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Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours

Nature volume 482, pages 538–541 (2012)Cite this article

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Abstract

Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers1. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.

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Figure 1: DCC loss does not affect latency of p53-deficient mammary tumour development.
Figure 2: Microphotographs of primary mammary carcinosarcoma (left) and metastasis in the lung (right) in serial sections.
Figure 3: DCC controls apoptosis induction in p53-deficient tumour cells in vitro and survival in vivo.

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Acknowledgements

We thank R. B. Ali for assistance in generating the mice, J. Blitz and the staff of the NKI animal facility for providing animal care, the staff of the histology department for the processing of tissues, I. Huijbers and H. van Zeeburg for help with apoptosis and FACS analysis, A. Kraft, S. Klarenbeek, S. Rottenberg and G. Doumont for discussions, and T. Braumuller and A. Kersbergen for technical support. We also thank the laboratory of P. Mehlen for the gift of netrin 1.

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Authors and Affiliations

  1. Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,

    Paul Krimpenfort, Natalie Proost, John Zevenhoven & Anton Berns

  2. Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,

    Jos Jonkers

  3. Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,

    Ji-Ying Song

  4. The Amsterdam Medical Center (AMC). The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,

    Anton Berns

Authors
  1. Paul Krimpenfort
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  2. Ji-Ying Song
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  5. Jos Jonkers
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Contributions

J.Y.S. carried out the histopathological analysis, N.P. was involved in animal experiments and J.Z. performed the confocal microscopy. J.J. and A.B. participated in discussions and interpretations of the experiments. P.K. was responsible for the design and execution of the experiments, and P.K. and A.B. wrote the paper.

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Correspondence to Anton Berns.

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The authors declare no competing financial interests.

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Krimpenfort, P., Song, JY., Proost, N. et al. Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours. Nature 482, 538–541 (2012). https://doi.org/10.1038/nature10790

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