Netrin-1 controls colorectal tumorigenesis by regulating apoptosis (original) (raw)

Nature volume 431, pages 80–84 (2004)Cite this article

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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Acknowledgements

We wish to thank N. Gadot, C. Guix and G. Perret for excellent technical assistance. We also thank R. Fodde and S. Robine for advice and materials. This work was supported by the Ligue Contre le Cancer (P.M.), the Schlumberger Fondation (P.M.), the NIH (to P.M. and D.E.B.) and the Region Rhone-Alpes (to P.M. and J.Y.S.).

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Author notes

  1. Agnès Bernet and Christelle Bonod-Bidaud: These authors contributed equally to this work.

Authors and Affiliations

  1. Apoptosis/Differentiation Laboratory—Equipe labellisée ‘La Ligue’—Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622, Villeurbanne, France
    Laetitia Mazelin, Agnès Bernet, Christelle Bonod-Bidaud, Laurent Pays, Ségolène Arnaud & Patrick Mehlen
  2. INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hospital Saint-Antoine, 75571, Paris, France
    Christian Gespach
  3. The Buck Institute for Age Research, Novato, California, 94945, USA
    Dale E Bredesen
  4. INSERM U45 and ANIPATH, IFR62, Faculté Laennec, Lyon, 69437, France
    Jean-Yves Scoazec
  5. Centre Leon Bérard, 69373, Lyon, France
    Patrick Mehlen

Authors

  1. Laetitia Mazelin
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  2. Agnès Bernet
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  3. Christelle Bonod-Bidaud
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  4. Laurent Pays
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  5. Ségolène Arnaud
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  6. Christian Gespach
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  7. Dale E Bredesen
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  8. Jean-Yves Scoazec
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  9. Patrick Mehlen
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Correspondence toPatrick Mehlen.

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Mazelin, L., Bernet, A., Bonod-Bidaud, C. et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.Nature 431, 80–84 (2004). https://doi.org/10.1038/nature02788

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