Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression
Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression
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DOI：
10.1093/carcin/bgn186
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发表时间：
2008-11-01
期刊：
影响因子：
4.7
通讯作者：
Boerboom, Derek
中科院分区：
文献类型：
--
作者：
Lague, Marie-Noelle;Paquet, Marilene;Boerboom, Derek
颗粒细胞瘤（GCT）发生的机制可能涉及促卵泡激素下游信号通路的失调，包括磷酸肌酸激酶(PI3K)/AKT通路。为了验证这一假设，我们建立了一个基因工程小鼠模型，通过有条件地靶向PI3K拮抗剂基因Pten(Pten（flox/flox);Amhr2(cre/+)）来抑制颗粒细胞中的PI3K/AKT通路。多数Pten(flox/flox)；Amhr2（cre/+）小鼠没有卵巢异常，但偶尔（约7%）发展为侵袭性、间变性GCT并肺转移。PI3K/AKT下游效应因子FOXO1在Pten（flox/flox）中表达缺失；Amhr2(cre/+) GCT，提示GCT细胞增加增殖和逃避凋亡的机制。为了将这些发现与自发发生的GCT联系起来，我们分析了PTEN和phospho-AKT在人和马肿瘤中的表达。尽管未检测到PTEN缺失，但许多GCT（2/5人，7/17马）的细胞核或核周磷酸化AKT定位异常，提示PI3K/AKT活性改变。由于WNT/CTNNB1信号的不适当激活导致晚发性GCT的发展，并且PI3K/AKT和WNT/CTNNB1信号通路之间存在串扰，我们测试了这些通路是否可以在GCT中协同作用。小鼠颗粒细胞中PI3K/AKT和WNT/CTNNB1通路的激活(Pten(flox/flox), CTNNB1 (flox(ex3)/+)；Amhr2(cre/+))导致GCT的发展与Pten（flox/flox）相似；Amhr2（cre/+）小鼠，但具有100%的外显率，围产期发病，极快的生长和通过播种进入腹腔扩散的能力。这些数据表明，PI3K/AKT和WNT/CTNNB1信号失调在GCT的发生和发展中具有协同作用，并为转移性GCT提供了第一个动物模型。
The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Pten(flox/flox);Amhr2(cre/+)). The majority of Pten(flox/flox);Amhr2(cre/+) mice featured no ovarian anomalies, but occasionally (similar to 7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Pten(flox/flox);Amhr2(cre/+) GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Pten(flox/flox);Ctnnb1(flox(ex3)/+);Amhr2(cre/+)) resulted in the development of GCT similar to those observed in Pten(flox/flox);Amhr2(cre/+) mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT.