Inflammatory angiogenesis is critical to tumor progression and other various pathological processes. In particular, we have focused on the role of inflammatory responses including angiogenesis in response to proinflammatory cytokines in acquirement of malignant phenotypes in cancer*1. We recently demonstrated that COX2 activation in tumor stroma cells and cancer cells is closely involved in IL-1β-induced angiogenesis in vivo as well as in vitro*2. In our present study, by using both in vitro (endothelial cells in culture) and in vivo (mouse corneal and dorsal air sac assay) models, we focused on how tumor associated-macrophages (TAMs) were involved in tumor angiogenesis and tumor growth*3. (1) Implantation of IL-1β in mouse corneas induced angiogenesis at a rate comparable to that of VEGF in harmony with infiltration of inflammatory cells, mainly monocytes/ macrophages; (2) IL-1β-induced, but not VEGF-induced, angiogenesis was markedly reduced in MCP-1 (-/-) mice; (3) Administration of macrophage-targeting drug (chlodronate-liposomes) also markedly reduced IL-1β-induced in mouse corneas; (4) By immunohistochemical analysis, macrophages infiltrating near IL-1β-induced neovasculatures were COX2-positive in mouse corneas; (5) Administration of a COX inhibitor also resulted in a significant reduction of tumor growth and angiogenesis as well as infiltration of macrophages in Lewis lung carcinoma cells expressing human IL-1β. Taken together, prerequisite role of integral inflammatory infiltration will be discussed in association with tumor angiogenesis and growth. *1 Torisu, H., Ono, M., Kiryu H. et al. Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFα and IL-1α. Int. J. Cancer 85: 182-188, 2000 *2Kuwano, T., Nakao, Ono, M., et al. Cyclooxygenase 2 is a key enzyme for inflammatory cytokine induced angiogenesis. FASEB J. 18: 300-310. 2004 *3 Nakao, S., Kuwano, T., Ono, M., et al. Infiltration of COX-2 expressing macrophage is prerequisite for IL-lβ-induced neovascularization and tumor growth. J. Clin. Invest. under revision.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]