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) synt hase II (NOS II) expression inhibits the metastatic ability of non-immunoge nic B16 melanoma cells in syngeneic mice. In the present study, the mechani sms for this metastasis suppression were determined. B16-BL6 and B16-F10 mu rine 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 les s and smaller experimental pulmonary metastases in NOS II-/- mice than in N OS II+/+ mice. Moreover, less metastatic pleural effusion was observed in N OS II-/- mice than in NOS II+/+ mice. Immunohistochemical analyses indicate d that absence of NOS II expression was correlated with decreased vascular endothelial growth factor expression and tumor-associated vascular formatio n. After activation with lipopolysaccharide and IFN-gamma, neither melanoma cell line produced detectable levels of NO. Our data demonstrate that tumo r-induced expression of host NOS II enhances melanoma metastasis and pleura l effusion, at least in part, through regulation of vascular formation and vascular permeability. (C) 2001 Wiley-Liss, Inc.