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Fewer intestinal tumors (outlined) form if NF-B is inactive in epithelial cells (right). Karin/Elsevier

The association of inflammation with tumors was first noted nearly 2,000 years ago by Galen. Today, chronic inflammation caused by intestinal diseases such as colitis is known to be a major contributing factor to the onset of colon cancer. In a new report by Florian Greten, Michael Karin (University of California, San Diego, CA), and colleagues, NF-B, an inflammation-inducing transcription factor, is shown to promote intestinal tumors via two pathways in two cell types.

Colon cancers depend on interactions between the intestinal epithelial cells that form the tumors and white blood cells, which trigger inflammation. The authors show that a mouse model of colitis-associated colon cancer is severely reduced if NF-B is inhibited in either cell type by deleting its activating kinase, IKKß.

If NF-B was inhibited in the white blood cell lineage, epithelial tumors were less numerous and smaller because white blood cells could not induce inflammation. Proliferation of the epithelial cells was limited, probably because the dormant mutant white blood cells did not secrete growth factors.

If NF-B activity was blocked in intestinal epithelial cells, fewer tumors formed. The scarcity of tumors was due to increased apoptosis of the epithelial cells. NF-B, possibly to help keep the intestinal epithelium intact, activates transcription of the anti-apoptotic protein Bcl-X_L. Since Bcl-X_L was not induced in the absence of IKKß, DNA damage surveillance mechanisms were able to kill premalignant intestinal cells.

Drugs that target IKKß are in preclinical testing. Past studies suggest they may have unwanted effects. "One red flag is skin cancer," says Karin. "In keratinocytes, if you knock out IKKß, you get more skin cancer. But this [increase] requires inflammation. A drug doesn't only affect one cell type." So a drug that also causes the loss of NF-B activity in blood cells may override the skin cancer risk.

Reference:

Greten, F.R., et al. 2004. Cell. 118:285–296.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                      What's this?