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Direct Demonstration of Negative Regulation of Tumor Growth and Metastasis by Host-inducible Nitric Oxide Synthase¹

Departments of Gastrointestinal Medical Oncology [D. W., E. L. R., K. Z., L. W., X. L., Y. H., K. X.], Neurosurgery [S. H.], and Cancer Biology [S. H., K. X.], The University of Texas M. D. Anderson Cancer Center, and the Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston [E. L. R., K. Z., S. H., K. X.], Houston, Texas 77030

Inducible nitric oxide synthase (NOS) II expression can be induced in the tumor bed, predominantly in host cells that infiltrate and surround a tumor. However, the impact of this physiological NOS II expression in host cells on tumor growth and metastasis remains unclear because of a lack of appropriate experimental approaches. In the present study, three NOS II-null (NOS II^-/-) tumor cell lines, KX-dw1, KX-dw4, and KX-dw7, were established and verified using Southern, Northern, and Western blot analysis, and nitric oxide production assays. Cells from these lines were then s.c. and i.v. injected into NOS II^+/+ and NOS II^-/- C57BL/6 mice. NOS II protein expression and enzyme activity were clearly detected in the tumors that formed in NOS II^+/+ mice but not in those that formed in NOS II^-/- mice. Consistent with the absence of NOS II expression in the tumor stroma, KX-dw1, KX-dw4, and KX-dw7 cells grew much faster and produced many more experimental lung metastases in NOS II^-/- mice than in NOS II^+/+ mice. Therefore, physiological expression of NOS II in host cells directly inhibits tumor growth and metastasis.

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