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¹ Department of Cell Differentiation, The Sakaguchi Laboratory, ² Division of Gene Regulation, Institute for Advanced Medical Research, and ³ Department of Plastic Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan
⁴ Pharmacological Research Laboratories, Research Division, Kyowa Hakko Kirin Co., LTD., Gunma 370-1295, Japan
⁵ Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan

CORRESPONDENCE Yoshiaki Kubota: ykubo33{at}sc.itc.keio.ac.jp OR Toshio Suda: sudato{at}sc.itc.keio.ac.jp

Antiangiogenic therapy for the treatment of cancer and other neovascular diseases is desired to be selective for pathological angiogenesis and lymphangiogenesis. Macrophage colony-stimulating factor (M-CSF), a cytokine required for the differentiation of monocyte lineage cells, promotes the formation of high-density vessel networks in tumors and therefore possesses therapeutic potential as an M-CSF inhibitor. However, the physiological role of M-CSF in vascular and lymphatic development, as well as the precise mechanisms underlying the antiangiogenic effects of M-CSF inhibition, remains unclear. Moreover, therapeutic potential of M-CSF inhibition in other neovascular diseases has not yet been evaluated. We used osteopetrotic (op/op) mice to demonstrate that M-CSF deficiency reduces the abundance of LYVE-1⁺ and LYVE1^– macrophages, resulting in defects in vascular and lymphatic development. In ischemic retinopathy, M-CSF was required for pathological neovascularization but was not required for the recovery of normal vasculature. In mouse osteosarcoma, M-CSF inhibition effectively suppressed tumor angiogenesis and lymphangiogenesis, and it disorganized extracellular matrices. In contrast to VEGF blockade, interruption of M-CSF inhibition did not promote rapid vascular regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside tumors. These results suggest that M-CSF–targeted therapy is an ideal strategy for treating ocular neovascular diseases and cancer.

© 2009 Kubota et al.
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This article has been cited by other articles:

• Kubota, Y., Takubo, K., Shimizu, T., Ohno, H., Kishi, K., Shibuya, M., Saya, H., Suda, T. (2009). M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. JCB 185: i6-i6 [Full Text]  

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