Attention has recently focused on the critical role of inflammatory responses in the
tumor stroma that provide favorable conditions for
cancer-cell growth and invasion/
metastasis. In particular, macrophages recruited into the
tumor stroma and activated, known as tumor-associated macrophages, are suggested to promote
tumorigenesis. In this study, we examined the effect of a decrease in the number of monocytes/macrophages in peripheral blood and the
tumor stroma on the development of bone and muscle
metastases by
lung cancer cells. Treatment with
clodronate encapsulated by
liposomes (Cl(2)MDP-LIP) has been developed for the depletion of monocytes/macrophages in an animal model. Subcutaneous administration of Cl(2)MDP-LIP markedly reduced the number of monocytes in peripheral blood, resulting in efficient suppression of both bone
metastasis and muscle
metastasis when
lung cancer HARA-B cells were injected into the left cardiac ventricle of mice. Treatment with Cl(2)MDP-LIP significantly reduced the number of macrophages in
tumors and the number of osteoclasts in bone marrow, as well as peripheral monocytes in mice harboring
lung cancer cells. In contrast, treatment with an osteoclast-targeting
antibiotic,
reveromycin A, inhibited bone
metastasis by
lung cancer cells, but not muscle
metastasis. The survival of human macrophages in culture was found to be specifically blocked by Cl(2)MDP-LIP, but not by
reveromycin A. Cl(2)MDP-LIP thus exerted antimetastatic effects in both bone and muscle whereas
reveromycin A did so only in bone.
Liposome-encapsulated
bisphosphonate may modulate
metastasis through decreasing the number of monocytes/macrophages in both peripheral blood and the
tumor stroma, suggesting that tumor-associated macrophages might be suitable targets for antimetastatic
therapy.