1. Apoptosis/Differentiation Laboratory—Equipe labellisée 'La Ligue'—Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622 Villeurbanne, France
2. INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hospital Saint-Antoine, 75571 Paris, France
3. The Buck Institute for Age Research, Novato, California 94945, USA
4. INSERM U45 and ANIPATH, IFR62, Faculté Laennec, 69437 Lyon, France
5. Centre Leon Bérard, 69373 Lyon, France
6. These authors contributed equally to this work.

Correspondence to: Patrick Mehlen^1,5 Email: mehlen@univ-lyon1.fr

Abstract

The expression of the protein DCC (deleted in colorectal cancer) is lost or markedly reduced in numerous cancers and in the majority of colorectal cancers due to loss of heterozygosity in chromosome 18q, and has therefore been proposed to be a tumour suppressor¹. However, the rarity of mutations found in DCC, the lack of cancer predisposition of DCC mutant mice, and the presence of other tumour suppressor genes in 18q have raised doubts about the function of DCC as a tumour suppressor². Unlike classical tumour suppressors, DCC has been shown to induce apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless DCC is engaged by its ligand, netrin-1 (ref. 3). Here we show that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract leads to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engenders aggressive adenocarcinomatous malignancies. These data demonstrate that netrin-1 can promote intestinal tumour development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumour suppressors.

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