Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers
Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers
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DOI：
10.1038/labinvest.3700180
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发表时间：
2004-12-01
影响因子：
5
通讯作者：
Perret, C
中科院分区：
文献类型：
--
作者：
Colnot, S;Niwa-Kawakita, M;Perret, C
家族性腺瘤性息肉病的小鼠模型在Apc肿瘤抑制基因上存在生殖细胞杂合突变。它们是研究肠道癌变的有价值工具，因为大多数人类散发性癌症都含有APC的失活突变。然而，Apc（+/-）小鼠，比如特征明确的Apc（Min/+）模型，主要在小肠发生癌症，而人类主要发生结直肠癌。我们采用Cre - loxP策略构建了一种新的生殖系Apc失活模型，其中第14外显子被缺失。我们将这些Apc（Δ14/+）小鼠的表型与经典的Apc（Min/+）小鼠的表型进行了比较。主要的表型差异是肿瘤转移到了远端结肠和直肠，通常伴有直肠脱垂。因此，结直肠表型的严重程度部分归因于特定的Δ14突变，但也与环境因素有关，因为在常规条件下饲养的小鼠比在无病原体条件下饲养的小鼠更容易患结肠癌。所有病变，包括早期病变，都显示出Apc基因杂合性缺失以及Apc基因表达缺失。它们积累β - 连环蛋白，过表达β - 连环蛋白的靶基因细胞周期蛋白D1和c - Myc，并且谷氨酰胺合成酶（一种最近在肝脏中发现的β - 连环蛋白靶基因）在肠道腺瘤中的分布模式是镶嵌式的。因此，Apc（Δ14/+）模型是研究结直肠肿瘤发生分子机制的一种有用的新工具。
Murine models of familial adenomatous polyposis harbor a germinal heterozygous mutation on Apc tumor suppressor gene. They are valuable tools for studying intestinal carcinogenesis, as most human sporadic cancers contain inactivating mutations of APC. However, Apc(+/-) mice, such as the well-characterized Apc(Min/+) model, develop cancers principally in the small intestine, while humans develop mainly colorectal cancers. We used a Cre-loxP strategy to achieve a new model of germline Apc invalidation in which exon 14 is deleted. We compared the phenotype of these Apc(Delta14/+) mice to that of the classical Apc(Min/+). The main phenotypic difference is the shift of the tumors in the distal colon and rectum, often associated with a rectal prolapse. Thus, the severity of the colorectal phenotype is partly due to the particular mutation Delta14, but also to environmental parameters, as mice raised in conventional conditions developed more colon cancers than those raised in pathogen-free conditions. All lesions, including early lesions, revealed Apc LOH and loss of Apc gene expression. They accumulated beta-catenin, overexpressed the beta-catenin target genes cyclin D1 and c-Myc, and the distribution pattern of glutamine synthetase, a beta-catenin target gene recently identified in the liver, was mosaic in intestinal adenomas. The Apc(Delta14/+) model is thus a useful new tool for studies on the molecular mechanisms of colorectal tumorigenesis.