PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine
PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine
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DOI：
10.1002/path.4312
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发表时间：
2014-05-01
影响因子：
7.3
通讯作者：
Clarke, Alan R.
中科院分区：
文献类型：
--
作者：
Davies, Emma J.;Durban, Victoria Marsh;Clarke, Alan R.
基因PTEN和KRAS的突变或缺失与人结肠直肠癌（CRC）有关，并且已经显示出共同发生，尽管两者都在PI3 '激酶（PI3' K）途径中发挥作用。我们使用基因工程小鼠模型研究了这些基因在体内肠道肿瘤进展中的作用，目的是产生更具代表性的人类CRC模型。在野生型（WT）小鼠和具有腺瘤发展倾向的小鼠（Apc（fl/+））中诱导Pten的肠特异性缺失和Kras的致癌等位基因的激活。当动物出现高肿瘤负荷的症状时，对其实施安乐死。进行组织的组织学检查，并使用免疫组织化学来表征信号传导通路激活。Pten和Kras的突变导致易患腺瘤的小鼠的寿命显著缩短。在这些动物中观察到浸润性腺癌，有PI3K途径激活的证据，但没有转移。然而，WT动物中Pten和Kras的突变不倾向于腺瘤，导致肠上皮细胞的稳态紊乱和增生性息肉，不典型增生的无蒂锯齿状腺瘤和转移性腺癌与锯齿状特征的发展。这些研究证明了Pten和Kras突变在肠道肿瘤进展中的协同作用，在本地和免疫活性小鼠模型中，具有潜在的临床前药物测试应用。特别是，他们表明Pten和Kras突变单独使小鼠易患锯齿状病变谱，反映了人类CRC进展的锯齿状途径。出版社：John Wiley & Sons，Ltd
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+)). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans. Published by John Wiley & Sons, Ltd.