Abstract
The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers1 and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development3. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.
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Acknowledgements
We wish to thank D. E. Bredesen and J.-G. Delcros for critical reading of the manuscript. We thank C. H. Herbreteau and C. Bonod-Bidaud for their initial involvement in this work and the animal facility staff for animal care. We thank the ICS for the generation of the DCC mutant mice. We thank the LMT (Laboratoire des Modèles Tumoraux) and AniPath for the analysis of animal models. This work was supported by institutional grants from the Ligue Contre le Cancer, INCA, ANR, IP ApoSys and the LabEX DEVweCAN (ANR-10-LABX-61).
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M.C., L.B., Y.M., G.C., L.M., L.J.-W., A.B. and P.M. designed the experiments, the mice models and performed data analysis. M.C., L.B. and Y.M. performed most of the experiments. J.-Y.S., M.B., N.G. and A.P. performed pathological analysis of tumour grade and in vivo quantification of apoptosis. M.C. and P.M. wrote the manuscript. P.M. and A.B. are co-senior authors.
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Castets, M., Broutier, L., Molin, Y. et al. DCC constrains tumour progression via its dependence receptor activity. Nature 482, 534–537 (2012). https://doi.org/10.1038/nature10708
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DOI: https://doi.org/10.1038/nature10708
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