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Senescence-messaging secretome: SMS-ing cellular stress

Nature Reviews Cancer volume 9, pages 81–94 (2009)Cite this article

This article has been updated

Key Points

  • Cellular senescence is a mechanism that blocks the proliferation of primary, and in some cases premalignant and malignant, cells. It can be activated by a plethora of stress conditions, including oncogene activation, loss of tumour suppressors or critical shortening of telomeres.

  • Oncogene-induced senescence has recently been recognized as a tumour-suppressive mechanism in vivo, in human lesions and in several mouse tumour models.

  • Recent evidence suggests that the induction of senescence requires several secreted factors, including members of Wnt, insulin, transforming growth factor-β, plasmin, interleukin and possibly also interferon signalling cascades. We term these collectively the senescence-messaging secretome (SMS).

  • The SMS and its signalling cascades may converge first at the level of several plasma membrane signalling receptors.

  • The use of secreted factors in senescence could provide a selective advantage to an organism, as it allows for communication between senescent cells and their microenvironment.

  • Counterintuitively, senescent cells may contribute to tumorigenesis by virtue of the SMS, which can cause stromal components to senesce, thereby establishing a pro-mitogenic loop.

Abstract

Oncogene-induced cellular senescence constitutes a strong anti-proliferative response, which can be set in motion following either oncogene activation or loss of tumour suppressor signalling. It serves to limit the expansion of early neoplastic cells and as such is a potent cancer-protective response to oncogenic events. Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment. How are such signals integrated into a coordinated response and what are the implications of this unexpected finding?

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Figure 1: Senescence-messaging secretome (SMS) factors that contribute to the induction and maintenance of senescence.
Figure 2: Signal transduction pathways (partly) used by the senescence-messaging secretome (SMS).
Figure 3: Functions of insulin-like growth factor 2 receptor (IGF2R) that may integrate senescence-messaging secretome (SMS) signalling cascades.
Figure 4: Transforming growth factor-β (TGFβ) receptor I (TβRI), TβRII and low density lipoprotein receptor-related protein 1 (LRP1) may integrate senescence-messaging secretome (SMS) signalling cascades.
Figure 5: The potential benefits and threats of the association of secreted factors with senescence.

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Change history

  • 13 January 2009

    In the version of this article initially published online, table 1 read "ERK" in place of "phosphoERK" in row 5 column 4, and "replication" in place of "replicative senescence" in row 6 column 3. Additionally, the fourth paragraph under "Interleukins" read "paracrine promoting functions" in place of "paracrine tumour-promoting functions". The errors have been corrected for the print, HTML and PDF versions of the article

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Acknowledgements

We are grateful to R. van Doorn, R. Kortlever, P. ten Dijke and T. Geiger for helpful suggestions and critical reading of the manuscript, and J. Campisi for kindly sharing data before publication. T.K. and D.S.P. are supported by grants from the Dutch Cancer Society (KWF) including a Queen Wilhelmina Program grant, and the Netherlands Organization for Scientific Research (NWO). D.S.P. is also supported by the EMBO Young Investigator Program.

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  1. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, the Netherlands

    Thomas Kuilman & Daniel S. Peeper

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Glossary

Kringle domains

Protein domains that fold into large loops stabilized by three disulphide linkages and are important for interaction of proteins with blood coagulation factors.

Antagonistic pleiotropy

The hypothesis that genes with beneficial effects early in life are favoured by selection even if they have detrimental effects at later ages.

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Kuilman, T., Peeper, D. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9, 81–94 (2009). https://doi.org/10.1038/nrc2560

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