M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis

Yoshiaki Kubota, Keiyo Takubo, Takatsune Shimizu, Hiroaki Ohno, Kazuo Kishi, Masabumi Shibuya, Hideyuki Saya, Toshio Suda

Research output: Contribution to journalArticle

233 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1089-1102
Number of pages14
JournalJournal of Experimental Medicine
Volume206
Issue number5
DOIs
Publication statusPublished - 2009 May 11

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Pathologic Neovascularization
Lymphangiogenesis
Macrophage Colony-Stimulating Factor
Blood Vessels
Neoplasms
Eye Neoplasms
Lymphatic System
Eye Diseases
Osteosarcoma
Therapeutics
Vascular Endothelial Growth Factor A
Extracellular Matrix
Monocytes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. / Kubota, Yoshiaki; Takubo, Keiyo; Shimizu, Takatsune; Ohno, Hiroaki; Kishi, Kazuo; Shibuya, Masabumi; Saya, Hideyuki; Suda, Toshio.

In: Journal of Experimental Medicine, Vol. 206, No. 5, 11.05.2009, p. 1089-1102.

Research output: Contribution to journalArticle

Kubota, Yoshiaki ; Takubo, Keiyo ; Shimizu, Takatsune ; Ohno, Hiroaki ; Kishi, Kazuo ; Shibuya, Masabumi ; Saya, Hideyuki ; Suda, Toshio. / M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 5. pp. 1089-1102.
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