Steroid hormones stimulate human prostate cancer progression and metastasis
Steroid hormones stimulate human prostate cancer progression and metastasis
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DOI：
10.1002/ijc.21614
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发表时间：
2006-05-01
影响因子：
6.4
通讯作者：
Cunha, GR
中科院分区：
文献类型：
--
作者：
Ricke, WA;Ishii, K;Cunha, GR
由小鼠泌尿生殖间充质（mUGM）和永生化的非致瘤性人前列腺上皮细胞系（BPH-1）组成的组织重组体（TR）在不同激素条件下生长于雄性无胸腺裸鼠的肾包膜下。目的是确定引起体内非致瘤性人前列腺上皮细胞进展的睾酮（T）和雌二醇-17 β（E-2）的时间血浆浓度。第二，确定[T+E-2]治疗的宿主中mUGM+BPH-1 TR是否会进展为转移。对照小鼠宿主未接受外源性激素支持，而治疗小鼠接受含有T和E-2的Silastic植入物1-4个月。在第1个月时，经直肠给药小鼠的血浆中含有显著更高（p < 0.01）的T浓度（11.7对0.9 ng/ml）。植入类固醇的小鼠中E-2的血浆水平在2个月（104.5对25.6 ng/l）和4个月（122.8对19.2 pg/ml）时显著更高（p < 0.05）。来自[T + E-2]植入小鼠的mUGM+BPH-1 TR的湿重显著大于（p < 0.001）来自未处理宿主的湿重。未经处理的mUGM+BPH-1 TR含有组织良好的分化上皮，周围有平滑肌基质，与发育中的前列腺相似。在[T+E-2]植入小鼠中，mUGM+BPH-1 TR形成癌，其中含有渗透肿瘤的纤维结缔组织基质;平滑肌（当存在时）与血管系统相关。从[T+E-2]处理的小鼠而非未处理的小鼠收集的肾淋巴结含有转移性癌细胞。此外，可在包括肺和肝在内的远处部位观察到转移。从未经处理的mUGM+BPH-1 TR中分离的上皮细胞显示出良性组织学，并在随后移植到无胸腺裸鼠中时形成小的非致瘤性移植物。相比之下，从[T+E-2]治疗宿主的mUGM+BPH-1肿瘤中分离的上皮细胞形成了不依赖于基质和激素支持生长的大肿瘤，并发生了淋巴结转移。我们得出结论，[T+E-2]-治疗促进mUGM + BPH-1 TR中的前列腺癌进展。在该系统中使用mUGM将允许未来的研究利用小鼠遗传学的力量来识别参与人类前列腺癌发生的旁分泌因子。(c)2005年Wiley-Liss，Mc.
Tissue recombinants (TRs) composed of mouse urogenital mesenchyme (mUGM) plus an immortalized nontumorigenic human prostatic epithelial cell line (BPH-1) were grown under the kidney capsule of male athymic nude mice under different hormonal conditions. The objectives were to determine temporal plasma concentrations of testosterone (T) and estradiol-17 beta (E-2) that elicit progression of nontumorigenic human prostatic epithelial cells in vivo. Second, to determine whether mUGM+BPH-1 TRs in [T+E-2]-treated hosts could progress to metastases. Control mouse hosts received no exogenous hormonal support, whereas treated mice received Silastic implants containing T and E-2 for 1-4 months. Plasma from hormonally treated mice contained significantly higher (p < 0.01) concentrations of T at 1 month (11.7 vs. 0.9 ng/ml). Plasma levels of E-2 in steroid implanted mice were significantly higher (p < 0.05) at 2 months (104.5 vs. 25.6 ng/l) and 4 months (122.8 vs. 19.2 pg/ml). Wet weights of mUGM+BPH-1 TRs from [T + E-2]-implanted mice were significantly larger (p < 0.001) than those from untreated hosts. Untreated mUGM+BPH-1 TRs contained a well organized differentiated epithelium surrounded by smooth muscle stroma similar to developing prostate. In [T+E-2]-implanted mice, mUGM+BPH-1 TRs formed carcinomas that contained a fibrous connective tissue stroma permeating the tumor; smooth muscle when present was associated with vasculature. Renal lymph nodes collected from [T+E-2]-treated mice, but not untreated mice, contained metastatic carcinoma cells. Moreover, metastases could be observed at distant sites including lung and liver. Epithelial cells isolated from untreated mUGM+BPH-1 TRs exhibited benign histology and formed small nontumorigenic grafts when subsequently transplanted into athymic nude mice. In contrast, epithelial cells isolated from mUGM+BPH-1 tumors of [T+E-2]-treated hosts formed large tumors that grew independent of stromal and hormonal support and developed lymph node metastases. We conclude that [T+E-2]-treatment promotes prostatic cancer progression in mUGM + BPH-1 TRs. Use of mUGM in this system will allow future studies to utilize the power of mouse genetics to identify paracrine factors involved in human prostatic carcinogenesis. (c) 2005 Wiley-Liss, Mc.