Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model.
Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model.
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DOI：
10.1371/journal.pone.0016786
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发表时间：
2011-02-02
期刊：
影响因子：
3.7
通讯作者：
Means AL
中科院分区：
文献类型：
--
作者：
Ray KC;Bell KM;Yan J;Gu G;Chung CH;Washington MK;Means AL
Kras基因的激活突变通常在一些但不是所有的上皮性癌症中发现。为了了解不同上皮组织对Kras诱导的肿瘤发生的敏感性，我们引入了一种最常见的Kras突变，KrasG12D，在上皮组织中广泛存在。我们使用了一个小鼠模型，在该模型中，G12D突变被放置在内源性Kras基因座上，由Cre介导的可诱导重组控制，在表达细胞角蛋白19的组织中，包括口腔、胃肠道、肺和肝、肾和胰腺的导管。在成年小鼠组织中引入KrasG12D突变导致这些组织中的一些但不是全部发生肿瘤性变化。值得注意的是，在口腔、胃、结肠和肺部观察到许多增生、化生和腺瘤，这表明暴露于外部环境的产品促进了KrasG12D启动的肿瘤形成。然而，环境暴露并不总是与肿瘤的形成相关，例如在小肠，这表明对Kras激活的敏感性也存在内在差异。胰腺出现少量粘液性化生，具有早期胰腺上皮内肿瘤(Panins)的特征，支持胰腺导管有可能诱发胰腺癌的假说。
Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, KrasG12D, broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the KrasG12D mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes KrasG12D-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer.
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DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
DOI：
10.1073/pnas.0810097105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Habbe, Nils;Shi, Guanglu;Maitra, Anirban
通讯作者：
Maitra, Anirban
影响因子：
30.8
作者：
Haigis, Kevin M.;Kendall, Krystle R.;Jacks, Tyler
通讯作者：
Jacks, Tyler
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA