Mouse models for lung cancer

Abstract

Lung cancer is a devastating disease and a major therapeutic burden with poor survival rates. It is responsible for 30% of all cancer deaths. Lung cancer is strongly associated with smoking, although some subtypes are also seen in non-smokers. Tumors in the latter group are mostly adenocarcinomas with many carrying mutations in the epidermal growth factor receptor (EGFR). Survival statistics of lung cancer are grim because of its late detection and frequent local and distal metastases. Although DNA sequence information from tumors has revealed a number of frequently occurring mutations, affecting well-known tumor suppressor genes and proto-oncogenes, many of the driver mutations remain ill defined. This is likely due to the involvement of numerous rather infrequently occurring driver mutations that are difficult to distinguish from the very large number of passenger mutations detected in smoking-related lung cancers. Therefore, experimental model systems are indispensable to validate putative driver lesions and to gain insight into their mechanisms of action. Whereas a large fraction of these analyzes can be performed in cell cultures in vitro, in many cases the consequences of the mutations have to be assessed in the context of an intact organism, as this is the context in which the Mendelian selection process of the tumorigenic process took place and the advantages of particular mutations become apparent. Current mouse models for cancer are very suitable for this as they permit mimicking many of the salient features of human tumors. The capacity to swiftly re-engineer complex sets of lesions found in human tumors in mice enables us to assess the contribution of defined combinations of lesions to distinct tumor characteristics such as metastatic behavior and response to therapy. In this review we will describe mouse models of lung cancer and how they are used to better understand the disease and how they are exploited to develop better intervention strategies.

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

“…A combination of Tp53 deletion and KRas G12D activation leads to significant reduction in latency and generates aggressive lung adenocarcinoma (7,18,19). Further, KRas G12D cooperates with deletion of other tumor suppressors (5) to develop lung adenocarcinoma, such as Lkb1 (20), Pten (21), and P19Arf (22) in genetic mouse models. However, cancer genomic studies have discovered a large number of unknown mutations or copy number alterations that coexisted with KRAS mutations in human patients, and experimental validation of all of the other mutations or copy number alterations by conventional genetic mouse models would be arduous.…”

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

“…GEMMs for SCLC and their relevance to the human disease have been reviewed in detail elsewhere (9)(10)(11). Briefly, these models are based on the near-ubiquitous inactivation of the RB and p53 tumor suppressors seen in human SCLC (12).…”

Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases

“…However, it is important to note that the staining pattern of a tumour is merely a snapshot of the gene expression of the tumour cells at that time point and might not match the initiating cell type. Our current understanding of cells of origin for lung cancer is mostly derived from experimental data using GEMMs 55 FIG. 2).…”

“…Three-dimensional culture techniques might also offer a new way to propagate normal and tumorigenic lung cells to better probe vulnerabilities of tumour cells 49,73 . Multiple in vivo models using mice to recapitulate lung cancer disease processes and treatment responses have been generated, including GEMMs harbouring specific genetic aberrations that have been identified in human tumours 55,80 …”