Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas (original) (raw)

Nature volume 445, pages 656–660 (2007)Cite this article

A Corrigendum to this article was published on 26 May 2011

Abstract

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence1,2. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies3. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma4,5. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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Acknowledgements

We thank L. Bianco and M. Jiao for technical assistance. We also thank G. Evan, T. Jacks, A. Ventura, M. Narita, A. Chicas, M. Yon, G. Hannon and other members of the Lowe and Hannon laboratories for advice and discussions. We thank M. McCurrach for editorial assistance. W.X. is in the MCB graduate program at Stony Brook University. This work was generously supported by the Emmy Noether Programme of the German Research Foundation, Alan and Edith Seligson, the Don Monti Foundation, and grants from the National Institutes of Health (C.C.C, S.W.L.). This work is dedicated to our friend and colleague Dr. Enrique (Henry) Cepero.

Author Contributions W.X.: study design and conduction of experiments; L.Z.: study design and conduction of experiments; C.M.: design and conduction of flow cytometry experiments; R.A.D.: vector development; E.H.: histopathological analyses; V.K.: microarray analysis; C.C.C: histopathological analyses; S.W.L.: study design, principal investigator.

Author information

Author notes

  1. Wen Xue and Lars Zender: These authors contributed equally to this work.

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA
    Wen Xue, Lars Zender, Cornelius Miething, Ross A. Dickins, Valery Krizhanovsky & Scott W. Lowe
  2. Howard Hughes Medical Institute, Cold Spring Harbor, New York, 11724, USA
    Ross A. Dickins & Scott W. Lowe
  3. Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, 10021, USA
    Eva Hernando & Carlos Cordon-Cardo

Authors

  1. Wen Xue
  2. Lars Zender
  3. Cornelius Miething
  4. Ross A. Dickins
  5. Eva Hernando
  6. Valery Krizhanovsky
  7. Carlos Cordon-Cardo
  8. Scott W. Lowe

Corresponding author

Correspondence toScott W. Lowe.

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

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Supplementary information

This file contains Supplementary Methods , Supplementary figures S1-S9 with legends and additional references. (PDF 5545 kb)

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Xue, W., Zender, L., Miething, C. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.Nature 445, 656–660 (2007). https://doi.org/10.1038/nature05529

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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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