Haltia Ulla-Maija, Pihlajoki Marjut, Andersson Noora, Mäkinen Lotta, Tapper Johanna, Cervera Alejandra, Horlings Hugo M, Turpeinen Ursula, Anttonen Mikko, Bützow Ralf, Unkila-Kallio Leila, Carpén Olli, Wilson David B, Heikinheimo Markku, Färkkilä Anniina
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
J Endocr Soc. 2020 Mar 16;4(4):bvaa034. doi: 10.1210/jendso/bvaa034. eCollection 2020 Apr 1.
Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multimodal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA hybridization, quantitative PCR, and circulating biomarker analysis, and correlated these results with clinical data. We show that FSH receptor and estrogen receptor beta (ERβ) are highly expressed in the majority of AGCTs, whereas the expressions of estrogen receptor alpha (ERα) and G-protein coupled estrogen receptor 1 are less prominent. ERβ protein expression is further increased in recurrent tumors. Aromatase expression levels show high variability between tumors. None of the markers examined served as prognostic biomarkers for progression-free or overall survival. In functional experiments, we assessed the effects of FSH, estradiol (E2), and the aromatase inhibitor letrozole on AGCT cell viability using 2 models: KGN cells and primary cultures of AGCT cells. FSH increased cell viability in a subset of primary AGCT cells, whereas E2 had no effect on cell viability at physiological concentrations. Letrozole suppressed E2 production in AGCTs; however, it did not impact cell viability. We did not find preclinical evidence to support the clinical use of aromatase inhibitors in AGCT treatment, and thus randomized, prospective clinical studies are needed to clarify the role of hormonal treatments in AGCTs.
成人型颗粒细胞瘤（AGCTs）是性索来源的肿瘤，具有晚期复发倾向。激素调节剂已被经验性地用于复发性AGCT的治疗，尽管效果有限。为了为AGCT的激素治疗提供更严谨的基础，我们采用多模态方法，通过RNA测序、免疫组织化学、RNA杂交、定量PCR和循环生物标志物分析，对175个肿瘤标本和51份血清样本中的关键激素生物标志物表达进行了表征，并将这些结果与临床数据相关联。我们发现，大多数AGCT中促卵泡激素（FSH）受体和雌激素受体β（ERβ）高表达，而雌激素受体α（ERα）和G蛋白偶联雌激素受体1的表达则不那么突出。ERβ蛋白表达在复发性肿瘤中进一步增加。芳香化酶的表达水平在肿瘤之间表现出高度变异性。所检测的标志物均未作为无进展生存期或总生存期的预后生物标志物。在功能实验中，我们使用两种模型评估了FSH、雌二醇（E2）和芳香化酶抑制剂来曲唑对AGCT细胞活力的影响：KGN细胞和AGCT细胞原代培养物。FSH在一部分原发性AGCT细胞中增加了细胞活力，而E2在生理浓度下对细胞活力没有影响。来曲唑抑制了AGCT中E2的产生；然而，它并未影响细胞活力。我们没有找到支持在AGCT治疗中临床使用芳香化酶抑制剂的临床前证据，因此需要进行随机前瞻性临床研究来阐明激素治疗在AGCT中的作用。
