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-γ, 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.