Increase of spontaneous lung metastasis of small cell lung cancer in the absence of Natural Killer cells in Pfp/Rag2 double knock out mice

Introduction: Most patients with small-cell lung cancer (SCLC) suffer from extensive disease and early metastatic spread, with an unimproved poor prognosis. The mechanisms of metastatic spread are still poorly understood. Earlier animal models of SCLC were of limited clinical value, as the process of metastasis was inefficient and had to be initialized by i.v. injection of human SCLC cells (dissemination) or orthotopic transplantation. The aim of this study was to develop a xenograft mouse model of spontaneous SCLC metastasis, and to test different SCLC cell lines in this system. Primary SCLC growth and metastatic pattern was compared within scid mice (lacking T- and B- cells) and the T-, B- and NK cell lacking double knock out perforin/recombination activating complex 2 (pfp/rag2) mice.

Methods: SCLC cell lines (H69, OH1, OH3, SW2, H82) were xenografted subcutaneously into scid and pfp/rag 2-mice. Local tumour growth and numbers of metastasis in the mouse lungs were compared among the cell-lines and between the mouse strains.

Results: Take rates (82%) of primary tumours were comparable in both mouse strains, while the tumour size was 1,6 fold increased in pfp/rag2 mice. The lung metastasis rate was significantly higher in pfp/rag 2-mice (74%), as in scid-mice (53%), with distinct differences among the various cell-lines. For OH1 cells a 22 fold increase in absolute numbers of lung metastasis in pfp/rag2 -/- was found. In contrast, H82 cells were characterized by lower numbers of lung metastasis in both mouse strains.

Conclusions: Different patterns concerning growth of primary tumours and spontaneous metastasis formation were observed between the two strains of mice. For the spontaneous formation of metastases, a clear benefit emerges if pfp/rag 2 -/- mice are used. This finding highlights the crucial role of NK cells in the metastatic spread in this model and suggests the pfp/rag2 -/- mouse system to be a valuable model to investigate these processes in vivo.