GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, The Netherlands.
J Pathol. 2018 Feb;244(2):203-214. doi: 10.1002/path.5004. Epub 2018 Jan 3.
The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17β-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
1 型 17β-羟甾脱氢酶（17β-HSD-1）可将低活性的雌酮（E1）转化为活性 17β-雌二醇（E2），在子宫内膜癌（EC）中过度表达，因此暗示在这种雌激素依赖性条件下，组织内 E2 的生成增加。在这项研究中，我们使用体外、体内和离体模型探索了抑制 17β-HSD-1 并损害 E1 生成 E2 的可能性。我们从分化良好的子宫内膜腺癌 Ishikawa 细胞系中生成了 EC 细胞系，并表达了类似于人体组织的 17β-HSD-1 水平。在这些细胞中，HPLC 分析表明，特异性 17β-HSD-1 抑制剂可阻断 17β-HSD-1 活性。体外，E1 给药引起类似于 E2 的集落形成，而 17β-HSD-1 抑制可损害该作用。在体内，植入鸡胚绒毛尿囊膜（CAM）上的肿瘤表明，E1 上调了雌激素反应性细胞周期蛋白 A 的表达，类似于 E2，而 17β-HSD-1 抑制可损害该作用。在没有 17β-HSD-1 的细胞（阴性对照）中，无论是在体外还是在体内，均未观察到 E1 的作用。使用 52 例原发性 EC 患者的队列，我们证明了 17β-HSD-1 酶活性的存在（离体在肿瘤组织中，如通过 HPLC 测量），在超过 45％的 EC 中，使用 17β-HSD-1 抑制剂抑制超过 90％。由于药物治疗通常用于转移性/复发性而非原发性肿瘤，因此我们接下来使用第二个 EC 患者队列（37 例患者）在转移性病变中证明了潜在药物靶标 17β-HSD-1 的 mRNA 表达。总之，17β-HSD-1 抑制可使用各种 EC 模型有效地阻止 E1 生成 E2。正在等待进一步的临床前研究和 17β-HSD-1 抑制剂的开发，以使候选化合物适合首次人体研究。版权所有 © 2017 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd 出版。
