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Senescence in tumours: evidence from mice and humans

Key Points

  • Senescence is a stress response prevalent in the aberrant environment of tumours.

  • Senescent cells are incapable of further proliferation and therefore tumour cell senescence is a brake to tumour progression.

  • A large body of evidence in mouse models indicates that in pre-malignant tumours most cells are senescent, therefore explaining the slow growth and low malignancy of these tumours. There are also examples of senescence in human pre-malignant tumours.

  • A class of tumour suppressors (for example, p53, INK4A and ARF) monitors stress signals, and the activation of these proteins triggers senescence. Their loss or inactivation is associated with impaired senescence, unleashing malignant progression.

  • Malignant tumours, despite their impaired ability to undergo senescence, can still be forced into senescence if crucial oncogenic pathways are disabled or tumour suppressors are restored.

  • Senescent tumour cells are rapidly cleared by immune cells, resulting in efficient tumour regression.

  • Senescence constitutes a new end point that might be relevant for the development of new drugs or prognostic markers and the evaluation of therapeutic treatments.

Abstract

The importance of cellular senescence, which is a stress response that stably blocks proliferation, is increasingly being recognized. Senescence is prevalent in pre-malignant tumours, and progression to malignancy requires evading senescence. Malignant tumours, however, may still undergo senescence owing to interventions that restore tumour suppressor function or inactivate oncogenes. Senescent tumour cells can be cleared by immune cells, which may result in efficient tumour regression. Standard chemotherapy also has the potential to induce senescence, which may partly underlie its therapeutic activity. Although these concepts are well supported in mouse models, translating them to clinical oncology remains a challenge.

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Figure 1: Pathways of oncogene-induced senescence.
Figure 2: Tumour suppressors can be grouped into two categories depending on their effect on senescence.

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Acknowledgements

Work in the authors' laboratory is funded by the Spanish National Cancer Research Centre, the Spanish Ministry of Science, the Regional Government of Madrid, the European Union (PROTEOMAGE), the European Research Council and the Marcelino Botin Foundation.

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DATABASES

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Glossary

Nevi

Benign skin lesions of melanocytes, also known as moles, which are thought to be senescent.

Senescence-associated heterochromatin foci SAHF.

Highly condensed chromatin regions established during senescence and thought to function as silencing domains.

Costello syndrome

A complex developmental syndrome with distinctive craniofacial features and predisposition to neoplasia development caused by activating germline mutations in HRAS.

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Collado, M., Serrano, M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10, 51–57 (2010). https://doi.org/10.1038/nrc2772

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