DCC constrains tumour progression via its dependence receptor activity

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Establishment of a mouse model with a mutation of the caspase cleavage site in DCC.
Figure 2: Mutation of DCC caspase cleavage site is associated with reduced apoptosis in mice.
Figure 3: Inactivation of DCC-induced apoptosis favours adenocarcinoma formation in an APC +/1638 mutant background.

References

  1. 1

    Fearon, E. R. et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247, 49–56 (1990)

  2. 2

    Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998)

  3. 3

    Fazeli, A. et al. Phenotype of mice lacking functional deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997)

  4. 4

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990)

  5. 5

    Mehlen, P. & Fearon, E. R. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J. Clin. Oncol. 22, 3420–3428 (2004)

  6. 6

    Takaku, K. et al. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92, 645–656 (1998)

  7. 7

    Roush, W. Putative cancer gene shows up in development instead. Science 276, 534–535 (1997)

  8. 8

    Goldschneider, D. & Mehlen, P. Dependence receptors: a new paradigm in cell signaling and cancer therapy. Oncogene 29, 1865–1882 (2010)

  9. 9

    Mazelin, L. et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 431, 80–84 (2004)

  10. 10

    Forcet, C. et al. The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. Proc. Natl Acad. Sci. USA 98, 3416–3421 (2001)

  11. 11

    Li, W. et al. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nature Neurosci. 7, 1213–1221 (2004)

  12. 12

    Forcet, C. et al. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature 417, 443–447 (2002)

  13. 13

    Watson, A. J. et al. Epithelial barrier function in vivo is sustained despite gaps in epithelial layers. Gastroenterology 129, 902–912 (2005)

  14. 14

    Kiesslich, R. et al. Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology 133, 1769–1778 (2007)

  15. 15

    Fodde, R. et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl Acad. Sci. USA 91, 8969–8973 (1994)

  16. 16

    Boivin, G. P. et al. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 124, 762–777 (2003)

  17. 17

    Ghoumari, A. M. et al. Implication of Bcl-2 and Caspase-3 in age-related Purkinje cell death in murine organotypic culture: an in vitro model to study apoptosis. Eur. J. Neurosci. 12, 2935–2949 (2000)

  18. 18

    Bernet, A. et al. Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies. Gastroenterology 133, 1840–1848 (2007)

Download references

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).

Author information

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.

Correspondence to Patrick Mehlen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-3 with legends. (PDF 2030 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.