Cyclin E transgenic mice: discovery tools for lung cancer biology, therapy, and prevention

Abstract

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 and in the identification of a novel antineoplastic 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.

Fig. 1

Strategies for assessing preventive and therapeutic regimens in cyclin E–overexpressing (CEO) murine lung cancer models. A representative mouse carrying the cyclin E transgene (left) shows a large lung cancer (arrow, middle-left), compared with the normal lung from the same mouse. These cancers typically arise between 6–12 months of age in heterozygous mice. Premalignant lesions and malignant lung cancers (adenocarcinomas) arise even more frequently and earlier in homozygous strains from the same recombinant mice (unpublished data). Hematoxylin and eosin (H and E) staining shows a lung cancer (arrow, bottom-left). Potential drug targets are initially confirmed both genetically and, when compounds are available, pharmacologically in vitro in ED-1 lung cancer cell lines derived from the transgenic mice. Promising targets are then tested in vivo in a transplantable model of syngeneic mice (right), where GFP-expressing ED-1 cells (middle-right) can be injected into tail veins. These cells can form lung cancers that can be detected by H and E staining (black arrow, lower-right) or by fluorescent microscopy (white arrow, insert in lower-right panel) in as few as seven days. The lead treatments are then tested in the transgenic mice (left) and ultimately in proof-of-principle clinical trials. The increasing sizes of arrows (middle) represent an increasing stringency in selecting and testing drugs or regimens for lung cancer prevention or therapy at each advancing stage of drug development.