GROW - School for Oncology & Developmental Biology, Maastricht University, the Netherlands; Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, the Netherlands.
GROW - School for Oncology & Developmental Biology, Maastricht University, the Netherlands; Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, the Netherlands.
Cancer Lett. 2021 Jun 28;508:18-29. doi: 10.1016/j.canlet.2021.03.019. Epub 2021 Mar 21.
Endometrial cancer (EC) is the most common gynaecological tumor in developed countries and its incidence is increasing. Approximately 80% of newly diagnosed EC cases are estrogen-dependent. Type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1) is the enzyme that catalyzes the final step in estrogen biosynthesis by reducing the weak estrogen estrone (E1) to the potent estrogen 17β-estradiol (E2), and previous studies showed that this enzyme is implicated in the intratumoral E2 generation in EC. In the present study we employed a recently developed orthotopic and estrogen-dependent xenograft mouse model of EC to show that pharmacological inhibition of the 17β-HSD-1 enzyme inhibits disease development. Tumors were induced in one uterine horn of athymic nude mice by intrauterine injection of the well-differentiated human endometrial adenocarcinoma Ishikawa cell line, modified to express human 17β-HSD-1 in levels comparable to EC, and the luciferase and green fluorescent protein reporter genes. Controlled estrogen exposure in ovariectomized mice was achieved using subcutaneous MedRod implants that released either the low active estrone (E1) precursor or vehicle. A subgroup of E1 supplemented mice received daily oral gavage of FP4643, a well-characterized 17β-HSD-1 inhibitor. Bioluminescence imaging (BLI) was used to measure tumor growth non-invasively. At sacrifice, mice receiving E1 and treated with the FP4643 inhibitor showed a significant reduction in tumor growth by approximately 65% compared to mice receiving E1. Tumors exhibited metastatic spread to the peritoneum, to the lymphovascular space (LVI), and to the thoracic cavity. Metastatic spread and LVI invasion were both significantly reduced in the inhibitor-treated group. Transcriptional profiling of tumors indicated that FP4643 treatment reduced the oncogenic potential at the mRNA level. In conclusion, we show that 17β-HSD-1 inhibition represents a promising novel endocrine treatment for EC.
子宫内膜癌（EC）是发达国家最常见的妇科肿瘤，其发病率正在上升。大约 80%的新诊断 EC 病例依赖于雌激素。17β-羟类固醇脱氢酶 1 型（17β-HSD-1）是一种酶，可通过将弱雌激素雌酮（E1）还原为强雌激素 17β-雌二醇（E2）来催化雌激素生物合成的最后一步，先前的研究表明，这种酶与 EC 中的肿瘤内 E2 生成有关。在本研究中，我们采用了一种新开发的、具有激素依赖性的 EC 原位异种移植小鼠模型，表明 17β-HSD-1 酶的药理学抑制可抑制疾病的发展。通过将高分化的人子宫内膜腺癌 Ishikawa 细胞系（经修饰后可表达与 EC 相当的人 17β-HSD-1 水平）和荧光素酶及绿色荧光蛋白报告基因经子宫内注射到无胸腺裸鼠的一个子宫角中，诱导肿瘤的发生。通过皮下 MedRod 植入物来控制去卵巢小鼠的雌激素暴露，该植入物可释放低活性的雌酮（E1）前体或载体。一部分接受 E1 补充的小鼠每天接受 FP4643 口服灌胃，这是一种经过充分研究的 17β-HSD-1 抑制剂。生物发光成像（BLI）用于非侵入性地测量肿瘤生长。在处死时，与接受 E1 并接受 FP4643 抑制剂治疗的小鼠相比，接受 E1 的小鼠的肿瘤生长明显减少了约 65%。肿瘤发生了腹膜转移、淋巴血管空间（LVI）转移和胸腔转移。抑制剂治疗组的转移扩散和 LVI 侵犯均明显减少。肿瘤的转录谱分析表明，FP4643 治疗在 mRNA 水平降低了致癌潜能。总之，我们表明 17β-HSD-1 抑制代表了一种有前途的新型 EC 内分泌治疗方法。
