Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer
Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer
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DOI：
10.1158/0008-5472.can-09-2092
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
de Jong, Frank H.
中科院分区：
文献类型：
--
作者：
Hofland, Johannes;van Weerden, Wytske M.;de Jong, Frank H.
去雄激素治疗前列腺癌(PC)最终导致去势抵抗前列腺癌(CRPC)。尽管血清雄激素浓度受到抑制，但肿瘤内雄激素的产生可能与肿瘤的进展有关。在目前的研究中，我们研究了PC或CRPC组织是否能够在肿瘤内合成雄激素。类固醇合成酶mRNAs在激素处理的人前列腺癌细胞系和异种移植中以及在正常前列腺、局部受限和晚期前列腺癌、局部非转移性前列腺癌和淋巴转移的人样本中进行了定量。总体而言，大多数样本显示从头合成类固醇所需的类固醇生成酶的mRNA表达很低或缺失。在88例患者样本中，有19例同时检测到CYP17A1和HSD3B1酶的低表达，这两种酶是从孕烯醇酮合成雄激素所必需的。在检测的19例CRPC组织中，只有5例同时表达这两种酶。雄烯二酮转化为睾酮(AKR1C3)和睾酮转化为双氢睾酮(DHT；SRD5A1)的酶得到了丰富的表达。在实验模型中，AKR1C3的表达受到雄激素的负调控，而在CRPC样本中表达增加。SRD5A1在局部晚期癌、CRPC和淋巴转移中表达上调。我们的结论是，肿瘤内类固醇生物合成的贡献小于循环肾上腺雄激素，这意味着阻断雄激素的产生及其在前列腺内向DHT的转化，例如通过抑制CYP17A1，可能是CRPC患者的有利治疗选择。癌症资源；第70(3)；1256年--。(C)2010年AACR。
Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC. Cancer Res; 70(3); 1256-64. (C) 2010 AACR.