Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappa B

To investigate the role of the transcription factor nuclear factor kappaB ( NF kappaB) in tumor metastasis, we generated a murine lung alveolar carcino ma cell line (Line 1) defective in NF kappaB-signaling by retroviral delive ry of a dominant negative inhibitor of NF kappaB. The NF kappaB signal bloc kade resulted in the down-regulation of prometastatic matrix metalloprotein ase 9, a urokinase-like plasminogen activator, and heparanase and reciproca l up-regulation of antimetastatic tissue inhibitors of matrix metalloprotei nases 1 and 2 and plasminogen activator inhibitor 2. NF kappaB signal block ade did not affect tumor cell proliferation in vitro or in vivo but prevent ed intravasation of tumor cells in an in vivo chick chorioallantoic membran e model of metastasis as well as spontaneous metastasis in a murine model. These findings suggest that NF kappaB plays a central and specific role in the regulation of tumor metastasis and may be an important therapeutic targ et for development of antimetastatic cancer treatments.