Cyclin E transgenic mice: discovery tools for lung cancer biology, therapy, and prevention.
Cyclin E transgenic mice: discovery tools for lung cancer biology, therapy, and prevention.
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Cyclin E 转基因小鼠：肺癌生物学、治疗和预防的发现工具。
DOI：
10.1158/1940-6207.capr-10-0297
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Dmitrovsky E
中科院分区：
文献类型：
--
作者：
Freemantle SJ;Dmitrovsky E
在美国和许多其他国家，肺癌是导致癌症相关死亡的主要原因。这一事实强调了临床相关模型的必要性，以增加我们对肺癌生物学的理解，并帮助设计和实施肺癌的预防和更有效的治疗干预措施。新的小鼠非小细胞肺癌（NSCLC）转基因模型已经为此目的而设计。在一个这样的模型中，细胞周期调节因子cyclin E的过表达是针对II型肺泡细胞的；该模型中发育不良、增生和腺癌形成的特征概括了NSCLC患者癌变的主要特征。这些特征包括染色体不稳定、肺发育不良和增生、刺猬通路激活、单发和多发腺癌，甚至转移。表达人类野生型或突变（蛋白酶体降解抗性）形式的细胞周期蛋白E的细胞系是从转基因小鼠肺癌中获得的。这些细胞系可移植到同基因宿主小鼠体内，使其迅速发展为肺肿瘤，从而促进了针对肺癌发生的药物的快速检测。这些转基因和可移植的模型已经帮助发现了致癌和生长抑制的microrna (mirna)，并鉴定了细胞周期蛋白依赖性激酶2抑制剂的一种新的抗肿瘤作用机制。本文综述了小鼠致癌物诱导和转基因肺癌模型的一般用途，并介绍了细胞周期蛋白e过表达的肺癌模型的优化及其在检测肺癌预防和治疗候选药物中的应用。
Lung cancer is the leading cause of cancer-related mortality in the United States and many other countries. This fact underscores the need for clinically relevant models to increase our understanding of lung cancer biology and to help design and implement preventive and more-effective therapeutic interventions for lung cancer. New murine transgenic models of non-small cell lung cancer (NSCLC) have been engineered for this purpose. In one such model, overexpression of the cell-cycle regulator cyclin E is targeted to type II alveolar lung cells; dysplasia, hyperplasia and adenocarcinoma forming in this model have features recapitulating key features of carcinogenesis found in NSCLC patients. These features include the presence of chromosomal instability, pulmonary dysplasia and hyperplasia, hedgehog-pathway activation, single and multiple adenocarcinomas, and even metastases. Cell lines that expressed either a human wild-type or mutant (proteasome-degradation–resistant) form of cyclin E were derived from the transgenic mouse lung cancers. These cell lines are transplantable into syngeneic host mice, which rapidly develop lung tumors and thus facilitate the rapid testing of agents targeting lung carcinogenesis. These transgenic and transplantable models have already aided in the discovery of oncogenic and growth-suppressive microRNAs (miRNAs) and in the identification of a novel anti-neoplastic mechanism of action for inhibitors of cyclin-dependent kinase 2. This review discusses the general utility of murine carcinogen-induced and transgenic models of lung carcinogenesis and describes the optimization of cyclin E–overexpressing lung carcinogenesis models and their use in testing candidate agents for the prevention and therapy of lung cancer.