Neuroendocrine Lung Cancer Mouse Models: An Overview

Abstract

Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early detection systems for lung cancer point them out as suitable frameworks for the identification of biomarkers at the initial stages of tumor development and for testing molecular imaging methods based on somatostatin receptors. Here, we review the relevant models reported to date, their impact on the understanding of the biology of the tumor subtypes and their relationships, as well as the effect of the analyses of the genetic landscape of the human tumors and molecular imaging tools in their development.

Pten and p53 Loss in the Mouse Lung Causes Adenocarcinoma and Sarcomatoid Carcinoma

“…The adeno-cre intratracheal infection has proven to be a robust method of modeling lung cancer in mice [ 19 , 21 , 45 ]. Both Ad5-CMVcre and Ad5-K5cre viral vectors have been successfully used in the generation of lung tumor in mice [ 20 , 25 , 46 ].…”

“…Mouse models of lung cancer provide critical insights into disease mechanisms [ 19 , 21 , 22 , 23 ], and while a number of different ADC models have been described [ 21 , 65 ], there is a critical need for translational PSC models that recapitulate human disease and provide opportunities for tumor characterization and pre-clinical testing. In addition, primary tumor cells isolated from these PSC tumors constitute a high valuable tool for preclinical use.…”

“…The impact of the combined inactivation of these tumor suppressors, a frequent event in squamous cell lung cancer [ 18 ], is poorly understood. Genetically Engineered Mouse Models (GEMMs) of lung cancer provide an excellent tool to dissect mechanisms responsible for the appearance and progression of the disease and to identify cells of origin [ 19 , 20 , 21 , 22 , 23 ]. To gain a deeper insight into the combined role of PTEN and TP53 deletions in lung cancer, we have generated mouse models in which both Pten and Trp53 are disrupted in lung epithelial cells, either widely (by means of an Ad5-CMVcre virus) or in a cell-type restricted manner (using an Ad5-K5cre virus) and determine its effect on tumor formation.…”

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

“…Tumor xenograft murine models, particularly patient-derived xenografts (PDXs), have emerged as powerful tools for translational cancer research and preclinical drug screening. However, the limited availability of lung carcinoid cells, because of the small size of post-surgical samples, together with the low engraftment rate in mice, due to the slow growth of these neoplasms, hampered the employment of these procedures for TCs and ACs [ 12 ].…”

Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer

“…However, to test such hypotheses, reliable preclinical models that reproduce the behavior of these different NEN entities are needed. Whereas there are several preclinical models of SCLC, including genetically engineered mouse models, more than fifty cell lines, and several tumor organoid lines, there is a relative dearth of models for pulmonary and extrapulmonary LCNEC (Gazdar et al, 2017; Kawasaki et al, 2018; Lorz et al, 2020). Similarly, only a handful of cell lines exist for NETs (Andersson-Rolf et al, 2021; Asiedu et al, 2014; Kawasaki et al, 2018; Lorz et al, 2020).…”