低分化肿瘤是TRAMP模型中的致死表型。
Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP) model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd) and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR). Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.