Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN.
Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN.
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DOI：
10.1371/journal.pone.0020715
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Teixeira JM
中科院分区：
文献类型：
--
作者：
Tanwar PS;Zhang L;Kaneko-Tarui T;Curley MD;Taketo MM;Rani P;Roberts DJ;Teixeira JM
尽管上皮性卵巢癌是妇科癌症死亡的主要原因，但对该疾病的病理生理学知之甚少。WNT和PI 3 K通路的突变在人卵巢类腺瘤中经常被观察到。然而，WNT/β-catenin和PTEN/AKT信号传导在这种疾病的病因和/或进展中的作用目前尚不清楚。在这份报告中，我们表明，在β-catenin的功能获得性突变，导致在卵巢表面上皮（OSE）细胞的β-catenin表达失调的核积累的小鼠发展惰性，未分化肿瘤的间充质和上皮的特点。OSE中β-连环蛋白失调与PTEN纯合缺失的组合导致显著更具侵袭性的肿瘤的发展，这与p53表达和细胞衰老的抑制相关。在惰性和侵袭性小鼠肿瘤以及具有核β-连环蛋白积累的人OEA中也观察到mTOR激酶（增殖的主要调节因子）和其下游靶标S6激酶磷酸化的诱导表达。具有β-catenin功能获得性突变和PTEN缺失的小鼠卵巢肿瘤细胞的异位同种异体移植物发展成具有OEA组织学的肿瘤，其生长被口服雷帕霉素治疗显著抑制。这些研究表明，雷帕霉素可能是一种有效的治疗与失调的Wnt/β-catenin和Pten/PI 3 K信号转导的人卵巢类固醇患者。
Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/β-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in β-catenin that leads to dysregulated nuclear accumulation of β-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated β-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear β-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in β-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
8
作者：
Ahmad, I.;Morton, J. P.;Singh, L. B.;Radulescu, S. M.;Ridgway, R. A.;Patel, S.;Woodgett, J.;Winton, D. J.;Taketo, M. M.;Wu, X-R;Leung, H. Y.;Sansom, O. J.
通讯作者：
Sansom, O. J.
DOI：
10.1111/j.1525-1438.2007.01127.x
发表时间：
2008-09-01
影响因子：
4.8
作者：
Gatcliffe, T. A.;Monk, B. J.;Holcombe, R. F.
通讯作者：
Holcombe, R. F.
影响因子：
4.8
作者：
Hsieh, M;Johnson, MA;Richards, JS
通讯作者：
Richards, JS