Restoration of p53 function leads to tumour regression in vivo (original) (raw)

Nature volume 445, pages 661–665 (2007)Cite this article

Abstract

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes1. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance2,3,4,5; this phenotype is referred to as oncogene addiction6. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR7,8,9,10. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers11, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-_loxP_-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.

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Acknowledgements

We thank N. Willis for helping to generate the LSL mice, H. Zheng for imaging mice, G. Wojtkiewicz for generating the movies with three-dimensional reconstruction, D. Crowley for help with histology, R. Bronson for reviewing the pathology, and M. Hemann for suggestions. A.V. is grateful to D. Ventura and G. Terranova for continuous support and encouragement. This work was supported by the Howard Hughes Medical Institute (T.J.), NCI (T.J., R.W., D.G.K.), and partially by a Cancer Center Support grant from the NCI (M.I.T.), the American Italian Cancer Research Foundation (A.V.), and the Leaf fund (D.G.K.). T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. D.A.T. is a Rita Allen Foundation Scholar.

Author Contributions A.V., D.G.K. and T.J. designed the experiments and wrote the paper. D.T. generated the p53-LSL mice and M.E.M. generated and characterized the Cre-ERT2 mice, determined the optimal Tamoxifen dosage, assisted with histopathological analysis and commented on the manuscript. A.V., D.G.K. and L.L. derived and characterized the tumour cell lines. A.V. performed the immunostainings, the TUNEL assays the SA-β-Gal stainings and the western blottings. A.V., D.K. and L.L. performed the tamoxifen intraperitoneal injections. E.E.R. derived the MEFs. L.L. and J.N. maintained the mouse colony and genotyped the animals. J.G. and D.G.K. evaluated the magnetic resonance images, J.G. supervised the magnetic resonance imaging, generated the three-dimensional reconstructions and determined tumour volumes. R.W. optimized in vivo imaging protocols, reviewed imaging data, discussed the results, and commented on the manuscript.

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Author notes

  1. Andrea Ventura and David G. Kirsch: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02142, USA
    Andrea Ventura, David G. Kirsch, Margaret E. McLaughlin, David A. Tuveson, Laura Lintault, Jamie Newman, Elizabeth E. Reczek & Tyler Jacks
  2. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, 02129, USA
    David G. Kirsch
  3. Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, Massachusetts, 02129, USA
    Jan Grimm & Ralph Weissleder
  4. Harvard Medical School, Boston, Massachusetts, 02115, USA
    Jan Grimm & Ralph Weissleder
  5. Howard Hughes Medical Institute, Chevy Chase, Maryland, 20815, USA
    Tyler Jacks

Authors

  1. Andrea Ventura
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  2. David G. Kirsch
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  3. Margaret E. McLaughlin
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  4. David A. Tuveson
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  5. Jan Grimm
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  6. Laura Lintault
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  7. Jamie Newman
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  8. Elizabeth E. Reczek
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  9. Ralph Weissleder
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  10. Tyler Jacks
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Corresponding author

Correspondence toTyler Jacks.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary file 1

This file contains Supplementary Methods, Supplementary Figures 1, 3, 5, 6 and 7 with legends. The Supplementary Figures 2 and 4 are represented as movie files. (PDF 3041 kb)

Supplementary file 2

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 2. (AVI 6872 kb)

Supplementary file 3

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 2. (AVI 7219 kb)

Supplementary file 4

This file contains movies of MRIs indicated in the main text as Supplementary Figures. (MOV 169 kb)

Supplementary file 5

This file contains movies of MRIs indicated in the main text as Supplementary Figures 2. (MOV 185 kb)

Supplementary file 6

This file contains movies of MRIs indicated in the main text as Supplementary Figures 2. (MOV 159 kb)

Supplementary file 7

This file contains movies of MRIs indicated in the main text as Supplementary Figures 2. (MOV 163 kb)

Supplementary file 8

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 4. (AVI 6481 kb)

Supplementary file 9

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 4. (AVI 6200 kb)

Supplementary file 10

This file contains movies of MRIs indicated in the main text as Supplementary Figures 4. (MOV 243 kb)

Supplementary file 11

This file contains movies of MRIs indicated in the main text as Supplementary Figures 4. (MOV 341 kb)

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Ventura, A., Kirsch, D., McLaughlin, M. et al. Restoration of p53 function leads to tumour regression in vivo.Nature 445, 661–665 (2007). https://doi.org/10.1038/nature05541

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Editorial Summary

p53 and tumour regression

The p53 tumour suppressor is either mutated or inactivated by other alterations in most human cancers. Two papers in this issue show that even brief reactivation of the endogenous p53 genes in established tumours can cause cancer regression in some animal models. In some tumours, p53 reactivation causes cellular senescence associated with an innate immune response that contributes to tumour clearance. These experiments used gene manipulation to alter p53 levels, but they lend further support to the idea that p53-boosting drugs could be a useful form of cancer treatment.

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