Tumor Metastasis and the Reciprocal Regulation of Prometastatic and Antimetastatic Factors by Nuclear Factor {{kappa}}B

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Tumor Metastasis and the Reciprocal Regulation of Prometastatic and Antimetastatic Factors by Nuclear Factor ${kappa}$ B

Valentine B. Andela, Edward M. Schwarz, J. Edward Puzas, Regis J. O’Keefe and Randy N. Rosier¹

Department of Orthopaedics [V. B. A., J. E. P., R. J. O., R. N. R.] and Immunology/Rheumatology Unit, Department of Medicine [E. M. S.], University of Rochester, Rochester, New York 14642

To investigate the role of the transcription factor nuclearfactor ${kappa}$ B (NF ${kappa}$ B) in tumor metastasis, we generated a murine lungalveolar carcinoma cell line (Line 1) defective in NF ${kappa}$ B-signalingby retroviral delivery of a dominant negative inhibitor of NF ${kappa}$ B.The NF ${kappa}$ B signal blockade resulted in the down-regulation of prometastatic matrixmetalloproteinase 9, a urokinase-like plasminogen activator,and heparanase and reciprocal up-regulation of antimetastatictissue inhibitors of matrix metalloproteinases 1 and 2 and plasminogen activatorinhibitor 2. NF ${kappa}$ B signal blockade did not affect tumor cell proliferationin vitro or in vivo but prevented intravasation of tumor cellsin an in vivo chick chorioallantoic membrane model of metastasisas well as spontaneous metastasis in a murine model. These findingssuggest that NF ${kappa}$ B plays a central and specific role in the regulationof tumor metastasis and may be an important therapeutic targetfor development of antimetastatic cancer treatments.

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