An orthotopic mouse model of small cell lung cancer reflects the clinical course in patients.

ABSTRACT

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with very poor prognosis due to early metastatic spread and development of chemoresistance. In the last 30 years the study of SCLC has been constrained by a lack of primary human tumor specimen thus highlighting the need of a suitable mouse model. In this article we present the establishment of an orthotopic xenograft mouse model which accurately reproduced the clinical course of SCLC. Orthotopic implantation enabled engraftment of primary lung tumors in all injected mice. Furthermore, immunodeficiency of mice allowed formation of spontaneous metastases in characteristic organs. Bioluminescence Imaging, Magnetic Resonance Imaging and Positron emission tomography were applied to monitor engraftment, metabolism and the exact growth of tumors over time. In order to mimic the extensive disease stage, mice were injected with aggressive human chemoresistant cells leading to development of chemoresistant tumors and early metastatic spread. As a proof of concept treatment of tumor-bearing mice with conventional chemotherapeutics reduced tumor volumes, but a complete regression of tumors was not achieved. By mimicking the extensive disease stage our mouse model can facilitate the study of mechanisms contributing to chemoresistance and metastasis formation, as well as drug screening and evaluation of new treatment strategies for SCLC patients.