Netrin-1 controls colorectal tumorigenesis by regulating apoptosis

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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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Figure 1: Netrin-1 is expressed in the mouse gastrointestinal tract.
Figure 2: Netrin-1 overexpression inhibits intestinal cell apoptosis.
Figure 3: Netrin-1 overexpression enhances the early stage of tumour development.
Figure 4: Netrin-1 overexpression enhances the adenoma to adenoma-carcinoma transition.

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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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Correspondence to Patrick Mehlen.

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The authors declare that they have no competing financial interests.

Supplementary information

Materials and Methods (DOC 67 kb)

Supplementary Figure 1

DCC inhibits anchorage-independent growth through apoptosis regulation. (JPG 38 kb)

Supplementary Figure 2

Netrin-1 overexpression does not modulate proliferation and differentiation of the intestinal epithelium. (JPG 118 kb)

Supplementary Figure 3

Increased cell death in the gastrointestinal tract of netrin-1 mutant mice. (JPG 42 kb)

Supplementary Figure 4

Netrin-1 and netrin-1 receptors localization in the intestinal epithelium and in hyperplastic/neoplastic lesions. (JPG 23 kb)

Supplementary Figure 5

Netrin-1 is overexpressed in 7% of human colorectal tumors. (JPG 132 kb)

Supplementary Figure Legends (DOC 25 kb)

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