The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081605
The Journal of Experimental Medicine, Vol. 206, No. 5, 1089-1102
The Rockefeller University Press, 0022-1007 $30.00
© Kubota et al.
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ARTICLE

 M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis

Yoshiaki Kubota1, Keiyo Takubo1, Takatsune Shimizu2, Hiroaki Ohno4, Kazuo Kishi3, Masabumi Shibuya5, Hideyuki Saya2, and Toshio Suda1

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.

Abbreviations used: BW, body weight; ECM, extracellular matrix; IHC, immunohistochemistry; ISH, in situ hybridization; M-CSF, macrophage CSF; MMP, matrix metalloproteinase; MNC, mononuclear cell; NVT, neovascular tuft; OIR, oxygen-induced retinopathy; op/op, osteopetrotic; VEGF, vascular endothelial growth factor.

© 2009 Kubota et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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