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Hallmarks of senescence in carcinogenesis and cancer therapy

Abstract

Cellular senescence is a signal transduction program leading to irreversible cell cycle arrest. This growth arrest can be triggered by many different mechanisms including recognition by cellular sensors of DNA double-strand breaks leading to the activation of cell cycle checkpoint responses and recruitment of DNA repair foci. Senescence is initiated by the shortening of telomeres (replicative senescence) or by other endogenous and exogenous acute and chronic stress signals (STASIS: stress or aberrant signaling-induced senescence). The process of carcinogenesis involves a series of changes that allow tumor cells to bypass the senescence program. Nevertheless, tumor cells retain the capacity to undergo senescence. Treatment of tumor cells with many conventional anticancer therapies activates DNA damage signaling pathways, which induce apoptosis in some cells and senescence in others. Overexpression of tumor suppressors or inhibition of oncogenes can also induce rapid senescence in tumor cells. Senescent cells, while not dividing, remain metabolically active and produce many secreted factors, some of which stimulate and others inhibit the growth of tumors. The emerging knowledge about the pathways that lead to senescence and determine the pattern of gene expression in senescent cells may lead to more effective treatments for cancer.

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Acknowledgements

We thank all the members of our laboratories who have contributed to various studies described in this review. The work in the authors’ laboratories was supported by NIH Grants R01 CA89636, R01 CA62099, R01 AG17921, and Grant 025-01 from Mary Kay Ash Charitable Foundation (IBR), and NIH Grants R01 AGO7992 and P50 CA070907 (JWS).

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Correspondence to Igor B Roninson.

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Shay, J., Roninson, I. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23, 2919–2933 (2004). https://doi.org/10.1038/sj.onc.1207518

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Keywords

  • replicative senescence
  • STASIS
  • telomeres
  • chemotherapy
  • apoptosis
  • mitotic catastrophe

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