Macrophage colony-stimulating factor induces vascular endothelial growth factor production in skeletal muscle and promotes tumor angiogenesis.
Although M-CSF has been used for myelosuppression due to chemotherapy in patients with solid tumors, the effect of exogenous M-CSF on tumor angiogenesis has not been studied. In this study we showed that M-CSF has the ability to accelerate solid tumor growth by enhancing angiogenesis with a novel mechanism. M-CSF accelerated intratumoral vessel density in tumors inoculated into mice, although it did not accelerate the proliferation of malignant cells and cultured endothelial cells in vitro. In both the absence and the presence of tumors, M-CSF significantly increased the circulating cells that displayed phenotypic characteristics of endothelial progenitor cells in mice. Moreover, M-CSF treatment induced the systemic elevation of vascular endothelial growth factor (VEGF). VEGFR-2 kinase inhibitor significantly impaired the effect of M-CSF on tumor growth. In vivo, M-CSF increased VEGF mRNA expression in skeletal muscles. Even after treatment with carageenan and anti-CD11b mAb in mice, M-CSF increased VEGF production in skeletal muscles, suggesting that systemic VEGF elevation was attributed to skeletal muscle VEGF production. In vitro, M-CSF increased VEGF production and activated the Akt signaling pathway in C2C12 myotubes. These results suggest that M-CSF promotes tumor growth by increasing endothelial progenitor cells and activating angiogenesis, and the effects of M-CSF are largely based on the induction of systemic VEGF from skeletal muscles.
Okazaki
Tatsuma
T
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan. tatsuma@geriat.med.tohoku.ac.jp
Ebihara
Satoru
S
Takahashi
Hidenori
H
Asada
Masanori
M
Kanda
Akio
A
Sasaki
Hidetada
H
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000276:immunology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009360:Neoplastic Cells, Circulating / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000276:immunology; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000097:blood
D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D016173:Macrophage Colony-Stimulating Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt