Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages

• Published in: Cancer science Vol. 99; no. 8; pp. 1595 - 1602
• Main Authors: Hiraoka, Koji, Zenmyo, Michihisa, Watari, Kousuke, Iguchi, Haruo, Fotovati, Abbas, Kimura, Yusuke N., Hosoi, Fumihito, Shoda, Takanori, Nagata, Kensei, Osada, Hiroyuki, Ono, Mayumi, Kuwano, Michihiko
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01.08.2008; Blackwell
• Subjects: Animals; Biological and medical sciences; Bone Density Conservation Agents - pharmacology; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Clodronic Acid - pharmacology; Disease Models, Animal; Diseases of the osteoarticular system; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Macrophages - drug effects; Medical sciences; Mice; Mice, Inbred BALB C; Monocytes - drug effects; Muscle Neoplasms - drug therapy; Muscle Neoplasms - secondary; Neoplasm Invasiveness; Original; Pyrans - pharmacology; Spiro Compounds - pharmacology; Tumors; Tumors of striated muscle and skeleton; Lung disease; Monocyte; Respiratory disease; Diseases of the osteoarticular system; Malignant tumor; Myocyte; Bone metastasis; Cancerology; Lung metastasis; Inhibitor; Tumor cell; Cancer; Macrophage
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2008.00880.x

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 (Cl2MDP‐LIP) has been developed for the depletion of monocytes/macrophages in an animal model. Subcutaneous administration of Cl2MDP‐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 Cl2MDP‐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 Cl2MDP‐LIP, but not by reveromycin A. Cl2MDP‐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. (Cancer Sci 2008; 99: 1595–1602)