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肿瘤内雄激素水平与前列腺癌中的 TMPRSS2-ERG 融合有关。

Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer.

机构信息

Research Centre for Integrative Physiology and PharmacologyInstitute of Biomedicine, University of Turku, Turku, Finland.

Turku Center for Disease Modeling (TCDM)Institute of Biomedicine, University of Turku, Turku, Finland.

出版信息

Endocr Relat Cancer. 2018 Sep;25(9):807-819. doi: 10.1530/ERC-18-0148. Epub 2018 May 17.

Abstract

Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate ( < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG-negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and -negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.

摘要

肿瘤内雄激素生物合成是前列腺癌进展的机制之一,也是新型前列腺癌治疗的重要靶点。我们使用气相色谱-串联质谱和全基因组 RNA 测序,分析了 48 名原发性前列腺癌患者的癌组织和形态良性前列腺组织标本以及血清样本中的雄激素浓度和雄激素调节基因表达。与良性前列腺组织相比,癌组织中的肿瘤内二氢睾酮(DHT)浓度显著升高(<0.001)。患者之间的组织/血清雄激素比值差异很大,表明存在个体雄激素代谢和/或雄激素在前列腺组织内摄取的模式。对组织内雄激素浓度进行无监督层次聚类分析表明,跨膜丝氨酸蛋白酶 2/ETS 相关基因(TMPRSS2-ERG)阳性患者与 TMPRSS2-ERG 阴性患者的雄激素谱不同。TMPRSS2-ERG 基因融合状态也与增强的雄激素调节基因表达相关,同时伴有肿瘤内雄激素代谢改变,表现为 TMPRSS2-ERG 阳性肿瘤中的睾酮浓度降低和 DHT/睾酮比值升高。TMPRSS2-ERG 阳性和阴性前列腺癌标本具有不同的肿瘤内雄激素谱,这可能是由于 TMPRSS2-ERG 阳性肿瘤中通过替代途径激活了与睾酮无关的 DHT 生物合成。因此,TMPRSS2-ERG 阳性前列腺癌患者可能受益于新型靶向替代 DHT 生物合成的抑制剂。

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