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.
