Low Testosterone Alters the Activity of Mouse Prostate Stem Cells.
Low Testosterone Alters the Activity of Mouse Prostate Stem Cells.
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DOI：
10.1002/pros.23290
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发表时间：
2017-04
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低血清睾酮（低T）已被反复与新诊断的前列腺癌（PC）男性的不良结局有关。低T对这些结果的影响尚不清楚。在这里，我们证明，暴露于低T导致小鼠前列腺和前列腺干细胞的显着变化。小鼠被阉割并植入胶囊以达到阉割、正常或亚生理水平的T。治疗6周后，LC-MS/MS用于定量血清和前列腺组织中T和双氢睾酮（DHT）的水平。流式细胞术用于定量小鼠前列腺中声称的前列腺干细胞和转运扩增（TA）细胞的百分比。还对前列腺组织进行染色以确定是否存在CD68+细胞，并从前列腺组织或特定细胞群中提取RNA以测量低T处理下转录物水平的变化。尽管血清中T和DHT的水平显著不同，但来自不同T处理组的前列腺组织中的T和DHT浓度相似。低T处理导致雄激素生物合成基因表达的显著改变，这可能与维持前列腺雄激素水平有关。此外，雄激素调节基因在前列腺中的表达在所有T治疗组中是相似的，这表明尽管血清T水平较低，小鼠前列腺仍能维持雄激素的功能水平。低T增加了成年前列腺组织中前列腺干细胞和TA细胞的频率，并导致这些细胞中的主要转录变化。基因本体分析表明，低T引起的炎症反应和免疫荧光染色表明，低T治疗导致前列腺组织中的CD68+巨噬细胞的存在增加。低T改变AR信号传导轴，这可能导致前列腺雄激素的功能水平的维持。低T还诱导前列腺干细胞的定量和定性变化，这似乎导致炎性巨噬细胞浸润。这些变化被认为是一旦癌症发展就导致侵袭性表型，并可能导致低T男性的不良结局。前列腺77：530 - 541，2017年。
Low serum testosterone (low T) has been repeatedly linked to worse outcomes in men with newly diagnosed prostate cancer (PC). How low T contributes to these outcomes is unknown. Here we demonstrate that exposure to low T causes significant changes in the mouse prostate and prostate stem cells. Mice were castrated and implanted with capsules to achieve castrate, normal, or sub-physiological levels of T. After 6 weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. FACS was used to quantify the percentages of purported prostate stem and transit amplifying (TA) cells in mouse prostates. Prostate tissues were also stained for the presence of CD68+ cells and RNA was extracted from prostate tissue or specific cell populations to measure changes in transcript levels with low T treatment. Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were similar. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining prostate androgen levels. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the mouse prostate can maintain functional levels of androgens despite low serum T levels. Low T increased the frequency of prostate stem and TA cells in adult prostate tissue and caused major transcriptional changes in those cells. Gene ontology analysis suggested that low T caused inflammatory responses and immunofluorescent staining indicated that low T treatment led to the increased presence of CD68+ macrophages in prostate tissue. Low T alters the AR signaling axis which likely leads to maintenance of functional levels of prostate androgens. Low T also induces quantitative and qualitative changes in prostate stem cells which appear to lead to inflammatory macrophage infiltration. These changes are proposed to lead to an aggressive phenotype once cancers develop and may contribute to the poor outcomes in men with low T. Prostate 77: 530–541, 2017.