Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 2009 Dec;150(12):5208-17. doi: 10.1210/en.2009-0644. Epub 2009 Oct 9.
Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-Müllerian hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.
卵巢颗粒细胞瘤（GCT）是一种罕见的性索间质肿瘤。尽管通常是惰性的，但 GCT 会复发，如果不在早期诊断和治疗，生存率会显著缩短。关于 GCT 的病因知之甚少。由于病例发生率低且缺乏标准诊断，因此用于研究 GCT 的颗粒细胞瘤小鼠模型是一种有价值的工具，并为开发诊断和治疗策略提供了模型。我们最近通过遗传删除卵巢颗粒细胞中的骨形态发生蛋白信号转导转录因子（SMADs），开发了一种转移性颗粒细胞瘤的新型小鼠模型。组织学和血清激素分析表明，这种小鼠模型最接近幼年型 GCT。我们进一步分析了人类幼年型 GCT（JGCT）样本中抗苗勒管激素的表达和两条主要信号通路的激活：转化生长因子β/ SMAD2/3 和无翅相关鼠 mammary 肿瘤病毒整合位点（Wnt）/β-连环蛋白。TGFbeta 家族在 Smad1-Smad5 双敲除肿瘤中是活跃的，在这里我们表明，该途径而不是β-连环蛋白途径，在人类 JGCT 样本中被激活。这些数据表明，SMAD 家族可能通过破坏 SMAD1/5 或激活 SMAD2/3 导致人类 JGCT 的发病机制。
