From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers

Abstract

Introduction: Studies of preclinical models are essential for determining the biology of lung cancers and testing new and novel therapeutic approaches. We review the commonly used preclinical models for lung cancers and evaluate their strengths and weaknesses.

Methods: We searched the MEDLINE database via PubMed using combinations of the following medical subject headings: lung cancer; animal models, mice; cell line, tumor; cell culture, mice; transgenic, mice; SCID, transplantation; heterologous; and genetic engineering. We reviewed the relevant published articles.

Results: Multiple examples of the three major preclinical models-tumor cell lines, patient-derived xenografts, and genetically engineered mouse models-exist and have been used by investigators worldwide, with more than 15,000 relevant publications. Each model has its strengths and actual or potential weaknesses. In addition, newer forms of these models have been proposed or are in use as potential improvements over the conventional models.

Conclusions: A large number and variety of models have been developed and extensively used for the study of all major types of lung cancer. While they remain the cornerstone of preclinical studies, each model has its individual strengths and weaknesses. These must be carefully evaluated and applied to the proposed studies to obtain the maximum usefulness from the models.

Keywords: Cell lines; Genetically engineered mouse models; Lung cancer; Neuroendocrine carcinomas; Non–small cell lung cancer; Patient-derived xenografts; Preclinical models; Small cell lung cancer.

Fig. 1

Lung cancer cell lines. Fig. 1A. NSCLC culture HCC1897, growing as flat adherent cells. Fig.1 B. SCLC culture, triple knockout mouse model. Both mouse and human SCLC cultures usually grow as floating aggregates or true spheroids (as illustrated). The larger spheroids frequently develop necrotic or hollow centers.

Fig 2

PDX of moderately differentiated SCC. The histological appearances of the PDX are similar to those of the original lung cancer.

Fig. 3

Typical Kras driven GEMM Model for lung adenocarcinoma. The most striking feature is the massive alveolar cell hyperplasia. If the mice do not die of respiratory failure, adenomas may develop which progress to adenomas with dysplasia, adenocarcinoma in situ and invasive carcinoma. Courtesy of James Kim

Fig 4

GEMM models for neuroendocrine lung cancers. Fig. 2a, Early central lesion arising in a large bronchus. Both the in situ and invasive components are characteristic of LCNEC with pseudoglandular formation. Fig. 2b. Massive mediastinal spread of SCLC component, even though corresponding intrapulmonary tumors are relatively small. Fig. 2C. Mixed tumor with LCNEC (on left) and SCLC (on right) components blending into each other. Fig 2D. Liver metastases having SCLC elements only, even though the primary tumor had both SCLC and LCNEC components. The SCLC component predominated in metastatic lesions, irrespective of the histology of the corresponding lung tumors. Triple knockout model (TP53-, RB1-, p130-) courtesy of Julien Sage, Trisha Savage and Jane Johnson.