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.

Tumor Angiogenesis and Anti-angiogenic Therapy

“…Accordingly, in a mouse osteosarcoma model, CSF-1 inhibition effectively suppressed tumor angiogenesis and disorganized empty sleeves of extracellular matrices. 47 Therefore, in contrast to VEGF blockade, interruption of CSF-1 inhibition did not promote rapid vascular regrowth. Continuous CSF-1 inhibition did not affect healthy vascular and lymphatic systems outside the tumor.…”

“…Recent evidence demonstrates that macrophages are also involved in vascular development by promoting angiogenic branching and anastomosis. 47,48 Macrophages stimulate vessel sprouting via a soluble factor other than VEGF, rather than through direct contact with endothelial cells. 49 These data suggest that macrophages promote angiogenesis independently of VEGF signaling.…”

Potential Anticancer Drugs Targeting Immune Pathways

“…A number of other drugs that have also known to inhibit macrophage infiltration include thalidomide, pentoxifylline, and genistein [16]. Furthermore, inhibition of CSF-1R signaling by antibody is also associated with TAM infiltration and tumor regression [18]. Reprogramming of M2 like TAMs toward M1 type macrophage is another potential therapeutic approach.…”

Developmental regression of hyaloid vasculature is triggered by neurons

“…After removal of the lenses through the pupils, hyaloid vessels were isolated en bloc with the iris, which acted as a frame. After that, retinal cups were dissected as described previously (Kubota et al, 2009). The wholemount tissues were postfixed for 30 min and then stained as described in the following section.…”

“…Immunohistochemistry of whole-mount samples or tissue sections was performed as previously described (Kubota et al, 2009). The primary monoclonal antibodies used were hamster anti-CD31 (MAB1398Z; EMD Millipore), PDG FRα (14-1401; eBiosci- ence), vascular endothelial cadherin (550548; BD), and F4/80 (MCA497R; Serotec).…”