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Influence of Nitric Oxide Synthase II Gene Disruption on Tumor Growth and Metastasis¹

Departments of Gastrointestinal Medical Oncology and Digestive Diseases [Q. S., Q. X., B. W., X. L., N. A. K., K. X.] and Cancer Biology [K. X.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The relationship between nitric oxide (NO) synthase II (NOS II) expression and the metastatic ability of tumor cells is inconclusive. We determined the role of host NOS II expression in the growth and metastasis of the B16-BL6 murine melanoma and M5076 murine ovarian sarcoma cell lines. The cells were either s.c. or i.v. injected into syngeneic wild-type (NOS II^+/+) and NOS II-null (NOS II^-/-) C57BL/6 mice. Both cell lines produced slightly larger s.c. tumors in NOS II^-/- mice than in NOS II^+/+ mice. However, B16- BL6 cells produced more and larger experimental lung metastases in NOS II^+/+ mice than in NOS II^-/- mice, whereas M5076 cells produced fewer and smaller experimental lung metastases in NOS II^+/+ mice than in NOS II^-/- mice. After activation with IFN- and lipopolysaccharide, macrophages isolated from NOS II^+/+ C57BL/6 mice produced NO-dependent cytotoxicity in sarcoma cells, whereas macrophages from NOS II^-/- C57BL/6 mice did not. In contrast, activated macrophages produced little to no NO-mediated cytotoxicity in melanoma cells. Immunostaining analyses indicated that NOS II expression was apparent in the metastases growing in NOS II^+/+ mice and correlated with increased cell proliferation in B16-BL6 lung metastases but with decreased cell proliferation in M5076 liver metastases. Our data suggest that disruption of host NOS II expression enhanced the growth and metastasis of NO-sensitive tumor cells but suppressed the metastasis of NO-resistant tumor cells, proposing that host-derived NO may differentially modulate tumor progression.

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