Preclinical, non-genetic models of lung adenocarcinoma: a comparative survey.

Florian Janker,Walter Weder,Wolfgang Jungraithmayr,Jae-Hwi Jang

doi:10.18632/oncotarget.25668

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide. Animal models are key in analyzing cancer biology and therapy evaluation.We here compared relevant non-genetic lung cancer models with regard to tumor induction period, incidence, morbidity and mortality rate and the immunological composition of primary tumors and the occurrence of tertiary lymphoid organs (TLO): (I) intraperitoneal Urethane injection (1g/kg), (II) Lewis lung carcinoma (LLC) cell line model (intravenous or subcutaneous), and (III) ex vivo three-dimensional (3D) primary cell culture model established from subcutaneously developed LLC-induced tumors.The incidence of Urethane induced lung tumors was 100% in both, C57BL/6 and BALB/c strains without morbidity or mortality at twenty weeks after injection. The mean size of tumor nodules after Urethane injection was significantly larger in BALB/c mice vs. C57BL/6 (p<0.01). Three times of Urethane injection produced significantly more tumor nodules in both mouse strains compared to one injection (BALB/c: p<0.01; C57BL/6: p<0.05). TLOs were only found in the Urethane-induced model. Although the cell line models also showed 100% induction rate, morbidity was high due to skin ulceration on the inoculation site and the development of pleural effusions in the subcutaneous model and the intravenous model, respectively. Tendencies, but no significant differences (p>0.05) could be found in the count of CD4+, CD8+, F4/80+ and NKp46+ cells in a tumor nodule among investigated models.All discussed models provided a high tumor incidence rate. TLOs were exclusively found in the Urethane-induced model. No significant difference could be found regarding immune cells across models.

Highlights

Mouse tumor models have been proven to be crucial to understand cancer biology and to develop therapeutics against cancer [1]
Tertiary lymphoid organs (TLOs) were exclusively found in the Urethane-induced tumor model compared to other models with a significant correlation of tertiary lymphoid organs (TLO) incidence and the number of tumor nodules within the lung (Figure 2G)
In the light of these emerging therapeutics, the characterization of relevant immune cells among most commonly used non-genetic mouse tumor models could be of help to optimize immunotherapy

Summary

Introduction

Mouse tumor models have been proven to be crucial to understand cancer biology and to develop therapeutics against cancer [1]. Urethane is known to activate the Kras proto-oncogene in early stages of murine lung tumor development and qualifies as such as an appropriate study model of Ras-driven lung cancer [8, 9] Another lung cancer model employs the injection of lung cancer cell lines intravenously into a mouse to induce tumor growth either orthotopically or heterotopically. Apart from these in vivo models, a three dimensional (3D) ex vivo/in vitro cell culture model is available as an emerging model technic with applications in cancer cell biology, drug discovery [11] and prediction of drug response in patients This method was shown to be effective in different cancer entities, including lung cancer [12, 13]. This 3D culture model is able to mimic tumor biology, tumor microenvironment, cell-cell and cellextracellular matrix interactions similar to in vivo tumors

Methods

Results

Conclusion