M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis.
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.
Kubota
Yoshiaki
Y
Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan. ykubo33@sc.itc.keio.ac.jp
Takubo
Keiyo
K
Shimizu
Takatsune
T
Ohno
Hiroaki
H
Kishi
Kazuo
K
Shibuya
Masabumi
M
Saya
Hideyuki
H
Suda
Toshio
T
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
D016173:Macrophage Colony-Stimulating Factor