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Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17146-51. doi: 10.1073/pnas.0901767106. Epub 2009 Aug 31.

Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression.

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Apoptosis, Cancer and Development Laboratory-Equipe labellisée La Ligue, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.


Chronic inflammation and cancer are intimately associated. This is particularly true for inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, which show a major increased risk for colorectal cancer. While the understanding of the molecular pathogenesis of IBD has recently improved, the mechanisms that link these chronic inflammatory states to colorectal cancer development are in large part unknown. One of these mechanisms is NF-kappaB pathway activation which in turn may contribute to tumor formation by providing anti-apoptotic survival signals to the epithelial cells. Based on the observation that netrin-1, the anti-apoptotic ligand for the dependence receptors DCC and UNC5H is up-regulated in colonic crypts in response to NF-kappaB, we show here that colorectal cancers from inflammatory bowel diseases patients have selected up-regulation of netrin-1. Moreover, we demonstrate that this inflammation-driven netrin-1 up-regulation is causal for colorectal cancer development as interference with netrin-1 autocrine loop in a mouse model for ulcerative colitis-associated colorectal cancer, while showing no effect on inflammation, inhibits colorectal cancer progression.

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