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6 j$ |& j+ @: r1 D. K) t" c5 OThe 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.
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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, IKK?.
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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.
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# \4 a2 N$ m7 R9 WIf 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-XL. Since Bcl-XL was not induced in the absence of IKK?, DNA damage surveillance mechanisms were able to kill premalignant intestinal cells., x, W8 I N$ k8 @, g# x5 a( P
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Drugs that target IKK? 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 IKK?, you get more skin cancer. But this 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.0 n1 X& d& }5 Y! f" K( _8 n V
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% h, X3 A1 M* ?& D' ^9 XGreten, F.R., et al. 2004. Cell. 118:285–296.(Fewer intestinal tumors (outlined) form ) |
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发表于 2009-3-6 08:23
发表于 2015-5-29 19:30
