The use of lacZ-transduced tumor cells enhances the sensitivity of micrometastasis detection: A comparative study of gemcitabine treatment efficacy in the mouse LM8 osteosarcoma cell model

Abstract

In osteosarcoma patients as well as in preclinical osteosarcoma animal models post-therapy detection of residual disease and of metastases in particular remains a great challenge. The therapeutic efficacy is often overestimated because disseminated tumor cells frequently persist undetectable as dormant micrometastases. This can be avoided in preclinical studies by tagging the tumor cells with reporter genes that allow their selective detection in normal tissue down to the single cell level. In the present study we made use of a lacZ reporter gene and reinvestigated the therapeutic effect of gemcitabine on subcutaneous primary tumor growth and metastasis of mouse LM8 osteosarcoma cells in syngeneic C3H mice. Furthermore we compared the sensitivity of LM8-lacZ and of non-transduced LM8 cells to gemcitabine in vitro and in vivo because it was recently demonstrated that expression of a GFP reporter gene in osteosarcoma cells altered their aggressiveness. The present study showed that, in contrast to previous reports, gemcitabine treatment did not completely eradicate metastasis although it efficiently suppressed the growth of primary tumors and macrometastases. The results also showed that minimal residual disease is not restricted to the lungs, but also occurs in the liver and the kidneys. The direct comparison of the LM8-lacZ with the LM8 cells furthermore demonstrated that constitutive expression of the lacZ reporter gene has no effect on the aggressiveness of the cells or their sensitivity to gemcitabine. The LM8-lacZ cell-derived osteosarcoma mouse model thus represents a highly sensitive and reliable model for evaluation of anticancer drug efficacy in vivo