Levine A C, Liu X H, Greenberg P D, Eliashvili M, Schiff J D, Aaronson S A, Holland J F, Kirschenbaum A
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Endocrinology. 1998 Nov;139(11):4672-8. doi: 10.1210/endo.139.11.6303.
Androgens are known to directly stimulate prostate cancer cell growth. We have previously reported that LNCaP prostate cancer cells were dependent upon stromal coinoculation for growth in nude mice and that the stromal cells secreted a potent angiogenic factor, vascular endothelial growth factor (VEGF), which stimulated tumor angiogenesis. Immunohistochemical staining localized VEGF expression primarily to the stromal cells of human fetal and adult hyperplastic prostates, with both stromal and epithelial cell VEGF expression in prostate cancer. In the present studies, we test the hypothesis that androgens, in addition to their direct effects on prostate epithelial cells, have indirect effects on these cells via up-regulation of stromal VEGF production and angiogenesis. Primary cultures of human prostate fetal fibroblasts were treated with dihydrotestosterone (DHT), and the effects on VEGF messenger RNA (mRNA) expression were determined by Northern blotting. DHT (10 nM) increased VEGF mRNA levels maximally after 2 h. Nuclear run-on transcription assays demonstrated a 2-fold increase in the VEGF transcription rate 2 h after the addition of DHT. VEGF mRNA stability was unaffected by DHT addition. VEGF protein levels were determined by enzyme-linked immunosorbent assay and were increased 2-fold 4 h after DHT addition. These data indicate that androgens increase VEGF transcription and secretion of biologically active VEGF from human prostatic stroma. Androgens, therefore, may indirectly enhance prostate growth via up-regulation of VEGF from the surrounding stroma.
已知雄激素可直接刺激前列腺癌细胞生长。我们之前报道过，LNCaP前列腺癌细胞在裸鼠体内生长依赖于与基质细胞共接种，且基质细胞分泌一种强效血管生成因子——血管内皮生长因子（VEGF），它可刺激肿瘤血管生成。免疫组化染色显示，VEGF表达主要定位于人胎儿及成人增生前列腺的基质细胞，在前列腺癌中基质细胞和上皮细胞均有VEGF表达。在本研究中，我们检验了这样一个假设：雄激素除了对前列腺上皮细胞有直接作用外，还通过上调基质VEGF生成和血管生成对这些细胞产生间接作用。用人前列腺胎儿成纤维细胞进行原代培养，用二氢睾酮（DHT）处理，通过Northern印迹法测定对VEGF信使核糖核酸（mRNA）表达的影响。DHT（10 nM）在2小时后最大程度地增加了VEGF mRNA水平。核转录分析表明，添加DHT 2小时后VEGF转录率增加了2倍。添加DHT不影响VEGF mRNA稳定性。通过酶联免疫吸附测定法测定VEGF蛋白水平，添加DHT 4小时后其增加了2倍。这些数据表明，雄激素增加人前列腺基质中VEGF转录及生物活性VEGF的分泌。因此，雄激素可能通过上调周围基质中的VEGF间接促进前列腺生长。
