Netrin-1 controls colorectal tumorigenesis by regulating apoptosis

Laetitia Mazelin, Agnès Bernet, Christelle Bonod-Bidaud, Laurent Pays, Ségolène Arnaud, Christian Gespach, Dale E Bredesen, Jean-Yves Scoazec and Patrick Mehlen ()
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Laetitia Mazelin: University of Lyon
Agnès Bernet: University of Lyon
Christelle Bonod-Bidaud: University of Lyon
Laurent Pays: University of Lyon
Ségolène Arnaud: University of Lyon
Christian Gespach: Hospital Saint-Antoine
Dale E Bredesen: The Buck Institute for Age Research
Jean-Yves Scoazec: INSERM U45 and ANIPATH, IFR62, Faculté Laennec
Patrick Mehlen: University of Lyon

Nature, 2004, vol. 431, issue 7004, 80-84

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02788

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