Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth
Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth
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DOI：
10.1158/0008-5472.can-08-0249
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Nelson, Peter S.
中科院分区：
文献类型：
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作者：
Montgomery, R. Bruce;Mostaghel, Elahe A.;Nelson, Peter S.
晚期前列腺癌的治疗集中在抑制全身雄激素和阻断雄激素受体（AR）的激活。尽管血清雄激素水平正常，但几乎所有的患者都发生去势抵抗性疾病。我们假设前列腺肿瘤内持续的类固醇生成和瘤内雄激素的维持可能有助于去势抵抗性生长。使用质谱和定量逆转录-PCR，我们评估了雄激素水平和编码类固醇生成酶的转录本在良性前列腺组织，未经治疗的原发性前列腺癌，去势抵抗性前列腺癌患者的转移瘤，以及来自去势抵抗性转移瘤的异种移植瘤。来自无前列腺男性的转移瘤中的睾酮水平[0.74 ng/g; 95%置信区间（95% CI），0.59-0.89]显著高于来自未经治疗的性腺正常男性的原发性前列腺癌中的水平（0.23 ng/g; 95% CI，0.03-0.44; P < 0.0001）。与原发性前列腺肿瘤相比，去势抵抗性转移瘤显示编码类固醇生成酶的基因发生改变，包括FXR、CYP 17 A1、HSD 3B 1、HSD 17 B3、CYP 19 A1和UGT 2B 17的表达上调，SRD 5A 2的表达下调（均P < 0.001）。与性腺正常的动物相比，来自去势抵抗肿瘤的前列腺癌异种移植物在去势中传代时保持相似的瘤内雄激素水平。来自anorchid男性的转移性前列腺癌表达编码雄激素合成酶的转录本，并将瘤内雄激素维持在能够激活AR靶基因和维持肿瘤细胞存活的浓度。我们的结论是，分泌类固醇激素可能允许肿瘤绕过低水平的循环雄激素。在去势抵抗性前列腺癌的治疗中的最大治疗功效将需要能够抑制前列腺肿瘤微环境内的分泌内类固醇生成途径的新型药剂。
Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% Cl, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.