title: M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis.
abstract: 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.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. ykubo33@sc.itc.keio.ac.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kishi
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D003930:Diabetic Retinopathy / Q000188:drug therapy; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012164:Retinal Diseases / Q000188:drug therapy / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D016173:Macrophage Colony-Stimulating Factor