Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB.
To investigate the role of the transcription factor nuclear factor kappaB (NFkappaB) in tumor metastasis, we generated a murine lung alveolar carcinoma cell line (Line 1) defective in NFkappaB-signaling by retroviral delivery of a dominant negative inhibitor of NFkappaB. The NFkappaB signal blockade resulted in the down-regulation of prometastatic matrix metalloproteinase 9, a urokinase-like plasminogen activator, and heparanase and reciprocal up-regulation of antimetastatic tissue inhibitors of matrix metalloproteinases 1 and 2 and plasminogen activator inhibitor 2. NFkappaB signal blockade did not affect tumor cell proliferation in vitro or in vivo but prevented intravasation of tumor cells in an in vivo chick chorioallantoic membrane model of metastasis as well as spontaneous metastasis in a murine model. These findings suggest that NFkappaB plays a central and specific role in the regulation of tumor metastasis and may be an important therapeutic target for development of antimetastatic cancer treatments.
Andela
V B
VB
Department of Orthopaedics, University of Rochester, New York 14642, USA.
Schwarz
E M
EM
Puzas
J E
JE
O'Keefe
R J
RJ
Rosier
R N
RN
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D000482:Allantois / Q000098:blood supply; D000818:Animals; D002455:Cell Division / Q000502:physiology; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005966:Glucuronidase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D000099175:Heparanase
D005966:Glucuronidase; D020672:I-kappa B Proteins; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014568:Urokinase-Type Plasminogen Activator; D000099175:Heparanase