肿瘤内高浓度双氢睾酮与去势小鼠中VCaP前列腺癌异种移植瘤的抗雄激素耐药相关。
High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice.
作者信息
Huhtaniemi Riikka, Sipilä Petra, Junnila Arttu, Oksala Riikka, Knuuttila Matias, Mehmood Arfa, Aho Eija, Laajala Teemu D, Aittokallio Tero, Laiho Asta, Elo Laura, Ohlsson Claes, Thulin Malin Hagberg, Kallio Pekka, Mäkelä Sari, Mustonen Mika V J, Poutanen Matti
机构信息
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
Orion Corporation, Orion Pharma, Turku, Finland.
出版信息
iScience. 2022 Apr 25;25(5):104287. doi: 10.1016/j.isci.2022.104287. eCollection 2022 May 20.
Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
抗雄激素治疗耐药是去势抵抗性前列腺癌（CRPC）治疗中的一个主要临床问题。我们利用VCaP细胞异种移植模型表明，抗雄激素耐药的CRPC肿瘤生长的特征是肿瘤内二氢睾酮（DHT）浓度高于治疗反应性肿瘤。此外，肾上腺切除术后肿瘤生长缓慢与肿瘤内DHT浓度低有关。几种雄激素依赖性基因的表达进一步表明恩杂鲁胺耐药肿瘤中雄激素信号的重新激活。数据表明，CRPC病变中肿瘤内DHT浓度和几种雄激素依赖性基因的表达是恩杂鲁胺治疗耐药的指标，也是进一步进行雄激素阻断的指征。已证明前列腺癌细胞中存在独立于CYP17A1活性的雄激素合成，因此，对于对阿比特龙无反应的恩杂鲁胺耐药CRPC肿瘤的治疗，需要新型雄激素合成抑制剂。
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