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.

[1]  D. Pieramici,et al.  Anti-VEGF therapy: comparison of current and future agents , 2008, Eye.

[2]  Fabian Kiessling,et al.  Flt-1 signaling in macrophages promotes glioma growth in vivo. , 2008, Cancer research.

[3]  C. Stewart,et al.  Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice. , 2008, The Journal of clinical investigation.

[4]  MasabumiShibuya,et al.  VEGFR1 Tyrosine Kinase Signaling Promotes Lymphangiogenesis as Well as Angiogenesis Indirectly via Macrophage Recruitment , 2008 .

[5]  N. Himes,et al.  VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma , 2008, The Journal of experimental medicine.

[6]  F. Peale,et al.  Bv8 regulates myeloid-cell-dependent tumour angiogenesis , 2007, Nature.

[7]  M. Giacca,et al.  Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels , 2007, Cell.

[8]  G. Fuh,et al.  Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells , 2007, Nature Biotechnology.

[9]  H. Verheul,et al.  Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition , 2007, Nature Reviews Cancer.

[10]  Marcus Fruttiger,et al.  Development of the retinal vasculature , 2007, Angiogenesis.

[11]  Minhong Yan,et al.  Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis , 2006, Nature.

[12]  J. Pollard,et al.  Macrophages regulate the angiogenic switch in a mouse model of breast cancer. , 2006, Cancer research.

[13]  Yoshiko Kobayashi,et al.  A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model , 2006, Molecular Cancer Therapeutics.

[14]  D. McDonald,et al.  Rapid vascular regrowth in tumors after reversal of VEGF inhibition. , 2006, The Journal of clinical investigation.

[15]  R. Schwendener,et al.  Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach , 2006, British Journal of Cancer.

[16]  E. Stanley,et al.  Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. , 2006, Cancer research.

[17]  D. Kerjaschki,et al.  Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants , 2006, Nature Medicine.

[18]  T. Gardner,et al.  Retinal angiogenesis in development and disease , 2005, Nature.

[19]  Napoleone Ferrara,et al.  Angiogenesis as a therapeutic target , 2005, Nature.

[20]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[21]  Tatiana V. Petrova,et al.  Lymphangiogenesis in development and human disease , 2005, Nature.

[22]  Andrew P. McMahon,et al.  WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature , 2005, Nature.

[23]  Seppo Ylä-Herttuala,et al.  Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. , 2005, The Journal of clinical investigation.

[24]  G. Yancopoulos,et al.  VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene- based discovery of the next generation of angiogenesis targets. , 2005, Cold Spring Harbor symposia on quantitative biology.

[25]  E. Stanley,et al.  Colony-Stimulating Factor-1 Blockade by Antisense Oligonucleotides and Small Interfering RNAs Suppresses Growth of Human Mammary Tumor Xenografts in Mice , 2004, Cancer Research.

[26]  P. Rutkowski,et al.  Cytokine and cytokine receptor serum levels in adult bone sarcoma patients: Correlations with local tumor extent and prognosis , 2003, Journal of surgical oncology.

[27]  K. Alitalo,et al.  VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia , 2003, The Journal of cell biology.

[28]  K. Alitalo,et al.  Double target for tumor mass destruction. , 2003, The Journal of clinical investigation.

[29]  G. Yancopoulos,et al.  VEGF-Trap: A VEGF blocker with potent antitumor effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Boulton,et al.  The pathogenesis of diabetic retinopathy: old concepts and new questions , 2002, Eye.

[31]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[32]  T. Noda,et al.  Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. , 2001, Cancer research.

[33]  Z. Werb,et al.  How matrix metalloproteinases regulate cell behavior. , 2001, Annual review of cell and developmental biology.

[34]  H. Schreuder,et al.  Osteosarcoma: Oncologic and functional results. A single institutional report covering 22 years , 1999, Journal of surgical oncology.

[35]  E. Cagliero,et al.  Fibronectin overexpression in retinal microvessels of patients with diabetes. , 1996, Investigative ophthalmology & visual science.

[36]  S. Nishikawa,et al.  Functional hierarchy of c-kit and c-fms in intramarrow production of CFU-M. , 1995, Oncogene.

[37]  J. Pollard,et al.  Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. , 1994, Development.

[38]  Lois E. H. Smith,et al.  Oxygen-induced retinopathy in the mouse. , 1994, Investigative ophthalmology & visual science.

[39]  Charles J. Sherr,et al.  The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF 1 , 1985, Cell.

[40]  P. Lane,et al.  Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. , 1976, The Journal of heredity.