Genetic disruption of host nitric oxide synthase II gene impairs melanoma-induced angiogenesis and suppresses pleural effusion.
Our previous study showed that genetic disruption of nitric oxide (NO) synthase II (NOS II) expression inhibits the metastatic ability of non-immunogenic B16 melanoma cells in syngeneic mice. In the present study, the mechanisms for this metastasis suppression were determined. B16-BL6 and B16-F10 murine melanoma cells were injected i.v. into syngeneic wild-type (NOS II(+/+)) and NOS II-null (NOS II(-/-)) C57BL/6 mice. Both melanoma cells produced less and smaller experimental pulmonary metastases in NOS II(-/-) mice than in NOS II(+/+) mice. Moreover, less metastatic pleural effusion was observed in NOS II(-/-) mice than in NOS II(+/+) mice. Immunohistochemical analyses indicated that absence of NOS II expression was correlated with decreased vascular endothelial growth factor expression and tumor-associated vascular formation. After activation with lipopolysaccharide and IFN-gamma, neither melanoma cell line produced detectable levels of NO. Our data demonstrate that tumor-induced expression of host NOS II enhances melanoma metastasis and pleural effusion, at least in part, through regulation of vascular formation and vascular permeability.
Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
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Wang
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Xiong
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Shi
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Tan
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Le
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Xie
D000818:Animals; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D016158:Genes, p53 / Q000235:genetics; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010996:Pleural Effusion / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008070:Lipopolysaccharides; D008222:Lymphokines; D009573:Nitrites; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II