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

Andrea Paradisi (1, 2) , Carine Maisse-Paradisi (1, 2) , Marie-May Coissieux (1, 2) , Nicolas Gadot (3) , Florian Lépinasse (4) , Céline Delloye-Bourgeois (1, 2) , Jean-Guy Delcros (1) , Magali Svrcek (5, 6) , Clemens Neufert (7, 8) , Jean-François Fléjou (5, 6) , Jean-Yves Scoazec (3, 4) , Patrick Mehlen (1, 2)

1 Apoptose Cancer et Développement
2 Université de Lyon
3 ANIPATH
4 U865
5 CHU Saint-Antoine [AP-HP]
6 UMR S 893, Team 13 Microsatellite Instability and Cancers
7 Medical Clinic
8 Institute for Molecular Medicine

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.

Mots clés: cell line; colorectal neoplasm; disease progression; reverse transcriptase polymerase chain reaction; mice

Mots clés: lignée cellulaire; cancer colorectal; évolution de la maladie; maladie inflammatoire intestinale; transduction du signal; apoptose; rt pcr; suppresseur de tumeur; régulation positive des récepteurs; souris

Domaines: Sciences du Vivant [q-bio]

Andrea Paradisi, Carine Maisse-Paradisi, Marie-May Coissieux, Nicolas Gadot, Florian Lépinasse, et al.. Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 (40), pp.17146-17151. ⟨10.1073/pnas.0901767106⟩. ⟨hal-01604345⟩