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Direct Correlation between Nitric Oxide Synthase II Inducibility and Metastatic Ability of UV-2237 Murine Fibrosarcoma Cells Carrying Mutant p53¹

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

The relationship between nitric oxide synthase II (NOS II) inducibility and the metastatic ability of UV-2237 murine fibrosarcoma cells was determined. Highly metastatic cells survived to produce numerous lung metastases after i.v. injection in syngeneic C3H/HeN mice, whereas poorly metastatic cells did not. Highly metastatic clones exhibited higher levels of NOS II than did poorly metastatic clones in response to interleukin 1 and IFN- stimulation. Furthermore, both poorly and highly metastatic clones contained an identical p53 mutation. Overexpression of NOS II in a highly metastatic clone by transfection with NOS II gene retarded tumor growth and completely suppressed metastasis. Our data indicate that a low to moderate level of NOS II expression directly correlates with metastatic ability of UV-2237 fibrosarcoma cells carrying mutant p53 and that a high level of nitric oxide production suppresses tumor growth and metastasis.

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