IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-kappaB whose activity is triggered in response to infectious agents and proinflammatory cytokines via the IkappaB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKbeta in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-kappaB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKbeta may link inflammation to cancer.
Greten
Florian R
FR
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla 92093, USA.
Eckmann
Lars
L
Greten
Tim F
TF
Park
Jin Mo
JM
Li
Zhi-Wei
ZW
Egan
Laurence J
LJ
Kagnoff
Martin F
MF
Karin
Michael
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003092:Colitis / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism*; D020895:Enterocytes / Q000201:enzymology / Q000378:metabolism; D051550:I-kappa B Kinase; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*
D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse