PTEN loss and KRAS activation cooperate in murine biliary tract malignancies
PTEN loss and KRAS activation cooperate in murine biliary tract malignancies
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DOI：
10.1002/path.4189
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发表时间：
2013-06-01
影响因子：
7.3
通讯作者：
Clarke, Alan R.
中科院分区：
文献类型：
--
作者：
Marsh, Victoria;Davies, Emma J.;Clarke, Alan R.
胆道癌是人类的侵袭性恶性肿瘤。肿瘤抑制因子PTEN的缺失以前与鼠模型中胆管癌的发展相关。据报道，在高达三分之一的人胆管癌和50%的胆囊癌中存在KRAS激活。在这项研究中，我们的目的是测试在胆道恶性肿瘤中PTEN和KRAS突变之间的潜在相互作用。我们使用了一种基于诱导型CreLoxP的方法来协调删除PTEN并激活成年小鼠胆管上皮内的KRAS。我们发现单独激活KRAS对胆管上皮细胞几乎没有影响。单独的PTEN缺失导致低级别肿瘤性病变的发展，潜伏期长且发生率低。两种突变的组合导致胆管上皮增生性病变的快速发展，其通过发育异常进展为浸润性癌。我们的结论是，激活PI 3 K通路后的损失，PTEN是足以驱动低级别的胆管病变的发展缓慢的小鼠。相反，KRAS的突变激活不会导致类似的表型，尽管预测这应该激活RAFMEKERK和PI 3-激酶途径。然而，这两个基因的突变导致快速肿瘤发生，认为PTEN通常作为PI 3-激酶途径的“刹车”发挥作用，限制了KRAS激活的影响。两个基因的突变创造了一个宽松的环境，允许两个突变的全部影响显现出来。这些数据揭示了这些突变之间的体内协同作用，并提供了一种新的胆道恶性肿瘤小鼠模型。版权所有（c）2013大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Carcinomas of the biliary tract are aggressive malignancies in humans. Loss of the tumour suppressor PTEN has previously been associated with cholangiocarcinoma development in a murine model. Activation of KRAS is reported in up to one-third of human cholangiocarcinomas and 50% of gall bladder carcinomas. In this study we aimed to test the potential interaction between PTEN and KRAS mutation in biliary tract malignancy. We used an inducible CreLoxP-based approach to coordinately delete PTEN and activate KRAS within the adult mouse biliary epithelium. We found that activation of KRAS alone has little effect upon biliary epithelium. Loss of PTEN alone results in the development of low-grade neoplastic lesions, following long latency and at low incidence. Combination of both mutations causes rapid development of biliary epithelial proliferative lesions, which progress through dysplasia to invasive carcinoma. We conclude that activation of the PI3K pathway following loss of PTEN is sufficient to drive slow development of low-grade biliary lesions in mice. In contrast, mutational activation of KRAS does not result in a similar phenotype, despite a prediction that this should activate both the RAFMEKERK and PI3-kinase pathways. However, mutation of both genes results in rapid tumourigenesis, arguing that PTEN normally functions as a brake' on the PI3-kinase pathway, limiting the influence of KRAS activation. Mutation of both genes creates a permissive' environment, allowing the full effects of both mutations to be manifested. These data reveal an in vivo synergy between these mutations and provides a new mouse model of biliary tract malignancy. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.